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

Abstract

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.

The Selective Serotonin2A Receptor Antagonist, MDL100,907, Elicits a Specific Interoceptive Cue in Rats

“…Second, the training dose of MDL100,907, as well as the Effective Dose 50 for its "auto-generalization", were low. These doses correspond well to actions of MDL100,907 in other models of 5-HT 2A receptor-mediated responses: notably, inhibition of a DOI-induced DS, blockade of DOI-induced head-twitches and antagonism of hyperlocomotion elicited by phencyclidine (Schreiber et al 1994(Schreiber et al , 1995aMillan et al 1999a). At these doses, MDL100,907 does not exert significant action in functional models of 5-HT 2C receptor-mediated activity (Millan et al 1997;Dekeyne et al 1999).…”

“…from saline in operant conditioning chambers equipped with two levers. The training dose was selected in light of the ability of MDL100,907 to abolish actions mediated by 5-HT 2A receptors in other paradigms without exerting significant effects at other receptors (Schreiber et al 1994(Schreiber et al , 1995aMillan et al 1999a;Gobert et al 2000).…”

Repeated antipsychotic treatment progressively potentiates inhibition on phencyclidine-induced hyperlocomotion, but attenuates inhibition on amphetamine-induced hyperlocomotion: Relevance to animal models of antipsychotic drugs

“…vehicle, olanzapine or chlordiazepoxide) as the between-subjects variable and test days as the within-subjects variable revealed a significant main effect of "Days" (F (4,72) = 3.139, P = 0.019) and a significant main effect of "Treatment" (F (2,18) = 22.052, P < 0.001), but no significant "Treatment" × "Days" interaction (F (8,72) = 0.967, P = 0.469). Repeated treatment of olanzapine and chlordiazepoxide significantly inhibited amphet- Shannon, 1997;Millan et al, 1999). Depletion of 5-HT in the nucleus accumbens by parachloroamphetamine abolishes phencyclidineinduced hyperlocomotion (Millan et al, 1999).…”

Clozapine and Haloperidol Differently Suppress the MK-801-Increased Glutamatergic and Serotonergic Transmission in the Medial Prefrontal Cortex of the Rat

“…Furthermore, the behavioral deficits observed in humans and rodents are distinctly responsive to clozapine (Bakshi et al, 1994;Maurel-Remy et al, 1995;Malhotra et al, 1997). Acute NMDA receptor antagonism has also been reported to increase the release of glutamate (Moghaddam et al, 1997;Adams and Moghadam, 2001;Lorrain et al, 2003), dopamine (Moghaddam and Adams, 1998;Mathé et al, 1999;Schmidt and Fadayel, 1996), and serotonin (5-HT) (Martin et al, 1998;Millan et al, 1999;Adams and Moghadam, 2001;Amargós-Bosch et al, 2006) in the medial prefrontal cortex (mPFC) of rats. These effects are coincident with an enhanced spontaneous firing rate of putative pyramidal neurons of the mPFC (Suzuki et al, 2002;Jackson et al, 2004).…”