The transmitters, central or peripheral, may be conveniently classified into two categories: 1. Non-peptide transmitter with molecular weight less than 200. These include amines and amino acids. The amines include acetylcholine (a tertiary amine) and biogenic amines e.g. dopamine, serotonin (5-HT), norepinephrine, epinephrine and histamine. The amino acids include glycine and GABA (monocarboxylic; inhibitory), and glutamate/aspartate (dicarboxylic; excitatory), and 2. Peptide transmitters with molecular weights more than 300.
They include four major sub-categories; most are likely candidates:
(i) Brain-gut peptides e.g. CCK-8, G-17, substance P, VIP, bombesin, neurotensin and many others.
(ii) Endogenous opioid peptides e.g. enkephalins, endorphins and dynorphins.
(iii) Hypothalamic neuropeptides e.g TRH, GnRH (LHRH), CRH, ACTH and MSH-like peptides, vasopressin and oxytocin.
(iv) Other peptides e.g. angiotensin-II, neuropeptide, bradykinin, carnosine, calcitonin and sleep peptide (s).
* E, established; P, putative; MP, most probable
** Reuptake may be followed by enzymatic inactivation
Acetylcholine:
Distribution:
The cholinergic neurons (estimated to be up to 10% in CNS) are widely distributed in CNS mostly in circuits engaged in motor controls. The important central regions include: Neocortex (Betz cells); Limbic system (hippocampus, amygdala, cingulate gyrus, septal nuclei, habenular system, fornix, thalamic nuclei, olfactory system); Basal ganglia particularly striatum (caudate and putamen nuclei); Diencephalon (thalamic, hypothalamic and metathalamic areas); Mid-brain (superior colliculi); Brainstem (medullary, pontile and reticular formation) and spinal cord (motor neuron collaterals to Renshaw cells).
Besides, skeletal alpha and gamma motor neurons and preganglionic autonomic neurons in the brain-stem and spinal cord (cell-bodies within CNS and processes to PNS) are also cholinergic for PNS activity.
Biosynthesis:
The neurons obtain choline from exterior (do not synthesize choline) and acetylate it by choline acetyltransferase (CAT) using mitochondrial acetyl CoA as co-factor. Following release and action, Ach is rapidly hydrolyzed by synaptic acetyl cholinesterase (AchE) to choline and acetate. The choline is taken up by the terminal for reuse.
The intra-neuronal levels of Ach are regulated by:
(i) Choline uptake, and
(ii) Activity of CAT.
Ach is the only established CNS transmitter that is not derived directly from an amino acid.
Actions:
The actions of Ach are mediated by activation of cholinergic receptors- nicotinic (Ionotropic) and muscarinic (metabotropic). Muscarinic receptors (nearly all sub-types M1, M2, M3 & M4) dominate in the CNS than nicotinic receptor (mainly N2). M1 receptors occur in striatum, cerebral cortex and hippocampus, and M2 receptors have been identified in cerebellum and brain-stem.
The usual synaptic action is dominantly excitatory both at nicotinic (e.g. Renshaw cells, brain-stem neurons) as well at muscarinic sites (dominant in brain), and less often inhibitory at muscarinic sites (e.g. hypothalamus brain, brain-stem, nucleus gracillus and nucleus cuneatus).
Implicated Roles in Health & Disease:
1. Motor control:
Cholinergic links in striatum, motor cortical neurons and at Renshaw cells indicate importance of cholinergic synaptic activity in maintaining or influencing optimal skeletal motor activity.
The central cholinergic defects have been related to motor function defects observed in Parkinson’s disease (hyper-activity of cholinergic system) and Huntington’s chorea (hypo-activity). Drugs with anti-muscarinic activity (e.g. benzotropine, trihexiphenidyl and diphenhydramine) are useful in the treatment of early PD or as an adjunct to dopamimitic therapy.
2. Cognition, Learning and Memory:
The cholinergic activity appears to play an important role in learning, memory and cognition; in fact, the transmitter is considered to be an important part of intrinsic memory system that accomplishes memory storage.
The following facts support the argument:
(i) Drugs favouring increase in cholinergic activity such as choline/lecithin (increase biosynthesis), arecoline (muscarinic agonist), and physostigmine, DFP or tacrine (AchE inhibitors) improve learning and/or memory,
(ii) Drugs that are used to improve memory and congnition (nootropics) such as piracetam improve cholinergic activity in limbic system (particularly in hippocampus),
(iii) Anti-muscarinic agents such as atropine and scopolamine cause amnesia or dementia and confusional states, and
(iv) Impaired memory and cognitive ability in Alzheimer’s disease is related to loss of cholinergic cells in cortex and hippocampus, and physostigmine and tacrine have improved the functions in the patients.
3. Thermoregulation:
Cholinergic links at hypothalamus co-operate and respond to signals from serotonergic (cold sensors), noradrenergic (heat sensors) or extra-hypothalamic neurons to increase or decrease heat production, heat conservation or heat dissipation mechanisms to regulate body temperature within limits set by hypothalamic body temperature ‘set-point’ of posterior hypothalamus.
4. Central Emetic Mechanism:
The cholinergic neurons constitute an important component of medullary emetic centre (and also at vestibular sites); these neurons respond to dopaminergic signals to initiate vomiting reflex. Anticholinergic drugs or antihistamines with anticholinergic activity (promethazine, diphenhydramine) are useful as anti-emetics or for preventing motion sickness.
5. Neuroendocrine Role:
The cholinergic signals to the magnocellular hypothalamic neurons stimulate the release of ADH and oxytocin through nerve impulse propagation along axons leading to Ca++-dependent exocytosis of secretory granules.
6. Cortical Arousal and REM-Sleep:
The cortical cells particularly Betz cells are kept in activated state by brain-stem reticular system projections and thalamo-cortical relays; increased cortical Ach release is associated with convulsive states and decreased release with deepening of anaesthesia.
Thus, background cholinergic activity keeps motor cortex in readiness to perform somatic motor functions. The cortical sites are mostly muscarinic while thalamo-cortical relays are both muscarinic as well as nicotinic. Besides, Ach appears to be associated with some ascending and deseeding pathways in spinal cord.
Cholinergic Influences Directly Affect Activated Sleep or REM- Sleep:
Ach application to locus ceruleus triggers REM-sleep, and atropine selectively suppresses it. This indicates cholinergic signals to the locus ceruleus are facilitatory (along with NE and 5-HT) to REM-sleep trigger mechanism.
Dopamine:
Distribution:
The dopaminergic neurons in the brain constitutes more than 50% of the total brain catecholamine, and number of synapses is estimated to be 0.5% of the total brain synapses. The important central regions include: Basal ganglia including corpus striatum (richest site, 15% nerve terminals dopaminergic) and substantia nigra (nigrostriatal pathway); Hypothalamus (major site of production) and Mesencephalon (ventral tegmentum).
From mesencephalon dopaminergic pathway spread almost to every region of the CNS-ascending and descending; notably mesolimbic pathway to limbic system (nucleus accumbens; olfactory tubercle and amygdaloid nucleus), mesocortical (to parts of cerebral cortex), and to spinal sensory nociceptive pathways.
Biosynthesis:
The amino acid tyrosine is taken up by dopaminergic neurons, converted by the enzyme tyrosine hydroxylase to 3, 4-dihydroxyphenylalanine (dopa), decarboxylated by the enzyme aromatic L-amino acid decarboxylase to dopamine, and stored in vesicles.
After release and following action, it is actively taken back (reuptake) by the nerve terminals. It is metabolized by monoamine oxidase (MAO, mitochondrial), and chief metabolite is homovanillic acid (HVA). DA levels are regulated by changes in – (i) the hydroxylase activity, and (ii) MAO activity.
