Search

Combined treatment with (-)-sulpiride plus a low dose of the D1 receptor antagonist SCH 23390, unlike (-)-sulpiride given alone, blocked rat striatal dopaminergic transmission. Five days after the withdrawal of 21-day repeated administration of the combined treatment, no increase in apomorphine-induced stereotyped behaviour was observed. The results suggest that the combination of a D2 blocker and a low dose of a D1 blocker produces a wider spectrum of neuroleptic activity without an overt risk of inducing dopaminergic behavioural supersensitivity.

The atypical neuroleptic sulpiride is also prescribed for depression because of its activating effect. However, such an effect does not necessarily imply an action identical to that of classical antidepressants, and a laboratory comparison of the neuroleptic and antidepressant activities of sulpiride may contribute to a better definition of its psychotherapeutic profile. Sulpiride isomers were studied in the rat in four behavioural models of depression which are thought to be influenced by neuroleptics in different ways. Desipramine (imipramine) and haloperidol were employed in each test as a standard antidepressant and neuroleptic, respectively. The four tests were: 1) prevention of apomorphine-induced sedation: 2) antagonism of apomorphine-induced hypothermia; 3) behavioural despair (swim test); 4) learned helplessness ( FR2 lever pressing escape). Desipramine ameliorated behaviour in all tests; haloperidol ameliorated the response to test 1, influenced that to test 2 in a neuroleptic-like way and worsened the responses to tests 3 and 4. (-)-Sulpiride worked in a similar way to haloperidol in all tests. (+)-Sulpiride significantly and dose-dependently ameliorated the responses to test 3 and was inactive in the others. No conclusion was drawn from test 1 owing to its lack of specificity; the results of the remaining tests indicated a neuroleptic profile of (-)-sulpiride and suggested a potential "antidepressant" activity of (+)-sulpiride which merits further investigation.

A critical dose of apomorphine (300 micrograms/kg SC) given immediately before placing rats into a novel environment produced a diphasic motility response (initial sedation followed by enhanced locomotion). Various neuroleptics having different clinical and/or pharmacological profiles were studied by using such a model. (-)-Sulpiride and sultopride preferentially antagonized apomorphine inhibition; haloperidol and tiapride antagonized both phases of apomorphine response at similar doses; chlorpromazine, fluphenazine, thioridazine, metoclopramide and SCH 23390 preferentially antagonized apomorphine stimulation. The results are discussed in terms of the dopamine receptor subtypes involved in the two phases of apomorphine effect. Apomorphine stimulation can be antagonized by D-1 as well as D-2 receptor blockade. A higher affinity for D-2 receptors seems a necessary requisite for the antagonism of apomorphine inhibition; moreover, the ability of neuroleptics to antagonize apomorphine inhibition seems to depend on the ratio of their presynaptic versus postsynaptic D-2 activity.

The selective D1 receptor stimulant SKF 38393 dose-dependently increased grooming time in rats without affecting locomotor activity or eliciting stereotyped behaviour. The selective D2 receptor agonist LY 171555 induced a dose-dependent increase in rat motility, a marked decrease in grooming time and a low occurrence of stereotyped behaviour. Concurrent administration of the two selective agonists induced high-degree stereotyped responses and reductions in locomotor and grooming behaviours. Rats withdrawn from repeated treatment with the selective D1 receptor blocker SCH 23390 (0.05 mg/kg twice daily for 21 days; 7 days of washout) did not exhibit any change of locomotor and grooming responses to threshold doses of LY 171555 and SKF 38393 given alone or in combination. On the contrary, a significantly greater occurrence of high-degree stereotyped responses to the combination of the two selective agonists was observed. The data support the view that D1 and D2 receptors have a cooperative role in the generation of stereotypies and suggest that D1 receptor supersensitivity needs D2 stimulation to be revealed.

