Dopamine/dopaminergic system neuroleptics

Postmortem studies of patients with idiopathic Parkinson s disease demonstrate cell loss in the striatal system (A-9), directly implicating this tract vis-a-vis the neuroleptic-induced pseudoparkinsonian side effects. The assumption that psychosis is related to the A-10 system is made by exclusion. Evidence also indicates that clozapine may differentially block DA pathways. Specifically, it seems to act on the mesolimbic dopaminergic system (A-10), while being relatively inactive in the striatal system (A-9) however, this remains controversial. Chronic administration of clozapine decreases the firing rate of A-10 mesocortical tract dopamine neurons... 

It is well known that typical neuroleptics, all of which have a high affinity for dopamine receptors (particularly D2 receptors), do not effectively treat all schizophrenic patients and have only limited beneficial effects on the negative symptoms of the illness. Furthermore, neither typical nor atypical neuroleptics have an immediate effect on the positive symptoms even though it can be shown by both experimental studies in animals and by imaging methods in schizophrenic patients that neuroleptics rapidly bind to dopamine receptors. Thus factors other than an overactive dopaminergic system are probably operative in this disorder. The question is which of the numerous neurotransmitters and modulatory neuropeptides are responsible for both the negative symptoms and the delay in onset of the therapeutic effects of neuroleptics on the positive symptoms ... 

Because of the discovery that all neuroleptics in clinical use are dopamine receptor antagonists, and that an abnormality in the dopaminergic system might underlie the pathology of the condition, the action of neuroleptics on the dopaminergic system has been extensively studied over the past two decades. Four major anatomical divisions of the dopaminergic system have been described ... 

More recent studies have indicated that TD may be the result of complex interactions between dopamine and the cholinergic system, which becomes more active when the suppressive or balancing effect of the dopaminergic system is blocked by the neuroleptics. In addition, the neuroleptics are directly toxic to neurons by means of disrupting a number of separate biochemical pathways (chapter 5). 

The administration of low doses of PCP to rodents induces hyperactivity and stereotypy (Chen et al. 1959 ). The observation that neuroleptics such as chlorpromazine, haloperidol, and pimozide, and adrenolytics such as alpha-methyl paratyrosine antagonize these behavioral effects of PCP suggests that they are mediated by facilitation of central dopaminergic neurotransmission (Murray and Horita 1979). The actions of PCP on central dopaminergic neurotransmission may be similar to amphetamine. A dose of PCP (2.5 mg/kg) in rats, which has no effects when given alone, enhances the behavioral effects of 1 and 3 mg/kg of d-amphetamine (Balster and Chait 1978). PCP, like dopamine, has also been shown to suppress plasma prolactin (Bayorh et al. 1983). However, the firm establishment of an excl usive relationship between dopamine neuro-transmission and PCP effects is difficult because of the prominent interactions of this drug with other neurotransmitter systems. 

Neuroleptic drugs are used in the treatment of psychosis, such as schizophrenia they are generally antagonist ligands of dopamine at the central nervous system level. " Indications and therapeutic effects of the various families of neuroleptics result from two factors. The first one is the specifity of the ligand toward the different types of dopaminergic receptors, which are unequally distributed in the... 

The heterogeneity of dopaminergic neurons may also be judged by the fact that the cotransmitter systems involving dopamine and peptides are varied in the central nervous system. For example, in the corpus striatum, in addition to dopamine, acetylcholine, y-aminobutyric acid, serotonin, glutamate, and aspartate, one also finds peptides such as enkephalin, substance P, somatostatin, neuropeptide Y, cholecystokinin, neurotensin, and vasoactive intestinal peptide. Although many neuroleptics block dopamine receptors, they may have selective effects on the peptides and other parts of the brain. A few examples will be cited. 

In addition to acute and chronic schizophrenia, the neuroleptics are sometimes used in the management of mania, delirium, and severe agitation, whatever the cause of these symptom complexes. It must be noted that unlike parkinsonism, where a definite dysfunction in the DA system has been established, for schizophrenia and other psychiatric diseases, no unequivocal evidence has yet been presented to prove that there is a disturbance of the DA system (e.g., dopaminergic overactivity or receptor hypersensitivity). In untreated schizophrenics the production of DA metabolites is normal. Conflicting results have been obtained in studies of the DA receptors in schizophrenics (11,12,13), but in the case of patients who have not received neuroleptics, the receptor density and affinity appear to be normal (13). The "dopamine hypothesis" in these disorders derives from the beneficial effects of drugs that block DA receptors. 

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