Actions:
The actions of dopamine are mediated by activation of dopaminergic receptors (all Metabotropic). The receptors are distinctly of two types; D1 (D5 is D1-like) and D2 (D3 and D4 are D2-like). D1 is coupled to Gs protein while D2 is coupled to Gi (multiple effector system including inhibition of adenylate cyclase, suppression of Ca++ currents and activation of K+ currents).
D1 density in limbic system and basal ganglia is 4-fold more than D2 density. The usual synaptic action is inhibitory (e.g. nigrostriatal, hypothalamus, and retina), and occasionally excitatory (e.g. some substantia nigral neurons).
Implicated Roles in Health & Disease:
1. Motor Control:
Dopaminergic circuits in basal ganglia (specifically nigrostriatal pathway) maintain optimal activity of extra pyramidal system (regulates muscle tone). These neurons are inhibitory to abundant cholinergic neurons in the corpus striatum, and increased/decreased activity leads to motor disorders;
(i) Dopaminergic system is overactive in Huntington’s chorea and underactive in Parkinson’s disease-both diseases characterized by motor disorders,
(ii) Prolonged use of most neuroleptics decreasing dopaminergic activity (e.g. haloperidol and fluphenazine) produce extrapyramidal side-effects resembling PD, and
(iii) Drugs improving central dopaminergic activity such as amantadine (increases DA release), 1-dopa (favours increased synthesis) and bromocriptine (D2 agonist) are all useful in PD. It appears D2 is underactive in PD and overactive in HC.
2. Behaviour, Learning and Memory:
Schizophrenia (psychoses) is partly related to increased DA-ergic activity in limbic system; anti-psychotic drugs act mainly by blocking dompamine receptors. L-dopa, amphetamine or apomorphine that increase dopaminergic activity have potential to cause alteration in behaviour (hyperactivity, stereotyped behaviour, agitation, excitement and psychotic phenomena).
Dopaminergic circuits are considered to be important for controlling arousal and drive, pre-requisite factors for learning and memory. Damage to dopaminergic system in limbic areas decreases attention to sensory stimuli, and causes lack of orientation and lack of coordinated efforts towards sensory stimuli.
3. Emetic Centre Activity:
Dopaminergic synaptic activity in medullary region controls activity of emetic centre. The synaptic activity is controlled by CTZ (vide astrocytes), and is potentiated by glutamatergic signals and inhibited by GABA- ergic signals. Centrally acting emetics stimulate DA receptors while anti-emetics block these receptors.
4. Control on Nociception:
Descending mesencephalic pathways inhibit nociceptive responses mediated vide spinal sensory system; the effect is modulatory, to dampen nociceptive impulse transmission.
5. Neuroendocrine Role:
Dopaminergic pathways from arcuate nucleus to the median eminence cause release of GnRH, and DA itself is known to act as prolactin- release inhibitory factor. The signal ratio of NE/DA is presumably dictating the proper ratio of GRH/somatostatin to be released into the hypophyseal portal blood from hypothalamus. Dopamine is known to increase growth hormone secretion through hypothalamic activity.
Norepinepherine:
Distribution:
The density of noradrenergic synapses in the CNS is estimated to be 0.5% (mostly brain); the highest content of NE is found in the hypothalamus (about 5% neurons are NAergic) The neuronal collections include the locus ceruleus complex (major-locus ceruleus) of pons lateral tegmental portion of reticular formation.
These areas project fibres widely to: Neocortex : Limbic system (most notably amygdala and hippocampal sites); Diencephalon; Mid-brain; Cerebellum (cortex); Brain-stem sites (reticular formation, raphe nucleus and medullary-fields) and spinal cord (nociceptive sensory relay sites).
Biosynthesis:
NE synthesis, like that of DA, starts with tyrosine up to dopamine, and dopamine is hydroxylated by dopamine-beta- hydroxylase to form NE, which is stored in vesicles. Upon release and following action, it is actively taken back by the nerve terminal.
Tyrosine hydroxylase and MAO regulate intraneuronal levels of NE. Metabolism of NE occurs via MAO and catechol-o- methyltransferase to inactive metabolites (e.g. normetanephrine, 3-methoxy-4-hydroxy-phenyl-ethylene glycol and vanillylmandelic acid, VMA.
Actions:
NE actions are mediated through activation of adrenergic receptors including alpha-1 (Gq-coupled), alpha-2 (Gi-coupled) and beta-1 (associated with neurons; Gs coupled) and beta-2 (associated with glia and vascular elements in CNS; Gs- coupled). Actions appear modulatory-type (altering neuronal response to other neurotransmitters).
It is either depolarizing (slow EPSP.) with alpha-1 (decreased K+ conductance, increased Ca++ conductance; potentiate cAMP generation by VIP) and beta (enhance Ca++ conductance) or hyperpolarizing with alpha-2 (increased K+ conductance and decreased voltage-gated Ca++ conductance). Metabolic effects depend upon the nature of G-protein coupled to the receptor subtypes. NE is the main inhibitory neurotransmitter in the thalamus, cerebral cortex and cerebeller cortex.
NE appears to act both as a transmitter as well as neuromodulator (perhaps released from varicosities). The fibres do not appear to make highly specific connections with target neurons, and appear to act in a modulatory fashion on specifically wired sets of neurons (like other biogenic amines); and effects appears to be largely inhibitory.
Implicated Roles In Health & Disease:
1. Arousal, Drive and Vigilance:
The discharge of locus ceruleus neurons is directly related to the animals’ level of vigilance and alertness (vide ascending reticular activity system, ARAS); decreases during sleep, on relaxing or on repetitive behaviour that do not require attention or orientation; and increases on awakening and with orientating stimuli. NAergic circuits are implicated in increasing signal to noise ratio in sensory systems (filtering out or damping down irrelevent signals) that facilitate vigilance and attention.
These factors also improve locomotor activity of the individual, as well as provide pre-requisite ground for learning and memory. Damage to the locus ceruleus can affect development of the cerebral cotex (kittens). The stimulant effects in ARAS and on cortex appear to be by way of dysinhibition (inhibiting inhibitory target neuronal circuits) Amphetamine and ephedrine (adrenergic agonists) are potent CNS stimulants.
2. Sleep-Wakefulness Cycle:
NE is essential for arousal and waking phases; and is possible important in dream regulation. The REM sleep (associated with deep sleep, dreaming, cortical arousal without accompanying motivational behaviour, active internally driven processes) trigger and clock (paramedian pontile reticular formation) is under the control of NAergic (and also 5-HTergic) inputs. Amphetamine and ephedrine cause insomnia.
Destruction of NAergic fibres (i.e. signals) to 5-HT raphe system causes profound hypersomnia (perhaps through reduced activity of 5-HT system). It appears NE is involved in active phases of sleep (i.e. REM) and wakefulness (arousal and drive).
Destruction of locus ceruleus suppresses REM-sleep without corresponding inhibition of typical sleep (5-Hr is essential for typical sleep); in reserpine-treated animals (5-HT and NE depletion) onset of REM as well as non-REM sleep is suppressed, and if dihydroxy phenyl alanine (precursor of NE) is given to these animals, onset of REM sleep is promoted; and drugs which prevent NE synthesis, (e.g. alpha-methyl- p-tyrosine) selectively inhibit REM sleep. All these indicate, NE is pre- requisite for onset of REM-sleep.
3. Anti-Nociceptive Potential:
Descending NAergic fibres reduce response of spinal neurons to nociceptive stimuli selectively (dorsal horn cells) without affecting flow of other sensory impulses (pressure, touch and mechano-receptor sensations). Opiates are known to act on locus ceruleus sites, and analgesia, component is perhaps partly mediated through this mechanism.