This study proposes a method capable of separating the pharmacodynamic from the pharmacokinetic component in the methamphetamine (MA) hyperactivity potentiation induced by antidepressants. Several antidepressants and neuroleptics, other centrally-acting drugs and the inhibitor of hepatic drug metabolism SKF 525-A were studied. The motility counts taken between 10 and 20 min after MA injection were considered as an index of pharmacodynamic interaction and the whole duration of the hyperactivity syndrome as an index of pharmacokinetic interaction. The duration of MA effect was prolonged by some of the drugs studied and left unchanged by the others regardless of their clinical classification. On the contrary, our evaluation of the intensity of MA effect produced a sharp differentiation between classical neuroleptics and typical antidepressants: the former antagonized and the latter potentiated MA peak intensity. Only the D-2 blocking neuroleptics sulpiride and tiapride potentiated MA intensity. Regarding the specificity of our model, none of the compounds known to be devoid of clinical antidepressant or antipsychotic activity interacted with MA in such a way as to be included in either category. As to the sensitivity of the test, two “false negatives” were obtained: the neuroleptic clozapine and the antidepressant mianserin. Such exceptions were discussed taking into account their peculiar mechanisms of action.

Rats were treated for 21 days with the selective D-1 blocker SCH 23390 (0.1 mg/kg SC). Threshold doses of apomorphine for hypermotility (0.15 mg/kg SC) and for stereotyped response (0.25 mg/kg SC) were given 7, 21, 35, and 77 days after discontinuation of the chronic treatment. The rats always showed enhanced stereotyped response to the higher dose of apomorphine but never any change in their motility response to the lower dose of dopamine agonist. This finding may represent a behavioral correlate of the reported supersensitivity of D-1 receptors induced by SCH 23390.

The present work proposes a simple behavioral method for studying the ability of certain neuroleptics to block preferentially dopamine receptors subserving sedation. The model is based on the temporally biphasic motor response induced in rats by a single critical dose of apomorphine. It was chosen from a preliminary apomorphine dose-response study which showed that the same doses between 6.25 and 625 micrograms/kg affected rat motility differently according to whether the animals were "naive" or "familiarized" to the apparatus for 90 min before administering the drug. When the motility response of naive rats to 300 micrograms/kg of apomorphine was recorded immediately after SC injection, an initial (1--5 min) inhibition and a subsequent (20--45 min) stimulation of motility were obtained. (--)-Sulpiride (1.25--50 mg/kg) was found to be approximately 6-fold more effective in counteracting the apomorphine inhibition than stimulation of locomotion. Haloperidol (0.005--0.1 mg/kg) incompletely antagonized apomorphine inhibition and markedly blocked stimulation, which suggests that it has no preferential activity on dopamine receptors subserving sedation. The results were in accordance with those obtained by other authors with different paradigms, and indicated that the time course of the rat motility response to a single dose of apomorphine may constitute a useful model for detecting selective influences on different dopamine receptors.

Several studies have indicated that the D2 dopamine receptors mediate the antidopaminergic activity of the neuroleptics; nevertheless, the selective blocker (-)-sulpiride weakly inhibits dopamine-mediated behaviour. The present study investigated whether the concomitant injection of doses of the D1 antagonist SCH 23390, which by themselves are without effect, would enable (-)-sulpiride to express fully neuroleptic activity in the rat. The benzamide YM 09151-2 that strongly inhibits dopamine-mediated behaviour was also studied. Rats receiving different doses of (-)-sulpiride, YM 09151-2 and SCH 23390 given alone or in combination were tested for exploratory activity, apomorphine-induced stereotyped behaviour and hyperactivity elicited by the D2 agonist LY 171555. When given alone, (-)-sulpiride (10, 20 and 40 mg/kg IP) had no effect on exploratory activity and stereotypy. When (-)-sulpiride was administered in combination with an ineffective dose of SCH 23390 (5 micrograms/kg) both responses were significantly inhibited. The combined administration of subthreshold doses of (-)-sulpiride (2.5 mg/kg) and SCH 23390 (2.5 micrograms/kg) significantly inhibited hypermotility induced by LY 171555. Moreover, the combined administration of ineffective doses of YM 09151-2 with subthreshold doses of SCH 23390 strongly inhibited all the behavioural responses. The results indicate that SCH 23390 allowed (-)-sulpiride to exhibit a wider spectrum of neuroleptic activity and potentiated the antidopaminergic activity of YM 09151-2.