Increased density of D2 receptors Increased cortical DA innervation Increased D4-like receptor binding Alterations in D3 receptor binding Decreased presynaptic markers Decreased HC AMPA and kainate receptor expression Minor changes in FC NMDA R sub-units Altered glutamate fibres in cingulate cortex
Decreased FC 5-HT2a receptor expression Increased FC 5-HT1A receptors Increased 5-HT transporter affinity Developmental and trophic roles of 5-HT
Increased density of FC GABAergic terminals
Increased GABAa receptor binding in limbic areas
Altered expression of FC GABAa receptor sub-units
Decreased FC expression of glutamic acid decarboxylase Altered density of cingulate GABAergic cells
DA-releasing agents produce psychosis All antipsychotics are D2 receptor antagonists Increased striatal release in vivo
NMDA receptor antagonists produce schizophrenia-like psychosis Roles of NMDA receptors in development and neurotoxicity Partial NMDA receptor agonists have some therapeutic benefits 5-HT2 agonists (e.g. LSD) are psychotomimetics 5-HT2 receptor polymorphisms associated with schizophrenia and clozapine response Atypical antipsychotics have high affinity for several 5-HT receptors Roles of GABA in stress and neurotoxicity
AMPA: amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; DA: dopamine; FC: frontal cortex; GABA: y-aminobutyric acid; HC: hippocampus; 5-HT: serotonin; LSD: lysergic acid diethylamide; NMDA: N-methyl-D-aspartate.
1. The nigrostriatal system, in which fibres originate from the A9 region of the pars compacta and project rostrally to become widely distributed in the caudate nucleus and the putamen.
2. The mesolimbic system, where the dopaminergic projections originate in the ventral tegmental area, the A10 region, and then spread to the amygdala, pyriform cortex, lateral septal nuclei and the nucleus accumbens.
3. The mesocortical system, in which the dopaminergic fibres also arise from the A10 region (the ventral tegmental area) and project to the frontal cortex and septohippocampal regions.
4. The tuberoinfundibular system, which originates in the arcuate nucleus of the hypothalamus and projects to the median eminence.
Following its release, dopamine produces its physiological effects by activating postsynaptic receptors which have been classified into the D1 and D2 families. The D1 receptors are linked to adenylate cyclase which, when activated, produces cyclic AMP as a secondary messenger. The D2 receptors are not positively linked to adenylate cyclase and may owe their physiological effects to their ability to inhibit this enzyme. The D2 receptors are probably the most important postsynaptic receptors mediating behavioural and extrapyramidal activity. Most therapeutically effective neuroleptics block the D2 receptors, while drugs like bromocriptine, which is a dopamine receptor agonist used in the treatment of parkinsonism, activate them. The correlation between the antagonist effect of a series of neuroleptics on brain D2 receptors and their appropriate therapeutic potency is shown in Figure 11.5. It should be emphasized that recent studies on the effects of atypical neuroleptics on the D2, D3 and D4 receptors show an even better correlation between dopamine receptor antagonism and the therapeutic dose.
Agonist stimulation of D1 receptors results in cyclic adenosine monophosphate (cyclic AMP) synthesis followed by phosphorylation of intracellular proteins, including dopamine- and AMP-regulated phospho-protein (DARPP-32). The receptor binding affinity of a dopamine agonist is dependent on the degree of association of the receptor and the guanine nucleotide binding regulatory protein, which is regulated by guanosine triphosphate (GTP) and calcium or magnesium ions. Thus the D1 receptor may exist in a high or low agonist affinity state depending on the balance between GTP (which favours low affinity) and the divalent cations (which favour high affinity). The high affinity D1 receptor is classified as a D5 receptor.