4. Mood Regulation:
Affective disorders (depression, mania) are related to impaired NAergic activity; depression is related to reduced NE (and increased beta- receptor density, ‘up-regulation’) and mania is related to increased NE levels (and decreased beta-receptor density, ‘down- regulation’). There are accompanying alteration in 5-HT system also (see 5-HT).
Anti-manic or anti bipolar disorder (manic-depressive illness potential of lithium salts has been related to the ability of Li ions to; (i) inhibit release of NE (and DA) while 5-HT release may be increased especially in hippocampus, & (ii) impair storage and reuptake of monoamines, and thus favour their inactivation.
5. Thermoregulation:
NAergic neurons in hypothalamus (heat-sensitive) are known to reduce response of cholinergic neurons to action of 5-HT, and activate a separate cholinergic pathway engaged in initiating activity of heat-loss mechanisms of the body (heat production cholinergic pathway is suppressed).
6. Blood Pressure Regulation:
Activation of alpha-2 adrenergic receptors by selective agonists (clonidine, guanabenz, guanfacine and alpha-methyl norepinephrine- active metabolite of methyl dopa) in the Ponto medullary region inhibit sympathetic outflow (vasoconstrictor component) from CNS to vascular system thus reducing blood pressure. These drugs are effective anti-hypertensive agents.
7. Neuroendrocrine Role:
Diminished NAergic signals from vasomotor centre to hypothalamic magnocellular neurons stimulate ADH release; and NE is known to inhibit ADH release and that of CRH and stimulate melatonin release from pineal gland.
8. Ingestive Behaviour:
The medial hypothalamic region contains ‘satiety centre’ the centre is under influence of inhibitory adrenergic inputs and stimulatory serotonergic inputs. Thus stimulation of NAergic signals to the centre can favour ingestive behaviour.
5-HT blocker cyproheptadine is known to improve appetite possibly by reducing serotonergic activity leaving inhibitory NAergic component to inhibit satiety centre; that facilitates activity of feeding centre (lateral hypothalamic region; under dopaminergic control) as the two centres operate by exhibiting reciprocal interaction (activation of one centre leads to inhibition of another centre and vice versa)
5-Hydroxytryptamine (Serotonin):
Distribution:
The density of 5-HTergic synapses in brain is estimated to be 0.5%. The maximum concentration of the neurons (e.g. collections is in and adjascent to the middle (raphe) regions of the pons and upper brain-stem, constituting several brain raphe nuclei.
The tryptaminergic fibres project from these sites to almost every region of the CNS: Neocortex; Limbic system (most regions with highest density in hippocampus and amygdala); Basal ganglia; cerebellum (cortex and nuclei); Thalamus; Hypothalamus; Brain-stem reticular formations; Locus ceruleus; Corpora quadregemina; Nucleus suprachiasmatica (very high density) and Spinal cord (substantia gelatinosae).
Biosynthesis:
Tryptophan amino acid is taken up by the neurons and converted into 5-hydroxytryptophan by the enzyme tryptophan hydroxylase, which is then decarboxylated by aromatic L-amino acid decarboxylase to serotonin (5-hydroxytryptamine). Levels of serotonin are controlled by the uptake of tryptophan and intra-neuronal MAO.
After release and following action, 5-HT is rapidly and actively taken up by the neurons. 5-HT escaping re-uptake is rapidly inactivated by MAO present in surrounding tissues. Metabolism occurs mainly via MAO to 5-hydroxyindoleacetic acid (HIAA).
Actions:
The actions are mediated by activation of 5-HT receptors; at least 4-types appear distinct, and many others also possible. All are G-protein coupled except 5-HT3 which is ionotropic.
Type-1 (Gi coupled; decreases Ca++ conductance and increases K+ conductance) is inhibitory type; identified in striatum, substantia nigra, raphe nuclei, hippocampus and cranial blood vessels (mediate vasoconstriction).
Type-2 (Gq coupled) appears excitatory stimulatory to metabolic cellular events; and is widely distributed in CNS including prefrontal cortex (4th layer), claustrum, choroid plexus (primary site of CSF production).
Type-3 (formerly called M-receptor) is ionotropic, eliciting excitatory/depolarizing response in target neurons, and has been identified in area prostema and nucleus tractus solitarius; this receptor type is implicated to participate in emetic response in vomiting species.
Type-4 is GS coupled activating cAMP dependent neuronal processes; it has been identified in neurons of hippocampus and of corpora quadrigemina. Other types 5, 6 and 7 have also been identified in the brain; types 6 (striatum) and 7 (hypothalamus) appear to be Gs coupled.
5-HT is both transmitter as well as neuromodulator i.e. released from varicosities. Monoaminergic circuits operate in a coordinated fashion for most of the physiologic and pathologic reactions of the CNS, and effects are generally modulatory to specifically wired excitatory/inhibitory circuits of the CNS. The usual synaptic action is inhibitory (e.g. Raphe nuciei, and pineal gland).
Implicated Roles In Health And Disease:
1. Sleep-Wakefulness Cycle:
Like NE, 5-HT is necessary for activation of cortexby dysinhibition leading to arousal, and like NE, it controls REM sleep trigger and clock in brain-stem (see NE). Intact serotonergic pathways (raphe nuclei projections) appear to be essential for in initiation of sleep, and particularly REM and also for maintenance of sleep.
Destruction of raphe nuclei cause prolonged insomnia, and depletion of serotonin by pretreatment with P-chlorophenylalanine (inhibitor of 5-HT synthesis) also causes insomnia that can be reversed by giving immediate precursor of 5-HT (i.e. 5- hydroxytryptophan).
The suprachiasmatic nucleus receives very high density of 5-HT fibres, and has been implicated to be the site to origin of the circadian rhythms particularly those involving day-night or sleep-wake cycles. L-tryptophan and non-selective 5-HT agonists are known to accelerate sleep onset and prolong sleep-time.
2. Mood Regulation:
5-HTergic system abnormalities appear to be related to aggression and impulsivity;
(i) Such patients show low CSF HIAA levels,
(ii) Defective 5HT1B subtype receptor has been correlated, and
(iii) Defective MAO too has been co-related to tendencies of aggression and impulsivity.
Reduced 5-HT levels have been implicated in both mania as well as in depression; in depression this alteration is accompanied by receptor ‘up-regulation’. Most of the anti-depressants favour increase in 5-HT levels at central synapses including MAO inhibitors (phenelzine, tranylcypromine and selegiline-raise DA, NE & 5-HT) and re-uptake blockers such as venlafaxine (5-HT and NE) or selective 5-HT blockers (fluoxetine, paroxetine, sertraline).
Anti-manic effect of Li salts may be related to increase in hippocampal 5-HT release (see NE). Hallucinogenic effects of LSD and related drugs have been related to their involvement in altering 5-HT turnover and/or 5-HT receptor mediated activities in the brain.
3. Pain Modulation:
Periaqueductal grey matter (PAG) neurons project to raphe sites which in turn project to neurons in substantia gelatinosae of dorsal horn (spinal cord).
The nociceptive relay neurons at spinal level are made less responsive to nociceptive stimuli; thus 5-HT fibres serve to modulate pain transmission from spinal relay sites. The analgesic effect of opiates is partly through this mechanism activating opiate sites in PAG that in-turn activate serotonergic fibres activity of raphe neurons.
4. Thermoregulation:
5-HT neurons in hypothalamus are ‘cold sensors’; they activate cholinergic neurons to initiate mechanisms for production and conservation of heat.
5. Migraine:
Disorder in the regulation of 5-HT in raphe neurons is considered a dominant feature of migraine; and the drugs that are useful in migraine either raise 5-HT concentration or activate 5-HT receptors; lower 5-HT increases and higher 5-HT decreases firing rates of these neurons.
