Clozapine exerts superior clinical efficacy and markedly enhances cortical dopamine output compared with classical antipsychotic drugs. Here the alpha2 adrenoceptor antagonist idazoxan was administered to rats alone or in combination with the D2/3 dopamine receptor antagonist raclopride. Dopamine efflux in the medial prefrontal cortex and conditioned avoidance responding were analyzed. Idazoxan selectively potentiated the cortical output of dopamine and augmented the suppression of conditioned avoidance responding induced by raclopride. These results challenge basic assumptions underlying the dopamine hypothesis of schizophrenia and provide insight into clozapine's mode of action.

We have previously provided evidence that the stimulatory action of systemic nicotine on dopamine release in the rat nucleus accumbens is initiated in the ventral tegmental area (VTA), and that it appears to be mediated partly through an indirect, presynaptic mechanism. Thus, it was found that blockade of N‐methyl‐D‐aspartate (NMDA) receptors in the VTA attenuates the enhancing effect of nicotine on extracellular levels of dopamine in the nucleus accumbens. Moreover, the nicotine‐induced dopamine output in the nucleus accumbens was found to be blocked by pretreatment with methyllycaconitine (MLA) in the VTA, indicating a role for α7* nicotinic acetylcholine receptors (nAChRs) in this mechanism. Thus, nicotine may exert its effects in the VTA through stimulation of α7* nAChRs localized on excitatory amino acid (EAA)ergic afferents. To test this hypothesis, we here measured extracellular concentrations of glutamate and aspartate in the VTA in response to systemic nicotine, with or without concurrent infusion of MLA in the VTA, using microdialysis in anaesthetized rats. Since the medial prefrontal cortex is an important source of EAA input to the VTA, we also assessed the density of α‐bungarotoxin binding sites in the VTA in rats lesioned bilaterally in the prefrontal cortex with ibotenic acid and in sham‐lesioned rats by means of quantitative autoradiography. Nicotine (0.5 mg/kg, s.c.) significantly increased extracellular levels of both aspartate and glutamate in the VTA. MLA (0.3 mM) infused locally in the VTA prevented the nicotine‐induced increase in glutamate and aspartate levels. Ibotenic acid lesions of the prefrontal cortex decreased the density of α‐bungarotoxin binding sites in the VTA by about 30%. These data indicate that nicotine increases the extracellular levels of excitatory amino acids in the VTA through stimulation of nAChRs in the VTA and that part of the α7* nAChR population in the VTA is localized on neurons originating in the prefrontal cortex. Synapse 38:375–383, 2000. © 2000 Wiley‐Liss, Inc.

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The effect of LY326325, a novel AMPA receptor antagonist, on the conditioned avoidance response and catalepsy was investigated in the rat. The conditioned avoidance response is a behavioral methodology which is regarded to predict potential antipsychotic efficacy of experimental drugs. Catalepsy ratings were utilized to assess the putative propensity of LY325326 to induce extrapyramidal side effects. Systemic administration of LY326325, 18 mg/kg subcutaneously, caused a selective suppression of conditioned avoidance response, without effect on escape behavior or intertrial crosses. In addition, no catalepsy was observed. Our present and previous results support an antipsychotic effect of AMPA receptor antagonists with a low liability for extrapyramidal side effects, i.e. pharmacological effects consonant with an atypical antipsychotic profile.

Observed metabolic syndrome prevalence rates were at least twice the rates observed in a normal, non-diabetic population. It appears that in this vulnerable population of patients with schizophrenia spectrum disorders, metabolic syndrome remains underdiagnosed and undertreated.