Contrasting mechanisms of action and sensitivity to antipsychotics of phencyclidine versus amphetamine: importance of nucleus accumbens 5‐HT 2A sites for PCP‐induced locomotion in the rat

In the present study, the comparative mechanisms of action of phencyclidine (PCP) and amphetamine were addressed employing the parameter of locomotion in rats. PCP‐induced locomotion (PLOC) was potently blocked by the selective serotonin (5‐HT) 2A vs. D 2 antagonists, SR46349, MDL100,907, ritanserin and fananserin, which barely affected amphetamine‐induced locomotion (ALOC). In contrast, the selective D 2 vs. 5‐HT 2A antagonists, eticlopride, raclopride and amisulpride, preferentially inhibited ALOC vs. PLOC. The potency of these drugs and 12 multireceptorial antipsychotics in inhibiting PLOC vs. ALOC correlated significantly with affinities at 5‐HT 2A vs. D 2 receptors, respectively. Amphetamine and PCP both dose dependently increased dialysate levels of dopamine (DA) and 5‐HT in the nucleus accumbens, striatum and frontal cortex (FCX) of freely moving rats, but PCP was proportionally more effective than amphetamine in elevating levels of 5‐HT vs. DA in the accumbens. Further, whereas microinjection of PCP into the accumbens elicited locomotion, its introduction into the striatum or FCX was ineffective. The action of intra‐accumbens PCP, but not intra‐accumbens amphetamine, was abolished by SR46349 and clozapine. Parachloroamphetamine, which depleted accumbens pools of 5‐HT but not DA, likewise abolished PLOC without affecting ALOC. In contrast, intra‐accumbens 6‐hydroxydopamine (6‐OHDA), which depleted DA but not 5‐HT, abolished ALOC but only partially attenuated PLOC. In conclusion, PLOC involves (indirect) activation of accumbens‐localized 5‐HT 2A receptors by 5‐HT. PLOC is, correspondingly, more potently blocked than ALOC by antipsychotics displaying marked affinity at 5‐HT 2A receptors.