Histamine:
Histamine is a putative transmitter, but appears to be likely candidate for transmitter functions:
(i) Neurons synthesize and destroy it continuously,
(ii) Enzymes of its synthesis and breakdown have been demonstrated in synaptosomal fractions of brain homogenates,
(iii) Histaminergic neurons, the concerned enzymes and synapses are non-uniformly distributed in the brain,
(iv) Histaminergic receptors exist in the brain, and
(v) Drugs inhibiting HI receptors (classical anti-histamines) produce sedation as a common side-effect.
Histamine or histaminergic neurons constitute lesser proportion of brain compared to other biogenic amines or aminergic neurons. Higher concentrations are confined to hypothalamus; projections from these sites are distributed to almost entire brain.
The neurons synthesize histamine from amino acid histidine, which is decarboxylated by L-histidine decarboxylase. There does not seem to be an active reuptake process for histamine. Histamine is metabolized by either diamine oxidase or by histamine N-methyltransferase followed by MAO.
Actions are mediated by histaminergic receptors including HI which is Gq-coupled, and widely distributed in CNS including neurons and glia, and densely concentrated in hypothalamus; whereas H2 is Gs-coupled, perhaps in hypothalamus, and H3 (nature of coupling not known) is localized in basal ganglia and olfactory regions.
Histamine has been implicated in increasing wakefulness (H1), inhibiting appetite (H1), participating in regulation of drinking, body temperature, ADH secretion, control of blood pressure and the perception of pain.
L-Glutamate:
Distribution:
L-glutamate is exclusively a central excitatory transmitter. The transmitter is widely distributed in CNS: Cerebral cortex (afferent and efferent pathways); Basal ganglia; Limbic system; Thalamus; Visual and auditory tracts; Cerebellum (granule cell parallel fibres; relatively lower concentrations are found in hypothalamus, medulla and pons. In spinal cord, L-glutamate is confined largely to ascending tracts (first-order somato-afferent neurons) that bring sensations from cutaneous and muscle receptors destined to CNS target neurons.
Biosynthesis:
Neurons utilize 1-glutamate from normal amino acid pool and confine it in synaptic vesicles for use as transmitter. It is synthesized and degraded by a common enzyme i.e. L-glutamate dehydrogenase (regulatory enzyme).
The precursor is alpha-ketoglutarate which is aminated (using ammonia from cellular metabolism) or by transamination from aspartate to L-glutamate. The amino acid following release and action is rapidly and actively taken back by the terminal. Metabolism involves mainly deamination.
Actions:
L-glutamate is fast-acting excitatory transmitter; the actions are mediated by (i) Quisqualate/AMP A receptor, agonist quisqualate (ii) Kainate receptor, agonists kainic acid and domoic acid, and (iii) NMDA receptor, agonist N- methyl-D-aspartate. These receptors are ionotropic and increase conductance of Na+ and K+ leading to rapid depolarization.
NMDA receptor activation also increases Ca++ conductance (Purkinje Cells in cerebeller cortex generate Ca++mediated action potentials at its dendrites; while their soma and axons have high density of Na+ channels). Actions elicited by L-glutamate in target neurons are of short-duration except at synapses where glutamate/aspartate are involved in LTP and LTD.
Implicated Roles In Health And Disease:
1. Motor Control:
Glutamatergic excitatory links are crucial for maintaining optimal functioning of forebrain neuronal circuit (basal ganglia, thalamus and cerebral cortex) to ensure optimal skeletal muscle activity, and adjustments of movements with respect to changes in posture (cerekeller influence). In Parkinson’s disease, besides roles pertaining to GABA, DA and Ach, reduced glutamatergic activity has been observed in thalamocortical links and increased activity in pallido-thalamic links.
Increased glutamatergic activity (and decreased GABAergic) is involved in epileptic seizures:
(i) agonists of different gluamate receptors trigger seizures in experimental animals,
(ii) glutamate antagonists inhibit seizures in diverse models including those evoked by electroshock and chemical convulsants such as pentylenetetrazol,
(iii) intractable seizures (and dementia) observed in Rasmussen’s encephalitis may be related to a defective glutamate receptor (see later),
(iv) NMDA receptor activity can be related to development of susceptibility to epileptic seizures and in the occurrence of seizure activity,
(v) NMDA antagonists in animal models have shown promising potential as anti-seizure drugs-may be available in future, and
(vi) hyper glutamatergic activity and hypo-GABAergic activity are two prominent features of epileptic seizures (see GABA).
2. Learning and Memory:
Glutamate appears to be involved in learning and memory:
(i) Glutamate has improved learning and memory in humans and in experimental animal models,
(ii) High levels of serum antibodies to a glutamate receptors subunit have been demonstrated in patients suffering from Rasmussen’s encephalitis, dementia may be related to the defective glutamate receptor activity, and
(iii) Glutamatergic synapses exhibit two novel behaviours such as long- term synaptic potentiation (LTP) or depression (LTD) that underly cellular model for learning and memory.
LTP has been observed in hippocampus; an important limbic area implicated in declarative and short-term memory, that transfers, perhaps, this memory to other areas, hirtheto unknown, for permanency if required. LTP occurs following repeated activation of pyramidal cells (at NMDA sites) or background depolarization provided by activation of adjascent non-NMDA sites (including quisqualate/kainate) or by spread of current from adjascent synapses; the background depolarization removes Mg++ – ion block from NMDA sites.
The receptors get activated and remain in this form for days to weeks. The underlying mechanism for LTP is thought to be opening of voltage-dependent chemically-operated Ca++ – channels at NMDA sites. An NMDA antagonist is reported to have interfered with spatial learning in rats.
LTD has been reported to occur in hippocampus at NMDA sites and in cerebeller cortex at quisqualate sites. The cerebeller cortex is important for cerebeller learning (e.g. motor skills) . LTD results when parallel fibre (origin local granule cells) activity (transmitter is aspartate) increases Ca++ influx into Purkinje dendritic spines (where action potential generation is Ca++ – dependent) involving non-quisqualate receptor sites (possibly NMDA).
The Ca++ influx desensitizes quisqualate sites of Purkinje cells; the receptors become refractory to the activation of climbing fibre activity (origin inferior olivary nucleus of medulla; transmitter glutamate). LTD persists for at-least 3 hours. LTD is thought to depress the cerebeller networks that are responsible for generation of cerebeller errors, thus aids in learning motor skills.
3. Sleep-Wakefulness Cycle:
Both glutamate as well as GABA appear to play crucial role in sleep and wakefulness.
4. Neuro-protection:
Optimal glutamate receptor activity ensures the concerned neuronal integrity; increased activity leads to neuronal degeneration consequent to excessive cytosolic Ca++ (from) influx or following mobilization from internal storage sites) that impairs cellular metabolism and destroys structural integrity of the neuronal components.
There are several evidences:
(i) Glutamate receptive neurons undergo degeneration when excess glutamate accumulates at the synapses either by increased release or following decreased uptake (e.g. hypoglycemia and cerebral ischemia),
(ii) Kainic acid, a rigid analog of glutamate, is used to destroy glutamate responsive neuronal cell-bodies for experimental production of Huntington’s chorea (characterized by abrupt jerky movements, purposeless and with no rhythmicity),
(iii) Increased glutamate activity is considered to be the primary cause of Huntington’s chorea in humans,
(iv) Amyotrophic lateral sclerosis (ALS) patients exhibit abnormal reuptake of glutamate, and the concerned neurons undergo degeneration-motor cortical, bulbar and spinal sites, and glutamate antagonists arrest progress of the disease, and
(v) NMDA antagonists have shown potential to block or attenuate neuronal death induced by activation of glutamate receptors.
