Dopamine D-1 and D-2 receptors can be labelled selectively by using 3H-SCH 23390 and 3H-Spiperone as ligands, respectively. Neuroleptics are divided into different groups according to their affinity for D-1 and D-2 receptors. Thioxanthenes have comparable affinities for D-1 and D-2 receptors. Phenothiazines have higher affinity for D-2 than for D-1 receptors. Butyrophenones, diphenylbutylpiperidines and substituted benzamides are almost selective inhibitors of D-2 receptors. The affinity of neuroleptics for several other receptor types is mentioned. The use of the receptor binding technique in diseased schizophrenics is discussed. In vivo receptor binding in vitro and ex vivo receptor autoradiography and PET scanning are discussed as alternative methods to evaluate neuroleptics, clinical outcome and treatment strategies.

Animals↗

PubMedDate not supplied

Behavioural correlates to the dopamine D-1 and D-2 antagonists.

The acute dopamine (DA) receptor blockade of neuroleptics can be demonstrated in mice by antagonism of stereotypies induced by the DA-agonist methylphenidate and in rats by antagonism of stereotypies induced by the DA-agonists amphetamine or apomorphine. Neuroleptics such as the thioxanthene, cis(Z)-flupentixol, the phenothiazine, fluphenazine, the butyrophenone, haloperidol and the benzamide clebopride are equipotent behaviourally as well as clinically. Also the D-1 receptor-antagonist SCH 23390 has the same pharmacological effects. In a series of experiments where the methylphenidate-induced stereotyped gnawing in mice was inhibited by neuroleptics it was shown that the effect of butyrophenones was greatly attenuated by concomitant treatment with scopolamine and diazepam. Similar results were obtained in rats experiments. The effect of phenothiazines was less influenced and that of thioxanthenes and SCH 23390 remained nearly unchanged. Besides, a clear differentiation of these drugs was seen when they were tested in mice rendered supersensitive by 12 days treatment with different neuroleptics. In the withdrawal phase the decrease effects against methylphenidate were shown by increased ED50 values for methylphenidate antagonism and an increased response to methylphenidate. The thioxanthenes and SCH 23390 retained the ability to antagonize the stereotyped gnawing, the phenothiazines showed a reduced effect, whereas the butyrophenones showed both tolerance and cross tolerance to the stereotyped behaviour. This behavioural classification of neuroleptics into three different groups is comparable with the classification obtained by DA-receptor binding techniques in vitro.

Adenylyl Cyclases↗

PubMedDate not supplied

Prolonged treatment with the specific 5-HT-uptake inhibitor citalopram: effect on dopaminergic and serotonergic functions.

The effect of prolonged administration of the clinically effective and specific serotonin (5-HT)-uptake-inhibitor, citalopram, has been studied in rats on behavioural measures of dopaminergic (DA) and serotonergic activity and on DA D-2, 5-HT2, alpha 1- and beta-adrenergic receptor number and affinity in vitro. Thirteen days treatment with citalopram in the diet (40 mg/kg/day) did not change receptor binding for either of the ligands studied, although citalopram was detected in high concentrations in brain and plasma and induced a 75% depletion of 5-HT in whole blood. This citalopram dose-regimen was followed by a potentiated hypermotility response to d-amphetamine. Also DA-dependent hypermotility induced by methylphenidate and (+)-3-PPP was increased. In contrast, the 5-HT2-receptor mediated head shake syndrome induced by 1-5-HTP or quipazine was decreased after prolonged citalopram treatment. Two weeks oral bolus treatment (10 mg/kg once or twice daily) with the 5-HT-uptake-inhibitors citalopram, fluoxetine, zimelidine, cyanimipramine or paroxetine induced d-amphetamine potentiation, whereas amitriptyline, nortriptyline, imipramine, iprindole, and mianserin treatment showed no effect. It is suggested that d-amphetamine potentiation induced by citalopram is mainly dependent on DA mechanisms, and that this profile is characteristic for preferential 5-HT-uptake-inhibitors. The lack of correlation between behavioural effect and receptor changes was important. Since citalopram has been shown to have clinical antidepressant activity, it is concluded that down-regulation of beta-adrenoceptors is not a prerequisite for antidepressant action.

Animals↗