Adjunctive α2-adrenoceptor blockade enhances the antipsychotic-like effect of risperidone and facilitates cortical dopaminergic and glutamatergic, NMDA receptor-mediated transmission

Abstract

Compared to both first- and second-generation antipsychotic drugs (APDs), clozapine shows superior efficacy in treatment-resistant schizophrenia. In contrast to most APDs clozapine possesses high affinity for alpha2-adrenoceptors, and clinical and preclinical studies provide evidence that the alpha2-adrenoceptor antagonist idazoxan enhances the antipsychotic efficacy of typical D2 receptor antagonists as well as olanzapine. Risperidone has lower affinity for alpha2-adrenoceptors than clozapine but higher than most other APDs. Here we examined, in rats, the effects of adding idazoxan to risperidone on antipsychotic effect using the conditioned avoidance response (CAR) test, extrapyramidal side-effect (EPS) liability using the catalepsy test, brain dopamine efflux using in-vivo microdialysis in freely moving animals, cortical N-methyl-D-aspartate (NMDA) receptor-mediated transmission using intracellular electrophysiological recording in vitro, and ex-vivo autoradiography to assess the in-vivo alpha2A- and alpha2C-adrenoceptor occupancies by risperidone. The dose of risperidone needed for antipsychotic effect in the CAR test was approximately 0.4 mg/kg, which produced 11% and 17% in-vivo receptor occupancy at alpha2A- and alpha2C-adrenoceptors, respectively. Addition of idazoxan (1.5 mg/kg) to a low dose of risperidone (0.25 mg/kg) enhanced the suppression of CAR, but did not enhance catalepsy. Both cortical dopamine release and NMDA receptor-mediated responses were enhanced. These data propose that the therapeutic effect of risperidone in schizophrenia can be enhanced and its EPS liability reduced by adjunctive treatment with an alpha2-adrenoceptor antagonist, and generally support the notion that the potent alpha2-adrenoceptor antagonistic action of clozapine may be highly important for its unique efficacy in schizophrenia.

Reboxetine Enhances the Olanzapine-Induced Antipsychotic-Like Effect, Cortical Dopamine Outflow and NMDA Receptor-Mediated Transmission

“…In addition, the prefrontal dopamine output induced by these APDs was markedly enhanced by idazoxan (Hertel et al, 1999;Marcus et al, 2009;Wadenberg et al, 2007). Furthermore, to a similar magnitude as that of clozapine, idazoxan enhanced the effects of both raclopride and risperidone on prefrontal NMDA receptor-mediated transmission, an effect that has been shown to be dopamine-dependent and executed through the dopamine D 1 receptor (Chen and Yang, 2002;Marcus et al, 2005Marcus et al, , 2009. The increased prefrontal availability of catecholamines induced by adjunctive treatment with idazoxan is probably due to a co-release of dopamine and norepinephrine that is controlled by a 2 -adrenoceptors located on norepinephrine nerve terminals (Devoto et al, 2001).…”

Brexpiprazole II: Antipsychotic-Like and Procognitive Effects of a Novel Serotonin-Dopamine Activity Modulator

“…Its target optimization included D 2 partial agonism with low intrinsic activity, 5-HT 1A partial agonism, and antagonism at 5-HT 2A , a 1B -and a 2C -adrenergic receptors (Maeda et al, 2014), supporting a favorable antipsychotic profile with low EPS risk and potential to treat core symptoms in schizophrenia, including cognitive deficits (Arnt and Skarsfeldt, 1998;Drouin et al, 2002;Marcus et al, 2010;Newman-Tancredi and Kleven, 2011;Sallinen et al, 2013).…”

Pharmacological Profile of 2-Bromoterguride at Human Dopamine D2, Porcine Serotonin 5-Hydroxytryptamine 2A, and α2C-Adrenergic Receptors, and Its Antipsychotic-Like Effects in Rats

“…In contrast to a 2A -adrenoceptors, which are widely distributed in the brain, a 2C -adrenoceptors are predominantly located in the striatum (Scheinin et al, 1994;Uhlén et al, 1997;Fagerholm et al, 2008). Animal experiments and clinical studies have demonstrated that the therapeutic effect of an antipsychotic drug can be enhanced by the addition of idazoxan or mirtazapine, drugs that block a 2C -and a 2A -adrenoceptors (Litman et al, 1996;Hertel et al, 1999;Wadenberg et al, 2007;Joffe et al, 2009;Marcus et al, 2010). Antipsychotics such as clozapine, olanzapine, risperidone, and quetiapine exhibited higher affinities for a 2C -over a 2A -adrenoceptors (Kalkman and Loetscher, 2003;Kroeze et al, 2003).…”