L-Aspartate:
L-aspartate is considered to be the most likely transmitter in the CNS.
It shares many features common with L-glutamate:
(i) Both are dicarboxylic acid amino acids,
(ii) Occur exclusively in CNS.
(iii) Metabolically inter-related-transamination from glutamate to oxaloacetate (aspartate amino transferase reversible reaction) forms alpha-ketoglutarate and aspartate,
(iv) Share common receptors, hence actions and roles, and
(v) Both are fast excitatory transmitters.
Glutamate/aspartate transmitters may act co-operatively to elicit synaptic potentiation and depression, or in their individualistic style as dictated by their relative predominance in various region of the CNS:
Apart from these relative distributional differences, both the transmitters show almost similar CNS distribution.
Gamma-Amino Butyric Acid:
Distribution:
GABA is widely distributed in the CNS. The brain contains about 2 to 5 fold more GABA than the spinal cord. Highest content is present in hypothalamus, globus pallidus and substantia nigra (5-10 umoles/g tissue) followed by thalamus, striatum, cerebral cortex, hippocampus, PAG, cerebellum (cortex and nuclei) and brainstem (2-4 µ moles/g tissue).
Spinal cord contains lower concentration with gray-matter (about 2 umoles/g tissue) content nearly twice of the white matter content (about 1 umoles/g tissue); dorsal gray is richer than ventral gray-matter. It is an important transmitter of cerebral cortical neurons at almost all sites particularly visual cortical neurons.
It is associated with basal ganglia (caudate nucleus to substantia nigra projections), hippocampus (basket cells), olfactory bulb (granule cells), cerebeller cortex (Purkinje and basket cells), lower brain-stem (vestibular nuclei to trochlear motor neurons) and spinal cord (D cell interneurons that are presynaptic to axons of dorsal root afferents at ventral motor neurons). The transmitter is mostly involved with local inter-neuronal circuits in brain and spinal cord, and in polysynaptic inhibitory spinal transmission pathways.
Biosynthesis:
GABA is a non-protein amino acid. It is the sole amino acid transmitter that is exclusively synthesized in the CNS (and in retinal amacrine cells). GABA is synthesized by neurons from glutamate by its decarboxylation catalyzed by glutamate decarboxylase.
After release and action, GABA is rapidly taken back (actively) by presynaptic nerve terminals. Astrocytes also take-up GABA from synaptic sites. It is metabolized by GABA transaminase to glutamate and succinic semi-aldehyde; the latter is converted to succinic acid by succinic semi-aldehyde DH.
Actions:
GABA is a major fast-acting central inhibitory transmitter; actions are mediated through activation of GABA receptors. These include GABA-A (ionotropic, increasing conductance of Cl– ions that causes hyperpolarization; dominant receptor form) and GABA-B (Gi coupled; reduces cAMP and Ca++ influx; increases K+ efflux: less predominant form). GABA is both postsynaptic as well as presynaptic inhibitor. It is involved in more specifically-wired neuronal circuits involved in signal processing and motor control mechanisms.
Implicated Roles In Health And Disease:
1. Motor Control:
GABA (inhibitory) and glutamate (excitatory) play crucial roles in basal ganglia arid cerebral cortical interrelated circuitry, to regulate optimal skeletal muscle functioning. Interference with GABA system leads to motor disorders:
(i) Drugs that increase GABA-ergic activity are anti-consultants including benzodiazepines (agonists at A- receptor, and potentiate GABA mediated CI– conductance), barbiturates (increase binding of GABA to A- receptor, and potentiate its action), valproate (stimulate glutamate decarboxylase, and inhibit succinic semi- aldehyde dehydrogenase favouring accumulation of GABA for increased release), gabapentin (release GABA) and gamma-vinyl GABA (inhibit GABA transaminase); these drugs are quite effective anti- seizure drugs.
(ii) Drugs that antagonize GABA at A-receptor site such as picrotoxin, bicuculline, penicillins and flumazepine are potential convulsants.
(iii) Parkinson’s disease is associated with abnormal GABA activity (hyper GABA-ergic is akin to hypo DA-ergic activity in basal ganglia; soma circuits are hyperactive and some hypoactive;
(iv) Huntington’s chorea is also associated with reduction in striatal GABA levels (besides other alterations).
2. Mood and Behaviour:
GABA-ergic pathways serve to regulate the firing of mono-aminergic neurons which is engaged in promoting behavioural arousal, and are important mediators of the inhibitory effects of fear and punishment on behaviour. Benzodiazepine-mediated tranquility is related to this phenomenon; flumazepine (inverse agonist, blocking binding of benzodiazepine to their binding sites are reducing effect of GABA on A-type receptors) can reverse the effects of benzodiazepines.
Anxiety has been associated with reduced GABA activity in the brain. Reduced GABA- B activity (or hyper DA-ergic) has been related to schizophrenia; GABA receptor agonist, is effective in combating schizophrenia. Behavioural alterations in alcoholics are partly related to increased GABA mediated CP fluxes, and consequent synaptic inhibition (ethanol also potentiates serotonin at ionotroic receptor, and inhibits glutamate at NMDA receptor).
3. Sleep and Wakefulness:
GABA to glutamate ratio may be critical in sleep-wakefulness cycle specifically wired circuits as compared to non-specifically wired monoaminergic circuits:
(i) Arousal state increases cortical glutamate but decreases GABA, and vice versa happens during sleep,
(ii) Sleep deprivation is accompanied by increased brain GABA content,
(iii) Destruction of reticular formation is accompanied by increase in GABA release and induction of sleep (GABA appears to mediate sleep induction at cortical level), and
(iv) Stimulation of mid-brain reticular formation causes arousal and increases release of glutamate at cortical level. General anaesthetics (e.g., inhalants, barbiturates and alphaxalone) are known to potentiate GABA-A synapses.
Glycine:
Distribution:
Glycine content in spinal cord is nearly 4-fold more than that in brain; a major inhibitory transmitter at spinal level and minor in the brain (reverse of GABA). The concentration of glycine progressively decreases from spinal cord to forebrain regions: Spinal cord/Brain-stem/ Cerebellum/Midbrain, thalamus, caudate nucleus and cortex.
The concentrations in spinal gray-matter are highest as compared to any other known amino acid transmitters. Glycine is largely confined to short- axoned local circuits maintained by interneurons in the spinal cord (e.g. Renshaw cells) and lower brain-stem (glycine and glycine receptor rich sites of the brain).
Biosynthesis:
The neurons can synthesis glycine from ammonia and carbon dioxide using glycine synthetase (reversible reaction) or from serine using serine hydroxymethyl transferase. After release and action, it is actively taken up by the nerve terminal, and may be metabolized by either of the cited enzymes, producing respective precursors.
Actions:
Glycine is fast-acting inhibitory transmitter, and produces actions vide activation of ionotropic glycine receptors (like GABA-A); opening of Cl– channels leads to increased Cl– influx causing hyperpolarization of effector neuron (rapid and brief action).
Implicated Roles in Health & Disease:
Local neuronal circuits involving glycine (or even GABA) that are inhibitory, serve to confine flow of nerve impulses in appropriate neuronal circuits; they act as servo-control mechanisms to ensure the facilitatory or motor activity functions are optimally conducted. Post-synaptic inhibitions mediated by interneurons are responsible for recurrent inhibition and reciprocal inhibition.
For instance, motor neuron collateral in spinal cord (cholinergic) activates glycinergic interneurons (i.e. Renshaw cells) which in turn inhibits motor neuron activity through glycine receptors present on motor neuron; thus excessive firing (stimulation) of motor neuron leads to its own inhibition vide Renshaw cell (recurrent inhibition).
