The role of α₂‐adrenoceptor antagonism in the anti‐cataleptic properties of the atypical neuroleptic agent, clozapine, in the rat

Abstract

1 The mechanism underlying the anticataleptic properties of the atypical neuroleptic agent, clozapine, has been investigated in the rat. 2 The close structural analogues of clozapine, loxapine (0.1 mg kg 71 s.c.) and iso-clozapine (1 and 3 mg kg 71 s.c.) induced catalepsy in rats. In contrast, clozapine and the regio-isomer of loxapine, isoloxapine (up to 10 mg kg 71 s.c.) did not produce catalepsy, but at a dose of 1 mg kg 71 signi®cantly inhibited catalepsy induced by loxapine (0.3 mg kg 71 s.c.). 3 Radioligand binding assays showed that cataleptogenic potential was most clearly predicted by the D 2 /5-HT 1A , D 2 /5-HT 1B/1D and D 2 /a 2 -receptor a nity (K D ) ratios: i.e. 30 ± 100-fold higher ratios were calculated for loxapine and iso-clozapine, whereas the ratios were less than 1 for clozapine and isoloxapine. The ratios of a nities for D 2 to 5-HT 2A , 5-HT 2C or D 1 did not re¯ect the grouping of cataleptic and non-cataleptic compounds. 4 Co-treatment with the a 2 -adrenoceptor antagonists, yohimbine (1 ± 10 mg kg 71 s.c.), RX 821002 (1 ± 10 mg kg 71 s.c.) and MK-912 (0.3 and 1 mg kg 71 s.c.) dose-dependently inhibited the cataleptic response to loxapine (0.3 mg kg 71 ). Yohimbine (1 ± 10 mg kg 71 s.c.) also dose-dependently inhibited the cateleptic response to haloperidol (0.3 mg kg 71 s.c.). The a 2 -adrenoceptor antagonists had no e ect per se. 5 Neither yohimbine (10 mg kg 71 ) nor RX821002 (3 mg kg 71 ) altered the cataleptic response to the D 1 receptor antagonist, SCH 23390 (1 mg kg 71 s.c.), while, like clozapine, both compounds abolished the response to the 5-HT 2A receptor antagonist, MDL 100,151 (3 mg kg 71 s.c.). 6 The present data strongly implicate a 2 -adrenoceptor blockade in the anticataleptic properties of clozapine and suggest that its lack of extrapyramidal side e ects in the clinic may also be a consequence of this property.

Contribution of a Mesocorticolimbic Subcircuit to Drug Context-Induced Reinstatement of Cocaine-Seeking Behavior in Rats

“…Furthermore, the effect of SCH23390 was anatomically specific to the OFC in that bilateral infusions of SCH23390 into the dorsally adjacent M1/2 region did not alter cocaine seeking (Figure 2d) similar to other reward-related motor behaviors in previous studies (Hosp et al, 2011;Luft and Schwarz, 2009;Molina-Luna et al, 2009). Although SCH23390 has been routinely used to ascertain the functional contribution of dopamine D1-like receptors, it also acts as a serotonin 5-HT 2C receptor agonist (Kalkman et al, 1998;Rupniak et al, 1986), and systemic 5-HT 2C receptor stimulation attenuates explicit cue-and context-induced Figure S1 for placement distribution) and retrogradely labeled cell bodies were quantified bilaterally in the areas identified on the schematics adapted from the rat brain atlas of Paxinos and Watson (1997). Numbers to the left of the schematics indicate the distance from bregma in millimeters.…”

Comparative Analysis of the Treatment of Chronic Antipsychotic Drugs on Epileptic Susceptibility in Genetically Epilepsy-prone Rats

“…However, clozapine is an antagonist with a high affinity at α2-adrenoceptors [66,85]; this mechanism may also be responsible for proconvulsant effects on audiogenic seizures in GEPRs, as previously described for other compounds acting on α2-adrenoceptors [86].…”

The Role of Serotonin in Antipsychotic Drug Action

“…Altar et al (1986) and Rasmussen and Aghajanian (1988) suggested that weak D 2 and potent 5-HT 2a receptor blockade was the basis for the ability of clozapine to cause low extrapyramidal side effects. However, other explanations for the low EPS of clozapine have been offered-namely its anticholinergic properties, lack of ability to increase acetylcholine in the striatum, D 1 and D 4 receptor blockade, and its effects as an ␣ 2 -adrenoceptor antagonist (Meltzer and Fatemi 1996;Parada et al 1997;Kalkman et al 1998). In order to test the role of 5-HT 2a receptor blockade, Meltzer et al (1989) studied a group of compounds which had antipsychotic activity in man or in animal models and which produced less EPS in man or weak catalepsy in animals.…”