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...