Neuroleptics dopamine receptors

FIGURE 58-7 The IC50 values (ordinate) are the concentrations of the antipsychotic drugs that reduce the stereospecific component of 3H-haloperidol binding by 50%. The abscissa indicates the average values (and ranges) of doses used for schizophrenia. (From Seeman, P. et al. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 261 717-719,1976)... 

Seeman P, Lee T, Chau-Wong M, Wong K. 1976. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 261 717-719. 

Farde, L, Wiesel, FA, Nordstrom, AL and Sedvall, G (1989) Dj and D2 dopamine receptor occupancy during treatment with conventional and atypical neuroleptics. Psychopharmacology 99 (Suppl) 528-531. 

Seeman, P (1992) Dopamine receptor sequences therapeutic levels of neuroleptics occupy D2 receptors, clozapine occupies D4. Neuropsychopharmacology 7 261-284. 

Another crucial problem for any neurochemical model is cause and effect. Neuroleptics have a high affinity for dopamine receptors, particularly the D2-subtype. There is also a highly significant positive correlation (r > +0.9) between this receptor binding and their clinical potency (Seeman, 1980). But, this does not necessarily implicate elevated dopamine levels as the cause of schizophrenia. Moreover, blockade of dopamine receptors happens very rapidly, whereas clinical benefits are only seen after chronic treatment. Rose (1973) has criticised the reductionist statement that an abnormal biochemistry causes schizophrenia because it relates cause and effect at different organisational levels (namely, the molecular and behavioural). But, while it can be legitimate to discuss cause and effect at the same level that chlorpromazine blocks dopamine receptors (one molecule altering the response of another), it is not valid to infer that increased dopamine activity causes schizophrenia. Put another way ... 

Chlorpromazine is technically described as a phenothiazine, as are thioridazine and fluphenazine. Together with their structural analogues the thioxanthenes (e.g., clopenthixol) and the butyrophenones (e.g., haloperidol), the phenothiazines comprise the three major families of typical neuroleptics. They were developed in the late 1950s and early 1960s (Table 11.3). All these drugs block dopamine receptors, principally the D2 subtypes, with an affinity that correlates highly (r = +0.90) with their clinical... 

Dopamine receptor blocking agents. Many of the neuroleptics used in the treatment of schizophrenia frequently produce parkinsonian symptoms as unwanted effects. Neuroleptics block dopamine receptors and their therapeutic effect seems to be related to this action. Although these drugs act on DA systems without distinction, some are more selective. Thioridazine, clozapine and molindone, for example, have electrophysiological effects in the limbic region of the brain but little action in the nigro-striatal area. This selectivity may be related to receptor subtype specificity (see Chs 12 and 54). 

Whatever the underlying causes may be, neuroleptic medications are the most effective treatment for schizophrenia. All antipsychotic medications have some form of dopamine receptor antagonism and they are distinguished by their chemical class. The phenothiazines include chlorpromazine (Thorazine), thioridazine (Mellaril), mesoridazine (Serentil), trifluoperazine (Stelazine), fluphenazine (Prolixin), and prochlorperazine (Compazine). The thioxanthenes include chlorprohixine (Taractan) and thiothixene (Navane). Butyrophenones are represented by haloperidol (Haldol). Loxapine (Loxitane) is a dibenzoxapine, and molindone (Moban) is a dihydroindolone. 

Tardive dyskinesia is a condition that sometimes results from chronic neuroleptic treatment lasting from months to years (Baldessarini 1996 Stahl et al. 1982). It occurs in 15-25% of treated chronic psychotic patients and is characterized by repetitive, athetoid writhing and stereotyped choreiform movements of the face, eyes, mouth, extremities, and trunk. Discontinuation of neuroleptic medication allows the symptoms to gradually decline, but sometimes they can persist indefinitely. The pathophysiology of tardive dyskinesia is poorly understood, but it appears to involve supersensitive postsynaptic dopamine receptors in the basal ganglia. 

Cravchik, A., Sibley, D. R., and Gejman, P. V. (1999) Analysis of neuroleptic binding affinities and potencies for the different human dopamine receptor missense variants. Pharmacogenetics. 9, 17-23. 

Drugs that are successful in treating the disease act as dopamine receptor blockers and are known as antipsychot-ics or neuroleptics (e.g. chlorpromazine, haloperidol). Antipsychotic drags reduce some of the symptoms, especially the delusions and hallucinations. A side-effect of the drugs is that they can result in symptoms similar to those seen in patients with Parkinson s disease. This is not surprising, since the hypothesis to explain Parkinson s disease is too low a concentration of dopamine in a specific area of the brain (see below). 

