Contrasting mechanisms of action and sensitivity to antipsychotics of phencyclidine versus amphetamine: importance of nucleus accumbens 5-HT2A 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 selecti ve serotonin (5-HT)(2A) vs. D-2 antagonists, SR46349, MDL100,907, ritanseri n and fananserin, which barely affected amphetamine-induced locomotion (ALO C). In contrast, the selective D-2 vs. 5-HT2A antagonists, eticlopride, rac lopride and amisulpride, preferentially inhibited ALOC vs. PLOC. The potenc y of these drugs and 12 multireceptorial antipsychotics in inhibiting PLOC vs. ALOC correlated significantly with affinities at 5-HT2A vs. D-2 recepto rs, respectively. Amphetamine and PCP both dose dependently increased dialy sate levels of dopamine (DA) and 5-HT in the nucleus accumbens, striatum an d frontal cortex (FCX) of freely moving rats, but PCP was proportionally mo re effective than amphetamine in elevating levels of 5-HT vs. DA in the acc umbens. 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 abo lished by SR46349 and clozapine. Parachloroamphetamine, which depleted accu mbens pools of 5-HT but not DA, likewise abolished PLOC without affecting A LOC. In contrast, intra-accumbens 6-hydroxydopamine (6-OHDA), which deplete d DA but not 5-HT, abolished ALOC but only partially attenuated PLOC. In co nclusion, PLOC involves (indirect) activation of accumbens-localized 5-HT2A receptors by 5-HT. PLOC is, correspondingly, more potently blocked than AL OC by antipsychotics displaying marked affinity at 5-HT2A receptors.