Similarly, motor neurons of antagonistic muscles (extensors/flexors) ensure relaxation of flexors when extensors are contracting, and vice versa through inhibitory controls exercised vide stimulating respective interneurons. (reciprocal inhibition).
Strychnine induced convulsions are due to blockade of glycine receptors (on motor neurons). Due to in-operating servo-loop, sensory stimuli produce exaggerated motor responses and convulsion tome dominant (Renshaw cell glycine unable to inhibit motor neurons). Pattern of convulsions is determined by the most powerful muscles acting at a given point.
Beta-AIanine and Taurine:
Both beta-alanine and taurine are putative amino acid inhibitory transmitters; taurine is considered to be better candidate; it is present in cerebellum (highest concentration); posterior pituitary, corpus callosum, (retinal cells, like DA & GABA), and thalamus (least content). It is synthesized from cystein.
Retinal photoreceptors are rich in taurine; cats require dietary taurine to prevent degeneration of these receptors. Actions of taurine (and also of beta-alanine) are perhaps through glycine receptors (potent agonists). Beta-alanine actions may also be related to its ability to block uptake2 of GABA, particularly at B-type receptor sites.
Endogenous Opioid Peptides:
Three distinct families have been identified:
1. The Enkephalins:
Leucine-enkephalin and methionine- enkephalin. Both are pentapeptides, identical except one amino acid as indicated by the prefix.
2. The dynorphins:
At least 7 members including dynorphin A (1- 17), dynorphin A (1-8) dynorphin B (1-13); all contain leu-enkephalin at amino terminus.
3. The endorphins:
Alpha-and beta-neoendorphins,, differ by one amino acid, deca-and nona-peptides respectively; contain leu-enkephalin at amino terminus; while beta-endorphin (31 residues), contains metaenkephalin at the amino terminus.
The enkephalins, dynorphin A and beta-endorphin represent prototypes of the peptides with established to more likely roles as transmitters in the CNS. Their differential features are given in the table 3.
Distribution:
Enkephalins and Dynorphin A:
The enkephalin content varies in different parts of the CNS: Hypothalamus and Brain-stem (high); Median eminence, amygdaloid complex and other limbic areas (moderate); and Thalamus and hippocampus (low).
The cells bodies have been found in these areas except hippocampus and thalamus. The enkephalins are primarily contained in interneurons (short-axoned circuits), and occasionally in long fibre tracts. The fibres also descend to spinal cord.
The dynorphins are present in the same areas as are the enkephalins. The two groups are usually contained in distinct neurons, but may be occasionally encountered together in the same neurons.
Both are present in areas that are concerned with pain perception (spinal cord to cerebral cortex), autonomic functions (medulla and hypothalamus), neuroendocrine release (median eminence), emotion and behaviour regulation (limbic system) and motor control modulation (caudate nucleus and globus pallidus).
Beta-endorphin:
The cells containing beta-endorphin have been found mainly in hypothalamus. The fibres from here (i.e. arcuate nucleus) project widely to limbic areas, Brain-stem, and to the spinal cord.
The concentrations vary from very high (hypothalamus) to moderate (median eminence and mid-brain) and to low (thalamus, limbic system and brain-stem). Their distribution is mainly concerned with areas implicated in pain perception, modulation and transmission (at-least in humans).
* Morphine and related alkaloids have been identified in the CNS, may be endogenous ligands for the known opioid receptors.
Biosynthesis:
They arise from distinct precursors. Amino acids are assembled in the respective cell-bodies (ribosomal sites) by several enzymes into large polypeptide precursors. The precursor is transported down the axon.
The processing (i.e. liberation of active peptide from the precursor by specific peptides) is thought to occur at nerve terminals within the Golgi apparatus in the developing secretory granules; the cleavages usually occur at sites where pairs of basic amino acids are present.
After release and action, the action is terminated by their proteolytic hydrolysis into peptide fragments and amino acids, and possibly by diffusion to non-target sites; there is no uptake process for peptides. The intra-neural levels of the peptides (including other neuropeptides) are regulated by genetic control connected to translational and post-translational changes of the concerned peptides.
Actions:
The actions of the peptides are mediated by opioid receptors; mu, kappa and delta types. The opioid receptors are G- protein coupled receptors (Gi-variety), and effector mechanisms include decrease in cyclic AMP production, activation of receptor operated K+ currents and suppression of Ca++ currents.
These mechanisms are responsible for inhibitory actions elicited by the peptides either on release of other transmitters, and/or blockade of neuronal circuits (e.g. those involved in pain perception and transmission). The receptors are often located presynaptically, and are inhibitory in nature (pre-and post synaptically).
The enkephalins appear to act purely as transmitters (mostly modulatory type) whereas endorphins appear to act both as transmitter as well as hormone-like. The transmitter status of dynorphins has not been established, but seem to be certainly involved in some central processes.
Implicated Roles In Health And Disease:
1. Analgesia, Stress and Acupuncture:
The endogenous opioids, mainly enkephalins and endorphins, modulate nociception by three ways:
(i) Reduce the transmission and perception of pain,
(ii) Dampen the psychophysiological response to pain, and
(iii) Cause sedation.
The perception and transmission of pain appears to be modulated by affecting release of substance P (see substance P) at spinal and at supraspinal sites either by presynaptic inhibition of its release or vide enkephalin-ergic interneurons that inhibit the other transmitter.
The role of involvement of other transmitter (e.g. 5-HT) systems especially at central levels is always there. Beta- endorphin is up to 1000 fold more potent analgesic than metenkephalin, while leu-enkephalin is about 1/2 as potent as metenkephalin. The analgesic potency of dynorphins appears to be relatively weaker than enkephalins.
There appears to be a definite relationship between the peptides and various types of stresses:
(i) Stress increases CRH release from hypothalamus, which in turn causes simultaneous release of ACTH and beta-endorphin from anterior pituitary; and cortisole is known to inhibit release of the endorphin (feed-back mechanism),
(ii) Beta-endorphin and/or enkephalins stimulate release of catecholamines (centrally mediated), and (iii) Beta-endorphin has been considered to be natural antidote for the pain and stress associated with parturition/ labour.
The release of beta-endorphin is known to increase nearly ten fold during the development of endotoxic shock. The release of endogenous opioids in stress appears to prepare an individual to meet incoming dangers with tranquility. The role of these peptides in mediating acupuncture analgesia has been implicated. Analgesia associated with nitrous oxide and other CNS anaesthetics appears to be mediated by activation of this peptide system.
2. Learning and Memory:
Beta-endorphin and enkephalins facilitate acquisition of avoidance behaviour (memory formation) and inhibit the extinction of avoidance behaviour on stimulus withdrawal i.e. persistence of learned response (Krieger, 1983). They appear to play an important part in intrinsic memory system; however their effects appear to be on short-term memory processes (see vasopressin).
Their effect on improving learning based on avoidance type behavioural studies can be related to their effect on attenuation of pain associated with aversively motivated tasks. Otherwise, beta-endorphin has been described as the most potent amnestic agent to be known; the effect being reversed by naloxone.
3. Alteration in Mood and Behaviour:
The peptides are known to increase ingestive behaviour (behavioural motivation), diminish sexual drive (endorphins & enkephalins) and modulate avoidance behaviour (beta-endorphin).
The central administration of the peptides (selected areas) stimulates feeding; obese animals (rat strain) have high brain levels of beta-endorphin, and fasting is associated with decrease in hypothalamic beta-endorphin content. Increased feeding is apparently related to activation of dopaminergic input to feeding center in the hypothalamus.
The euphoria observed with mu-and possibly delta-receptor agonists (enkephalins and endorphins) has also been related to activation of dopaminergic neuronal firing (that project form tegmentum to limbic areas leading to feelings of tranquility and mood elevation.
