Clinical studies suggest that adjunct galantamine may improve negative and cognitive symptoms in schizophrenia. These symptoms may be related to impaired dopaminergic function in the prefrontal cortex. Indeed, galantamine has been shown to increase dopamine release in vitro. Galantamine is an allosteric modulator of nicotinic acetylcholine receptors (nAChRs) and, at higher doses, an acetylcholine esterase (AChE) inhibitor. We have previously shown that nicotine, through stimulation of nAChRs in the ventral tegmental area (VTA), activates midbrain dopamine neurons and, hence, potentiation of these receptors could be an additional mechanism by which galantamine can activate dopaminergic pathways. Therefore, the effects of galantamine (0.01-1.0 mg/kg s.c.) on dopamine cell firing were tested in anaesthetized rats. Already at a low dose, unlikely to result in significant AchE inhibition, galantamine increased firing activity of dopaminergic cells in the VTA. The effect of galantamine was prevented by the nAChR antagonist mecamylamine (1.0 mg/kg s.c.), but not the muscarinic receptor antagonist scopolamine (0.1 mg/kg s.c.), and it was not mimicked by the selective AChE inhibitor donepezil (1.0 mg/kg s.c.). Our data thus indicate that galantamine increases dopaminergic activity through allosteric potentiation of nAChRs. Galantamine's effect was also prevented by the a7 nAChR antagonist methyllycaconitine (6.0 mg/kg i.p.) as well as the N-methyl-Daspartate antagonist CGP39551 (2.5 mg/kg s.c.), indicating a mechanism involving presynaptic facilitation of glutamate release. In parallel microdialysis experiments, galantamine was found to increase extracellular levels of dopamine in the medial prefrontal cortex. These results may have bearing on the enhancement of negative and cognitive symptoms in schizophrenia.

These preclinical data suggest that asenapine may exhibit highly potent antipsychotic activity with very low EPS liability. Its ability to increase both dopaminergic and glutamatergic activity in rat mPFC suggests that asenapine may possess an advantageous effect not only on positive symptoms in patients with schizophrenia, but also on negative and cognitive symptoms.

Adjunctive treatment with the selective alpha2 adrenoceptor antagonist idazoxan augments the effect of conventional antipsychotics in treatment-resistant schizophrenics comparing favourably with clozapine. Clozapine has high affinity for alpha2 adrenoceptors. Previously, we found that adjunctive idazoxan treatment to the dopamine (DA) D2/3 antagonist raclopride enhanced raclopride-induced effects in an animal model of antipsychotic activity (conditioned avoidance response, CAR) and, similarly to clozapine, reversed the disruption of working memory induced by N-methyl-D-aspartate receptor blockade in rats with a concomitant increase in prefrontal DA efflux. To further investigate the significance of alpha2 adrenoceptor affinity for antipsychotic efficacy, we here investigated, in rats, the effects of adjunctive idazoxan treatment to low doses of a typical (haloperidol) and an atypical (olanzapine) antipsychotic drug, both lacking appreciable alpha2 adrenoceptor affinity, on (i) CAR; (ii) catalepsy; and (iii) DA output in the prefrontal cortex and the nucleus accumbens using microdialysis. Adjunctive treatment with idazoxan to haloperidol or olanzapine enhanced suppression of CAR to a level predicting sufficient antipsychotic activity, increased DA output preferentially in the prefrontal cortex, and reversed haloperidol-induced catalepsy. Our data confirm and extend our previous findings as well as clinical observations, and suggest that adjunctive alpha2 adrenoceptor blockade both typical and atypical antipsychotic drugs, lacking appreciable affinity for the alpha2 adrenoceptor, may contribute to a more advantageous therapeutical profile of these drugs in schizophrenia treatment, allowing for reduced DA D2 occupancy and reduction of unwanted side-effects.

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.

We have previously observed that addition of an (see Carlsson 1988; Farde et al. 1988). However, while being efficient in ameliorating positive symptoms, most of the typical antipsychotic drugs exhibit only a limited efficacy on, and may even exacerbate, negative symptoms in schizophrenia (Carpenter 1996). In addition, since clinically adequate dosage of (Farde et al. 1992). In contrast to the clinical profile of typical D 2 receptor antagonists, clozapine, which unfortunately may cause serious side effects such as agranulocytosis, is efficacious at considerably lower levels of D 2 receptor occupancy (Farde et al. 1992), and rarely induces EPS (see Safferman et al. 1991). The diminished induction of EPS, as well as a purportedly advantageous effect on negative and certain cognitive symptoms in schizophrenia, has led to the definition of clozapine as the prototypical atypical antipsychotic drug (Kane et al. 1988;Meltzer et al. 1989). Theories regarding the mode of action of typical versus atypical antipsychotics have emphasized the frequently potent antagonistic effect of the atypicals on serotonin (5-HT) 2A receptors and/or ␣ 1 -adrenoceptors (Meltzer et al. 1989; see Svensson et al. 1995), as well as their differential effect on regional DA neurotransmission. Thus, whereas classical antipsychotic drugs mainly enhance extracellular DA concentrations in subcortical brain regions, atypical antipsychotics preferentially increase DA, as well as noradrenaline (NA), concentrations in the medial prefrontal cortex (mPFC) of experimental animals (Imperato and Angelucci 1989; Moghaddam and Bunney 1990;Nomikos et al. 1994;Westerink et al. 2001), an effect that to a large extent seems to be mediated locally in the mPFC (Gessa et al. 2000).Among other properties, clozapine displays considerable affinity also for ␣ 2 -adrenoceptors (see Ashby and Wang 1996), and we recently reported that addition of an ␣ 2 -adrenoceptor antagonist to a selective D 2 receptor antagonist, results in a markedly enhanced DA output specifically in the mPFC, as well as an enhancement of the D 2 receptor blockage induced effect in the conditioned avoidance response (CAR) paradigm, a preclinical test with high predictive validity for clinical antipsychotic effect (Arnt 1982; see Wadenberg and Hicks 1999). Thus, when adding the ␣ 2 -adrenoceptor antagonist idazoxan to the D 2 receptor blocking regimen, an antipsychotic-like effect was obtained in spite of a considerably lower dose of the D 2 -blocker being used (Hertel et al. 1999a), yet without any concomitant increase in catalepsy, thus indicative of an atypical antipsychotic profile of the drug combination. This notion is also supported by previous clinical data demonstrating an augmenting effect of idazoxan on the therapeutic efficacy of haloperidol (Litman et al. 1996).Reboxetine is a new selective NA reuptake inhibitor (NRI), clinically used as an antidepressant, which unlike the tricyclic antidepressants shows low affinity for the muscarinic, cholinergic and adrenergic receptor families (Won...