Effects of neuroleptics on phencyclidine (PCP)-induced locomotor stimulation in mice

Pharmacological and Behavioral Profile of N-(4-Fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl) Carbamide (2 R,3 R)-Dihydroxybutanedioate (2:1) (ACP-103), a Novel 5-Hydroxytryptamine2A Receptor Inverse Agonist

“…To extend the antipsychotic-like behavioral profile beyond direct 5-HT 2A receptor interactions, ACP-103 attenuated hyperactivity induced by the noncompetitive NMDA antagonist MK-801, with a minimal effective dose of 0.1 mg/kg s.c. or 3 mg/kg p.o. These effects are consistent with previous reports that other 5-HT 2A receptor antagonists and inverse agonists, as well as atypical antipsychotics, have been shown to reduce MK-801-and phencyclidine-induced behavioral effects (Freed et al, 1984;Carlsson et al, 1999b;Weiner et al, 2001;Vanover et al, 2004).…”

“…To extend the antipsychotic-like behavioral profile beyond direct 5-HT 2A receptor interactions, ACP-103 was tested for its ability to attenuate hyperactivity induced by the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 (dizocilpine maleate). Blockade of NMDA antagonist-induced hyperactivity is predictive of antipsychotic-like efficacy (Freed et al, 1984). It was hypothesized that ACP-103 would attenuate DOI-induced head twitches and PPI deficits as well as MK-801-induced hyperactivity.…”

Pharmacological Characterization of AC-90179 [2-(4-Methoxyphenyl)-N-(4-methyl-benzyl)-N-(1-methyl-piperidin-4-yl)-acetamide Hydrochloride]: A Selective Serotonin 2A Receptor Inverse Agonist

“…Similarly, in the present study, clozapine and haloperidol attenuated phencyclidineinduced hyperactivity. These effects are consistent with previous reports that the selective 5-HT 2A receptor antagonist M100907 {R(ϩ)-␣-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol}, less selective 5-HT 2 receptor antagonists, such as ketanserin and ritanserin, as well as atypical antipsychotics, such as clozapine and olanzapine, have been shown to reduce dizocilpine-and phencyclidineinduced behavioral effects (Freed et al, 1984;Corbett et al, 1995;Maurel-Remy et al, 1995;Gleason and Shannon, 1997;Ninan and Kulkarni, 1998;Carlsson et al, 1999b;Millan et al, 1999;O'Neill and Shaw, 1999). Haloperidol has been reported to block dizocilpine-and phencyclidine-induced locomotion only at doses that decreased spontaneous activity (Gleason and Shannon, 1997;Vanover, 1997;O'Neill and Shaw, 1999), consistent with the present findings.…”

Dopamine is not Required for the Hyperlocomotor Response to NMDA Receptor Antagonists

“…However, our findings contrast with some studies that demonstrate a requirement for dopamine in mediating the effects of NMDA receptor antagonists. For example, dopamine receptor antagonists have been shown to reduce the locomotor stimulatory effects of PCP and MK-801 (Sturgeon et al, 1981;Freed et al, 1984;Lapin and Rogawski, 1995). Also, 6-OHDA lesions can block NMDA receptor antagonist-induced behaviors (French and Vantini, 1984;French et al, 1985;Steinpreis and Salamone, 1993).…”

“…Systemic administration of NMDA receptor antagonists results in an increase in both dopamine and glutamate efflux in limbic brain regions such as the nucleus accumbens (NAc) and prefrontal cortex, presumably through a disinhibitory mechanism (Imperato et al, 1990;Miller and Abercrombie, 1996;Adams and Moghaddam, 1998). Systemically administered PCP increases the firing rate of dopaminergic neurons (Freeman and Bunney, 1984;French et al, 1993), and dopamine receptor antagonists, including antipsychotic drugs such as haloperidol and clozapine, attenuate PCP-induced stereotypies and locomotion (Sturgeon et al, 1981;Freed et al, 1984). Finally, PCP-induced hyperlocomotion can be reversed by 6-hydroxydopamine (6-OHDA) lesions of the NAc (French and Vantini, 1984;French et al, 1985;Steinpreis and Salamone, 1993).…”