Humber, L.G., Bruderlin, F.T., Philipp, A.H., Gotz, M., Voith, K. Mapping the dopamine receptor. 1. Features derived from modifications in ring E of the neuroleptic butadamol./. Med. Chem. 1979, 22, 761-767. 

Two types of dopamine receptors have been characterized in the mammalian brain, termed and D2. This subtyping largely arose in response to the finding that while all types of clinically useful neuroleptics inhibit dopaminergic transmission in the brain, there is a poor correlation between reduction in adenylate cyclase activity, believed to be the second messenger linked to dopamine receptors, and the clinical potency of the drugs. This was particularly true for the butyrophenone series (e.g. haloperidol) which are known to be potent neuroleptics and yet are relatively poor at inhibiting adenylate cyclase. 

Detailed studies of the binding of H-labelled haloperidol to neuronal membranes showed that there was a much better correlation between the therapeutic potency of a neuroleptic and its ability to displace this ligand from the nerve membrane. This led to the discovery of two types of dopamine receptor that are both linked to adenylate cyclase but whereas the Di receptor is positively linked to the cyclase, the D2 receptor is negatively linked. It was also shown that the receptor is approximately 15 times more sensitive to the action of dopamine than the D2 receptor conversely, the receptor has a low affinity for the butyrophenone and atypical neuroleptics such as clozapine, whereas the D2 receptor appears to have a high affinity for most therapeutically active neuroleptics. 

Besides the poor specificity of many of the assays used to determine plasma drug concentrations, another problem which has arisen from these studies has been the length of the "wash-out" period necessary before the patient is given the neuroleptic under investigation. As a result of the prolonged duration of blockade of dopamine receptors in the brain by conventional neuroleptics and their metabolites, it is necessary to allow a wash-out period of several weeks before the patients are subject to a pharmacokinetic study. This raises serious ethical questions. Perhaps with the advent of new imaging techniques it may be possible in the near future actually to determine the rate of disappearance of neuroleptics from the brain of the patient. This may enable the relationship between plasma concentration and clinical response to be accurately determined. 

Aquatic frogs and toads probably need less toxin for defense than terrestrial forms. The compounds in the frogs mucus are thought to be neuroleptic, blocking dopamine receptors. They also possibly are antibacterial and aid wound repair, and they are known to elevate the level of prolactin, the amphibian Juvenile hormone (Barthalmus and Zielinski, 1988). 

The antipsychotic effect is probably due to an antagonistic action at dopamine receptors. Aside from their main antipsychotic action, neuroleptics display additional actions owing to their antagonism at... 

Acute dystonias occur immediately after neuroleptization and are manifested by motor impairments, particularly in the head, neck, and shoulder region. After several days to months, a parkinsonian syndrome (pseudoparkinsonism) or akathisia (motor restlessness) may develop. All these disturbances can be treated by administration of antiparkin-son drugs of the anticholinergic type, such as biperiden (i.e., in acute dystonia). As a rule, these disturbances disappear after withdrawal of neuroleptic medication. Tardive dyskinesia may become evident after chronic neuroleptization for several years, particularly when the drug is discontinued. It is due to hypersensitivity of the dopamine receptor system and can be exacerbated by administration of anticholinergics. 

It also seems plausible that antipsychotic drugs competitively bind with dopamine receptors and block the action of dopamine on corresponding receptor sites, thus lowering psychotic activity. Central dopamine receptors are subdivided into Dj, D2, and according to some sources, Dj receptors. These receptors have a high affinity for dopamine, but they differ in sensitivity to neuroleptics of various chemical classes. For example, drugs of the phenothiazine series are nonselective competitive Dj and D2 antagonists. Unlike phenoth-iazines, antipsychotics of the butyrophenone series such as haloperidol display selective action only on D2 receptors. 

Neuroleptic malignant syndrome (NMS) is a rare, medication-induced syndrome that may be due to dopamine receptor blockade in the basal ganglia. An altered level of consciousness, autonomic instability, hyperthermia, and severe muscular rigidity typically... 

Staunton DA, Magistretti PJ, Shoemaker WJ, et al Effects of chronic lithium treatment on dopamine receptors in the rat corpus striatum, II no effect on denervation or neuroleptic-induced supersensitivity. Brain Res 232 401-412, 1982b... 

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