The dysphoria produced by Kappa-receptor agonist (dynorphin) has been associated to inhibition of firing of dopamine neurons in the substantia nigra, and inhibition of release of dopamine at striatal and cortical sites. The opioids are also known to inhibit activity of noradrenergic neurons of locus ceruleus (rich ion opioid receptors); the region plays a critical role in feelings of alarm, panic, fear and anxiety.
The behavioural alterations in opiate addicts are apparently related to these mechanisms; heroin addicts are relatively docile and compliant after taking heroin but become irritable and aggressive during withdrawal.
4. Motor control:
The opioids are known to cause catalepsy, circling and stereotyped behaviour in animals. Beta-endorphin has been implicated to participate in the cataleptic seizures.
In fact, the peptides at supra-analgesic doses are known to inhibit release of GABA from interneurons leading to excitation of hippocampal pyramidal cells (operating in limbic system to govern psychosomatic motor activity). The concentration of enkephalin (and also CCK and substance P) is decreased in basal ganglia in Huntington’s chorea.
5. Thermoregulation:
The opioids are known to later the equilibrium point of the hypothalamic heat-regulatory mechanisms such that body temperature tends to fall; high doses are hypothermic and low doses hyperthermic. Besides, naloxone has been reported to produce disordered thermal regulation in animals exposed to cold and hot environments suggesting a role of endogenous opioids is temperature adaptation.
6. Neuroendocrine Role:
The opioid receptor activation in the hypothalamus is associated with release of GnRH (hence LH/FSH, and consequent sex- steroids) and CRH (hence ACTH and consequent glucocorticoids) Mu agonists favour prolactin release (DA release inhibition) and produce antidiuretic effect i.e ADH release).
Kappa agonists inhibit ADH release, and hence produce diuretic effect. The hypothalamic- pituitary-adrenal/gonadal axises are abnormal in heroin addicts; suggesting role of endogenous opioids in modulating their operations.
7. Blood Pressure Regulation:
The role of endogenous opioids particularly beta- endorphin in affecting blood pressure regulation is based on following relations:
(i) endotoxic shock is accompanied with increase in endogenous beta-endorphin levels,
(ii) naloxone reverses various forms of hypotensive shock,
(iii) TRH (physiologic antagonist of endorphins) can reverse hypotensive manifestation of shock, and
(iv) clonidine increases central beta-endorphin levels and reduces blood pressure (apart from acting on vasomotor centre activity in medulla oblongata).
Substance P:
Substance P is a brain-gut peptide composed of eleven amino acids. It occurs in both brain and spinal cord. The important-brain locations include limbic system, basal ganglia, hypothalamus, mid-brain and brain-stem. Low concentrations are found in thalamus, hippocampus and median eminence.
In the spinal cord, it is associated with raphe-spinal projection and dorsal sensory neuron fibres projecting to substantia gelatinosae neurons. Its synthesis and fate are similar to those of other neuropeptides. The usual synaptic action of substance P is excitatory; depolarization is most probably caused by closure of K+ channels, responsible for late slow EPSP. It may be released from dendrite varicosities.
Substance P is thought to be a major transmitter of pain pathways operating at spinal cord (substantia geiatinosae) and brain level; facilitating transmission of pain impulses.
The substance P containing nerve fibres are known to be under the control of enkephalinergic interneurons; these neurons act presynaptically and postsynaptically to inhibit the release of substance P, and thus diminish the activity of substantia geiatinosae neurons that project from spinal cord to higher centres for pain impulses transmission (i.e. spinothalamic tracts).
Opiate mediated analgesia is partly through inhibition of release of substance P from primary afferent nerve terminals at spinal cord level; directly by activating opiate receptors on the nerve terminals and indirectly by activating local enkephalinergic interneurons.
Acupuncture based analgesia is explainable on these mechanisms: excitation of large myelinated peripheral nerve fibres (A-delta) by acupuncture procedures (mechanical or electrical) excite enkephalinergic interneurons in the substantia geiatinosae that in turn inhibit passage of nociceptive impulses by small un-myelinated fibres (C-fibres) at spinal cord level (substance P activity reduced).
C-fibre stimulation is known to inhibit interneurons and thus promote passage of pain impulses to higher centres (the two fibre systems appear to interact at dorsal horn level through interneurons).
Substance P neuronal activity at usual frequency appears to produce algesia (higher doses hyperalgesic) by facilitating nociceptive transmission; under-activity (low doses) appears to favour analgesia (by releasing endogenous opioid peptides) Substance P is known to increase vasopressin secretion (like dynorphins).
Cholecystokinin (CCK-8):
CCK-8 is a brain-gut peptide composed of eight amino acids. Its concentrations are very high in neocortex following by limbic system (high), brain-stem (moderate), thalamus, hypothalamus, median eminence and mid-brain (low).
The cell-bodies have been demonstrated in neocortex, hippocampus and hypothalamus. It has been also found in striatum, raphe nuclei and dorsal horn cells (i.e. substantia geiatinosae). Its synthesis and fate are like those of other neuropeptides.
It acts through activation of CCK-receptors (metabotropic-Gq- variety; A and B types) leading to increased production of IP3 and DAG with consequent cell stipulatory effects.
Its presence in neocortex in very high concentrations along with cell-bodies (like VIP) might suggest its significance in cortical functioning, but no definite role has been ascertained to this presence. It is believed to govern ingestive feeding behaviour (decreases feed-intake); the effect possibly related to decreased endogenous opioid activity as it is considered to be an endogenous opiate antagonist.
A reduction in striatal CCK receptors has been related to Huntington’s chorea-suggesting possible involvement in motor control. It has been found in sensory neurons whose terminals expectedly release the transmitter at central sites to facilitate manly the transmission of afferent impulses from autonomic structures. Its co-presence with DA in mesencephalic cells (some) has not been yet assigned any significance.
Somatostatin:
Somatostatin, also called somatotrophin release inhibiting hormone, is composed of 14 amino acids, and is synthesized mainly by hypothalamic neurons-hypothalamus contains very high content of the peptide. The cell-bodies have been found in neocotrex, limbic system and brain-stem. Low concentrations occur in striatum, thalamus, mid-brain, spinal sensory and dorsal horn neurons.
Somatostatin receptors (type 1 and type 2) are G-protein coupled (Gi-variety) leading to decreased cyclic AMP production, decreased Ca++ and increased K+ conductances; the peptide is accordingly inhibitory type. Its central role (apart from neuroendocrine function of inhibition release of growth hormone) is not definitely known.
It has been implicated in sleep regulation (sleep is accompanied with growth-hormone release, to ensure growth and repair functions during sleep); its release in higher during wakefulness and lower during sleep (whether this is cause or effect accompanying sleep is not known.
It is also suspected to play role in the transmission of afferent impulses form autonomic structure (associated with sensory neurons). Its synthetic analog octreotide has potential greater than bromocriptine (bromocriptine activates dopaminergic neurons, that activate somostatinergic cells) in the treatment of acromegaly.
Its levels are known to be decreased in cerebral cortex degenerated areas in Alzheimer’s disease, and to be increased in basal ganglia in Huntington’s chorea.
Vasopressin:
VP, nonapeptide, concentrations are very high in median eminence; followed by hypothalamus (high; major site of synthesis) neocortex, limbic system, thalamus, midbrain and brain-stem (low content).
The cell-bodies are concentrated mainly in hypothalamus (magnocellular neurons of the para-ventricular and supraoptic nuclei). It has been also found associated with descending supraspinal pathways. Its co-localization with CRF has been observed in periventricular nucleus neurons.
The CNS effects appear to be mediated predominantly by V1 receptors (Gq- coupled increasing IP3 and DAG) while V2 receptors (Gs-coupled) appear to mediate mainly peripheral effects (renal tubules and vascular sites).
