Silicone pellets containing d-amphetamine base were implanted subcutaneously in rats. These pellets release amphetamine continuously for at least 10 days. Several days after implantation, swollen dopamine axons concomitant with large decreases in tyrosine hydroxylase activity were observed in the caudate nucleus. Decreased tyrosine hydroxylase activity was still present 110 days after pellet removal in the caudate but not in several other brain regions, nor in the caudate of rats injected with an equivalent amount of amphetamine in daily injections. This implies that continuous amphetamine administration has a selective neurotoxic effect on dopamine terminals in the caudate.

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Members of the series of title compounds were tested for potential antipsychotic activity in relevant receptor binding assays and behavioral screens. Structure-activity relationships within the series are discussed. Compound 24 (BMY 13859-1), a (1,2-benzisothiazol-3-yl)piperazine derivative, was selected for further study because of its potent and selective profile in primary CNS tests. It was active in the Sidman avoidance paradigm and blocked amphetamine-induced stereotyped behavior in dogs for up to 7 h. The compound's lack of typical neuroleptic-like effects in the rat catalepsy test and its failure to produce dopamine receptor supersensitivity following chronic administration indicate that it should not cause the movement disorders commonly associated with antipsychotic therapy. Although 24 has potent affinity for dopaminergic binding sites, its even greater affinity for serotonin receptors suggests that a serotonergic component may be relevant to its atypical profile. Compound 24 is currently undergoing clinical evaluation in schizophrenic patients.

SynopsisWhen amphetamines are administered to humans every few hours for several days, either during the ‘speed runs’ of addicts or in controlled laboratory settings, the psychosis which reliably results is similar to paranoid schizophrenia in a number of important aspects. This unique regimen of drug intake, which involves the continuous presence of stimulants over a prolonged period of time, can be simulated in animals using subcutaneously implanted slow-release silicone pellets containing d-amphetamine base. Monkeys and rats implanted with these pellets develop stages of behavioural alterations which are somewhat similar in sequence to those observed in humans who have received frequent doses of amphetamine. An initial period of hyperactivity and exploratory behaviour is followed by the gradual development of motor stereotypies which become virtually incessant. A period of relative inactivity then appears which is followed, at 4–5 days after pellet implantation, by a late stage. This final stage is characterized by ‘wet-dog’ shakes, parasitotic-like grooming episodes, and a variety of other forms of hallucinatory-like behaviour. At about the same time there are distinctive and partially irreversible alterations in dopaminergic innervations of the caudate nucleus, but not in mesolimbic dopamine innervation of the nucleus accumbens or in several other neurotransmitter systems. Continuous amphetamine administration may reproduce some aspects of the prolonged excitation which accompanies an acute psychotic episode and may be a fruitful model for the clarification of the dopamine theory of schizophrenia.