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In vivo microdialysis was used to investigate the effects of acute injections of harmine on extracellular concentrations of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxindoleacetic acid (5-HIAA) in the striatum of awake rats. Administration of harmine in doses of 0.5, 2.5, and 10 mg/kg (i.p.) elicited a dose-dependent increase of the dopamine efflux to 152, 173, and 243% and a decrease in DOPAC to 52, 36, and 10%, and HVA to 67, 45, and 20% throughout, respectively; 5-HIAA concentrations were decreased to 81, 74, and 72% only. In contrast to D-amphetamine, which also increases dopamine release and decreases its metabolites, the stimulatory action of harmine on dopamine release in the striatum was totally abolished in the presence of tetrodotoxin (1 microM). Similar to monoamine oxidase (MAO)-A inhibitors, harmine potentiated the stimulatory effect of D-amphetamine (10 microM), infused by reverse microdialysis in the striatum, on dopamine release. Pre-treatment with the benzodiazepine receptor antagonist flumazenil (5 mg/kg, i.p.) did not modulate the effect of harmine on striatal dopamine release and metabolism. Administration of the reversible MAO-A inhibitor, moclobemide (20 mg/kg, i.p.), induced an increase in dopamine to 256% and a decrease in DOPAC, HVA, and 5-HIAA to 30, 24, and 62%, respectively, reproducing a pattern similar to that of harmine. Taken together, these results indicate that harmine affects the brain dopamine system probably by acting as a MAO-A inhibitor and not as an inverse agonist for the benzodiazepine receptors.

IntroductionThe serotonin 5-HT4 receptor agonist prucalopride is approved in the European Union for the treatment of chronic constipation. This offered the unique opportunity to include real-world observational data on cardiovascular safety in the new drug application for approval of prucalopride in the USA.MethodsThis observational population-based cohort study (EUPAS9200) conducted in five data sources (three in the UK, one in Sweden, and one in Germany [which was subsequently excluded from the pooled analyses]) aimed to estimate the pooled adjusted incidence rate ratio for major adverse cardiovascular events (defined as hospitalization for non-fatal acute myocardial infarction or stroke, and in-hospital cardiovascular death) in adult initiators of prucalopride compared with initiators of polyethylene glycol 3350 (PEG) following a common protocol. Standardized incidence rates and incidence rate ratios of major adverse cardiovascular events were derived using propensity score stratification. Sensitivity analyses explored the impact of exposure definition, outcome categories, interim cancer, and unmeasured confounding.ResultsThe pooled analyses included 5715 initiators of prucalopride and 29,372 initiators of PEG. Average duration of use was 175 days for prucalopride and 82 days for PEG. The pooled standardized incidence rate per 1000 person-years (95% confidence interval) of major adverse cardiovascular events was 6.57 (3.90–10.39) for patients initiating prucalopride and 10.24 (6.97–14.13) for PEG. The pooled adjusted incidence rate ratio for major adverse cardiovascular events was 0.64 (95% confidence interval 0.36–1.14). Results remained consistent in various sensitivity analyses.ConclusionsThe pooled incidence rate ratio estimate was consistent with no indication of an increased risk above the pre-specified safety threshold of 3.00 for major adverse cardiovascular events in patients with chronic constipation using prucalopride as compared with PEG.

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...

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