Vasopressin is one of the strongest neuropeptides (others include opioid peptides, alpha-MSH and fragments of ACTH) with implicated role in learning and memory processes. It is known to facilitate acquisition (like other peptides) and to inhibit extinction (favour memory persistence) of learned behaviour.
Compared to other peptides that affect short-term memory processes, vasopressin is implicated in affecting long-term memory processes, (like Ach). It has been found to improve learning and/ or memory in experimental animals, human volunteers and clinical subjects. Deglycinamidelyside-vasopressin is devoid of endocrine activity but shares the behavioural effects of vasopressin-indicating inherent capacity in the molecule to have this central effect.
Nasal spray of vasopressin, and its analog desmopressin, in humans has improved arousal, mood, attention and memory. Its potential as an endogenous antipyretic, at least in some species, has been mooted as it tends to reduce fever when given directly into the brain (i.e. i.c.v.).
The vasopressin has been implicated in modulating CNS autonomic control on heart rate, blood pressure, respiratory rate and sleep patterns, it also enhance ACTH secretion, The peptide appears to be a likely central transmitter and/or modulator considering its distributional pattern in CNS and its potential to affect CNS processes.
Other Neuropeptides:
There is a long list of neuropeptides that have been demonstrated in the CNS (i.e. localization) and implicated to play central roles. The distribution and implicated role (s) of some of these neuropeptides are given in the table 5.
At present very little is known about the definite physiologic and/or pathologic functioning of these peptides in the CNS.
The present knowledge is largely based on relatively convincing evidences based on one or more of the following approaches or procedures:
(i) Determination of their concentrations in various parts of the brain in health or disease (i.e. post-mortem material), former most often in experimental animals,
(ii) Demonstration of the neurons containing these substance in various regions of the CNS,
(iii) Pharmacologic effects of intra-cerebrally given substances,
(iv) Mimicing of physiological significance by creating their deficiency in the CNS (using selective antagonists or specific antibodies, or chemicals capable of interfering with their functioning),
(v) Studying neuronal excitability in response to the substances in presence or absence of antagonists and/or other transmitters/neuromodulators, (e.g. using iontophoretic techniques), and
(vi) Monitoring their concentrations in CSF of normal individuals and those suffering from CNS-related disorders.
The Concluding Remarks:
The concluding remarks pertain to recapitulating the role of central transmitters in relation to central circuitry and with respect to physiologic and pathologic alterations manifested by the transmitter inter-play, and futuristic prospects of such studies in unraveling the mysteries of CNS functioning.
*DSP, descending spinal pathways; PAG, periaquiductal gray matter; SG, substantia geiatinosae; BG, basal ganglia; LS, limbic system,; MB, mid-brain; NS, brain-stem
The neuronal circuitry:
There are about 100 billion neurons operating in the CNS and about 50- billion in the cerebral cortex alone. The central neuronal circuitry underly the CNS functioning. These circuits are established by neuronal contacts called synapses (dominantly chemical and rarely electrical in operation) such that any central neuron is in contact (and hence in communication) with any other neuron directly or indirectly vide interposed neurons (range one to several).
The contact points (most often axodendritics and axosomatic; less often axoaxonal, and least occurring dendro-dendritic and somo-somatic are operated by transmitters. Each transmitter either activates (opens the contact point for signal communication) or inactivates (closes the synaptic transmission) or modifies the degree of opening or closing of the circuit-point for other input-signals.
Thus, a wide variety of combinations and permutations get ordered for integeration (balancing) and regulation. The neuronal output signal is determined by algebraic sum of influences (excitatory, inhibitory or modulatory) impinging upon the neuron (range up to a million inputs per single neuron).
The circuit output signalling (for some specific function) is determined by algebraic sum of varied influences operating at different synapses constituting a given neuronal circuit.
At more advanced integration, the output from a multi-unit complex circuit (for more integrated functions) is similarly governed by algebraic sum of influences exerted by various circuits constituting the given multi-unit circuit. Thus, different levels of neuronal integrations are accomplished for varying degrees of complexities required for different physiologic functions.
The Transmitter-Interplay:
The functions regulated by the circuitry are apparently governed by the ultimately placed circuit unit (motor neuron, nerve collection to form a physiologic centre or nuclei).
The function may pertain to simple reflex (spinal and brain-stem motor neuron), to moderately complex function (such as vasomotor control at medullary level), to more complex (such as neuroendocrine and psychomotor controls operated by hypothalamus in combination with influences of limbic system) to highly complex functions involving many circuits (dominant role played by cerebral cortex) such as abstract thinking, learning, memory, imagination, sleep, consciousness, and other related psychological phenomena.
The neuronal circuitry is established and operated as per in- built intrinsic programme, determined by genetic constitution of a given species. The primary objective being preservation and regulation of physiologic functions with respect to each other to ensure preservation of individuals and species. The programming is improved or altered by environmental influences during the individuals life-time; again genetic expression playing a crucial role.
The transmitter action plays a crucial role in operating the central circuitry. Any alteration at one or several points, alters many other transmitter-operated sites. The result is abnormality in physiologic functioning.
Often, a given physiologic function is governed by a number of transmitters:
Motor control – Ach, GABA, glutamate, DA, glycine
Thermoregulation – Ach, NE, 5-HT
Sleep-arousal – Ach,’NE, 5-HT, GABA, glutamate
Pain-perception – Substance P, endogenous opioids, 5-HT and possibly neurotensin
Learning/memory – Ach, glutamate/aspartate, vasopressin, endogenous opioids, ACTH fragments
Emotional behaviour – DA, 5-HT and neuropeptides
Vomiting – Ach, DA, Glutamate, GABA
These is turn are being affected by other transmitter signals that have direct access to the main circuits operated by respective transmitters. Thus, physiological and pathological significance of the transmitters has to be viewed against the background of their mutual cooperation and interaction for a given function (normal or abnormal)
The Prospects:
The central functioning is not only the consequence of changes in neuronal excitability (governed by alterations in ionic conductances), but the functions are more diverse, subtle and complex.
The complexity, as explained, is the function of neuronal circuitry, but the circuits have to be operated and even generated, maintained and regulated with apparent stimuli or with mysteriously operating (e.g. thought process), and mere conductance alterations for some ionic species that too confined to bio-phase around the nerve membrane are not suitable for the latter mentioned activity domain.
Alteration in ionic conductances is an apparent trigger for initiation of operation or stoppage of one or more neuronal circuits. However, the subtle functions require not only initiation but their maintenance, direction, integration and regulation with respect to one or more circuits functioning for a defined physiologic and psychologic function with no apparent mistake and error each time the given process is conducted or recapitulated. The implicated role of central ‘biochip’ is most suited for this operation.
Thus, DNA is implicated to play a pivotal role in such regulatory, time independent neuronal functions. The DNA controls biosynthesis, breakdown and storage of the transmitters, their receptor profile and their transportation within or form outside-besides being capable of generating a wide variety of peptides of varying sequences and of varying configurations to accomplish the regulatory phases of neuronal life-cycle.
The DNA is more responsive to signals obtained from G-protein coupled transduction mechanisms, than those regulating purely ionic conductances (ionotropic mechanisms).
The neuropeptides assume special significance in this regard:
(i) As peptides they are directly controlled by DNA,
(ii) As a class they operate primarily through G-protein transduction mechanisms, besides some altering ionic conductances,
(iii) Stimulus (due to their slow break-down) persists longer (than amines and amino acids), and
(iv) Effects persist relatively for a longer period. The continuing and future studies are expected to unravel the central functions of these and perhaps of many more hirtheto unknown neuropeptides in health and disease, and their intimate relationship with DNA expression and regulation.