Haloperidol, but not clozapine, produces dramatic catalepsy in Δ9‐THC‐treated rats: possible clinical implications

The effect on rat catalepsy induced by Δ9-tetrahydrocannabinol (Δ9-THC) in association with haloperidol (HP) or clozapine (CLOZ) administration was investigated. Δ9-THC dose-dependently increased HP (0.05–1 mg kg−1, s.c.)-induced rat catalepsy, while no catalepsy was observed after CLOZ (1–20 mg kg−1, s.c.) or Δ9-THC+CLOZ administration. The CB1 antagonist SR141716A (0.5–5 mg kg−1, i.p.) reversed the increase mediated by Δ9-THC on HP-induced catalepsy. The D2 agonist quinpirole completely reversed the catalepsy induced by both HP and HP+Δ9-THC; however, higher doses of quinpirole were needed in the presence of Δ9-THC. The M1 antagonist scopolamine and α2 antagonist yohimbine were able to reduce the catalepsy induced by HP and HP+Δ9-THC in a similar manner. CLOZ and the 5-HT2A/2C antagonists ritanserin, RS102221 and SB242084 were more effective in antagonizing HP than HP+Δ9-THC-induced catalepsy. HP and CLOZ failed to inhibit in vitro [3H]CP-55,940 binding, while Δ9-THC and SR141716A did not show an appreciable affinity for the D2 receptor. It was suggested that the different effects on rat catalepsy induced by Δ9-THC following HP or CLOZ administration may depend on the receptor-binding profiles of the two antipsychotics. The preferential use of CLOZ rather than HP in the treatment of psychotic symptoms in cannabis abusers was discussed. Keywords: Antipsychotic, bar test, extrapyramidal symptoms, serotonin Introduction Considerable research has indicated that cannabis use may precipitate psychosis-like symptoms among vulnerable individuals. Moreover, it has been shown that cannabis use increases the risk of relapse, as well as worsens and prolongs the psychotic symptoms among patients who have already developed the disorder (for review, see Degenhardt & Hall, 2002). Antipsychotic drugs are largely employed in the management of schizophrenia and other psychotic disorders; however, a possible interaction between cannabis and antipsychotic administration has not been adequately investigated. Depending on their pharmacological properties, the antipsychotics currently used in clinical practice are divided into conventional antipsychotics, such as haloperidol (HP), and atypical antipsychotics, such as clozapine (CLOZ). The clinical improvements observed in patients treated with conventional antipsychotics are often accompanied by the appearance of extrapyramidal side effects (EPS), such as akinesia, rigidity and tremors. The blockade of the dopamine D2 receptor in the basal ganglia has been associated with the development of EPS (Kapur & Remington, 2001). Atypical antipsychotics are able, in different grades, to antagonize the striatal dopamine D2 receptor at therapeutic doses; however, they have shown low or no propensity to induce EPS (Tarsi et al., 2002). Depending on which author is being read, this peculiarity of atypical antipsychotics was associated with a favorable D2/M1 (Haraguchi et al., 1997), D2/5-HT2A/2C (Meltzer et al., 1989; Reavill et al., 1999), or D2/α2 receptor antagonism ratio (Kalkman et al., 1998). It was, indeed, hypothesized that a receptor-binding profile similar to that observed for CLOZ might counteract the dopamine D2 receptor blockade effect in the basal ganglia, leading to a reduced incidence of EPS. Like D2 receptor blockade, cannabinoid CB1 receptor stimulation is known to affect motor activity. Consistently, several researches involving volunteers given CB1 agonists in the laboratory showed impairment in a variety of motor tasks (Yesavage et al., 1985; Wilson et al., 1994). In rats, dose-dependent ataxia and catalepsy were observed after the systemic administration of cannabinoids (Chaperon & Thiebot, 1999). Furthermore, cannabinoid agonists microinjected into the striatum produced rat immobility (Gough & Olley, 1978). Within the central nervous system, the D2 and CB1 receptors are densely expressed in the basal ganglia (Herkenham et al., 1991), and colocalization between the two receptors has been indicated in the rat striatum (Hermann et al., 2002). In a previous study, Anderson et al. (1996) showed that the cannabinoid agonist CP-55,940 exacerbated the catalepsy induced by the D2 receptor antagonist raclopride. The aim of the present study was to determine the effect of HP or CLOZ on rat catalepsy following the administration of Δ9-tetrahydrocannabinol (Δ9-THC), the most psychoactive component of marijuana.