The D3 and D4 receptors appear to be largely restricted to the limbic areas of the rat and human brain. These receptors are of particular interest as they have a high affinity for such atypical neuroleptics as clozapine. Such
0.1 1.0 10 100 (K-|. nM) Inhibition of [3H]haloperidol binding to neuronal membranes
Figure 11.5. Correlation between the average daily dose of various neuroleptics and their affinity for D2 receptors. (1)=promazine; (2)=chlorpromazine; (3)=thio-ridazine; (4)=clozapine; (5)=triflupromazine; (6)=penfluridol; (7)=trifluoperazine; (8)=fluphenazine; (9)=haloperidol; (10)=pimozide; (11)=fluspirilene; (12)=benper-idol; (13)=spiroperidol (spiperone).
findings suggest that the D3 and D4 receptors in the human brain may mediate the antipsychotic actions of many typical and atypical neuroleptics. The restriction of these receptors to the limbic regions may lead to the development of neuroleptics which are specifically targeted to these areas but so far the results have been disappointing. This may assist in the development of drugs that combine antipsychotic potency with reduced extrapyramidal side effects.
In the mammalian brain, the Dj receptors are located postsynaptically in the striatum, nucleus accumbens, olfactory tubercle, substantia nigra, etc., but their precise physiological function in the brain is currently unclear. The partial Dj receptor agonist SKF 38393 stimulates grooming and stereotypic motor behaviour in rodents, effects that are blocked by the Dj antagonist SCH 23390. This antagonist also blocks the behaviour initiated by the selective D2 receptor agonist quinpirole (LY171555), which suggests that there is a functional interaction between the Dj and the D2 receptors.
Unlike the D1 receptor, the function of the D2 receptor in the brain is at least partially understood. The anterior lobe mammotrophs of the pituitary control lactation via prolactin release, and dopamine acting on the D2 receptor in this area acts as the prolactin release inhibitory factor. In the intermediate lobe of the rat, dopamine inhibits alpha melanocyte-stimulating hormone release. In the striatum, D2 receptors inhibit acetylcholine release, while on the dopami-nergic nerve terminals the D2 receptors function as autoreceptors and inhibit the release of dopamine. D2 receptors occur on the dopaminergic neurons in the substantia nigra where they inhibit the firing of the neurons. In man, these receptors stimulate growth hormone release. Lastly, in the chemoreceptor trigger zone, stimulation of the D2 receptors elicits emesis. The selective agonist for D2 receptors is quinpirole (LY171555), while the selective antagonist is spiroperidol (spiperone).
Increased motor activity and stereotypic behaviour arises as a result of the activation of central D2 receptors in rodents, while in man psychosis, stereotypic behaviour and thought disorders occur. Conversely, neuroleptic drugs with selective D2 antagonist properties (e.g. the benzamides such as sulpiride) are antipsychotic and can lead to Parkinsonism in man or catalepsy in rodents, although the propensity of the benzamide neuroleptics to cause these effects is much less than the phenothiazine neuroleptics that have mixed D1 and D2 receptor antagonist properties. The butyrophenone neuroleptics such as haloperidol are approximately 100 times more potent in acting as D2 receptor antagonists than as D1 antagonists.
The results of such studies suggest that the major classes of neuroleptics in therapeutic use owe their activity to their ability to block D2 and/or D1 receptors, particularly in the mesocortical and mesolimbic regions of the brain. Side effects, such as parkinsonism and increased prolactin release, would seem to be associated with the antagonistic effects of these drugs on D2 and/or D1 receptors in the nigrostriatal and tuberoinfundibular systems.
While the precise importance of D1 and D2 receptors in the clinical effects of neuroleptics is still uncertain, there is experimental evidence from studies in primates that oral dyskinesia (which may be equivalent to tardive dyskinesia in man) is related to an imbalance in D1 and D2 receptor function, the dyskinesia arising from a relative overactivity of the D1 receptors. Thus the elucidation of the precise function of these receptor subtypes may be important not only in determining the mode of action of neuroleptics but also in understanding their side effects.
The relationship between pre- and postsynaptic receptors and a summary of the suspected sites of action of the different classes of drugs that modulate the functioning of the dopaminergic system in the striatum are shown in Figure 11.6.
While there is extensive experimental evidence showing that all clinically effective neuroleptic drugs block dopamine receptors, and a general agreement that blockade of the D2 receptors in the mesocortical regions is particularly important for antipsychotic activity, only with the advent of
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