RU-24969 disrupts d-amphetamine self-administration and responding for conditioned reward via stimulation of 5-HT1B receptors.

Abstract

Behavioural and neurochemical evidence indicates a facilitatory effect of 5-hydroxytryptamine (5-HT), acting via 5-HT1B receptors, on dopamine (DA) systems. To explore this interaction further, these experiments examined the effects of the 5-HT1A/1B agonist RU-24969 on behaviours known to involve the mesolimbic DA system. These behaviours were locomotor activity, intravenous self-administration of d-amphetamine, responding for a conditioned reward (CR), and the response potentiating effects of amphetamine on CR responding. Locomotor activity was enhanced by 1 and 3 mg/kg RU 24969, and both doses also reduced responding for d-amphetamine (60 microg/kg/infusion). Changing the unit dose produced a characteristic U-shaped dose-response curve. This dose-response relationship was not apparent following injection of RU-24969. Across all unit infusion doses of amphetamine, the level of responding was fairly constant. In the CR experiments, rats responded for a conditioned stimulus that was previously paired with water. RU-24969 completely disrupted responding for CR, and also abolished CR responding in rats injected with 3 microg d-amphetamine in the nucleus accumbens. RU-24969 also markedly suppressed responding for water. The suppressant actions of RU-24969 on amphetamine self-administration and CR responding involve stimulation of 5-HT1B receptors, since they were reversed by the 5-HT1B/1D antagonist GR 127935 (3 mg/kg), but not by the 5-HT1A antagonist WAY-100635 (1 mg/kg). None of the behavioural effects of RU-24969 are consistent with a selective action to enhance mesolimbic DA function. Rather, global activation of 5-HT1B receptors appear to exert a general disruptive effect on operant responding.