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

Eur J Neurosci. 1999 Dec;11(12):4419-32. doi: 10.1046/j.1460-9568.1999.00858.x.


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. D2 antagonists, SR46349, MDL100,907, ritanserin and fananserin, which barely affected amphetamine-induced locomotion (ALOC). In contrast, the selective D2 vs. 5-HT2A 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-HT2A vs. D2 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-HT2A receptors by 5-HT. PLOC is, correspondingly, more potently blocked than ALOC by antipsychotics displaying marked affinity at 5-HT2A receptors.

Publication types

  • Comparative Study

MeSH terms

  • Amphetamine / metabolism
  • Amphetamine / pharmacology*
  • Animals
  • Antipsychotic Agents / pharmacology*
  • Area Under Curve
  • Binding, Competitive / drug effects
  • Corpus Striatum / drug effects
  • Corpus Striatum / physiology
  • Dopamine / metabolism
  • Dose-Response Relationship, Drug
  • Drug Antagonism
  • Frontal Lobe / drug effects
  • Frontal Lobe / physiology
  • Locomotion / drug effects
  • Locomotion / physiology
  • Male
  • Microdialysis
  • Motor Activity / drug effects*
  • Motor Activity / physiology*
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / physiology
  • Phencyclidine / antagonists & inhibitors*
  • Phencyclidine / metabolism
  • Rats
  • Rats, Wistar
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Dopamine D2 / drug effects
  • Receptors, Dopamine D2 / physiology
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin / physiology*
  • Serotonin / metabolism


  • Antipsychotic Agents
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Dopamine D2
  • Receptors, Serotonin
  • Serotonin
  • Amphetamine
  • Phencyclidine
  • Dopamine