Effects of the 5‐HT3 receptor antagonist, GR38032F, on raised dopaminergic activity in the mesolimbic system of the rat and marmoset brain

1 The ability of the selective 5‐HT3 receptor antagonist GR38032F to reduce raised mesolimbic dopaminergic activity was studied in behavioural experiments in the rat and marmoset. 2 GR38032F injected into the nucleus accumbens (0.01–1 ng) or peripherally (0.01–1 mg kg−1 i.p.) inhibited the locomotor hyperactivity caused by the acute intra‐accumbens injection of amphetamine (10 μg) in the rat. Similar treatments with sulpiride and fluphenazine also inhibited the amphetamine‐induced hyperactivity. 3 The peripheral administration of GR38032F (0.001–0.1 mg kg−1 i.p., b.d.) during a 13 day period of dopamine infusion (25 μg 24 h−1) into the nucleus accumbens of the rat reduced the dopamine‐induced hyperactivity response to control (vehicle infused) levels. Locomotor activity remained at control levels after discontinuing the dopamine/GR38032F treatment regimen. 4 The hyperactivity caused by the infusion of dopamine into the rat nucleus accumbens was also inhibited by fluphenazine (0.01‐0.05 mg kg−1 i.p., b.d.), but locomotor activity was suppressed to levels below control values and a rebound hyperactivity occurred after discontinuation of the dopamine/fluphenazine treatment regimen. 5 The discontinuation of a concomitant 13 day intra‐accumbens infusion of dopamine with haloperidol, 0.01 mg kg−1 i.p. t.d.s., caused a rebound hyperactivity. This hyperactivity was suppressed by GR38032F (0.001‐0.1 mg kg−1 i.p.). 6 The unilateral infusion of dopamine (25 μg 24 h−1, 13 days) into the left amygdala of rats having right hemispheric dominance (as measured in a turn preference test) caused locomotor hyperactivity. Intraperitoneal administration of GR38032F (0.1–100 μg kg−1) or fluphenazine (0.025‐0.1 mg kg−1), and the intra‐amygdaloid injection of GR38032F (0.1–100 ng) or fluphenazine (25–500 pg), either into the infused or non‐infused side, inhibited the dopamine‐induced locomotor hyperactivity. 7 Marmosets receiving bilaterial infusions of dopamine (25 μg 24 h−1 for 13 days) into the nucleus accumbens also exhibited increased locomotor activity. GR38032F (0.1‐1.0 μg kg−1 t.d.s.), reduced the hyperactivity to control levels with no rebound hyperactivity following the discontinuation of the dopamine/GR38032F treatment regimen. Fluphenazine (0.01–2.5 mg kg−1 i.p., t.d.s.) also inhibited the hyperactivity, but locomotor activity was reduced to values below control levels and a rebound hyperactivity followed the discontinuation of the dopamine/fluphenazine treatment. 8 It