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      Adjunctive treatment with mianserin enhances effects of raclopride on cortical dopamine output and, in parallel, its antipsychotic-like effect

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          Abstract

          Clinical studies indicate that adjunctive treatment with the antidepressant drug mianserin, a 5-hydroxytryptamine (5-HT) 2A/C receptor antagonist and an α 2- and α 1-adrenoceptor antagonist, may enhance the effect of conventional antipsychotic drugs in schizophrenia, in particular on negative symptoms such as withdrawal retardation, akathisia, and some aspects of cognitive impairment. Here, we have examined the effect of mianserin in combination with the selective dopamine (DA) D 2/3 receptor antagonist raclopride on conditioned avoidance response (CAR), a preclinical test of antipsychotic efficacy with high predictive validity; catalepsy, a preclinical test of extrapyramidal side effect liability; and DA output in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAC), respectively. Mianserin (5 mg/kg intraperitoneal) significantly enhanced the suppressant effect of a low dose of raclopride (0.1 mg/kg subcutaneous) on CAR without any increase in catalepsy. Administration of raclopride to rats pretreated with mianserin resulted in a large enhancement of DA output in the mPFC and, at the same time, a small but significant reduction in the raclopride-induced DA output in the NAC. These experimental results indicate that adjunctive treatment with mianserin to a typical D 2 antagonist generates an atypical antipsychotic profile.

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          Most cited references 58

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          What are the functional consequences of neurocognitive deficits in schizophrenia?

          It has been well established that schizophrenic patients have neurocognitive deficits, but it is not known how these deficits influence the daily lives of patients. The goal of this review was to determine which, if any, neurocognitive deficits restrict the functioning of schizophrenic patients in the outside world. The author reviewed studies that have evaluated neurocognitive measures as predictors and correlates of functional outcome for schizophrenic patients. The review included 1) studies that have prospectively evaluated specific aspects of neurocognition and community (e.g., social and vocational) functioning (six studies), 2) all known studies of neurocognitive correlates of social problem solving (five studies), and 3) all known studies of neurocognitive correlates and predictors of psychosocial skill acquisition (six studies). Despite wide variation among studies in the selection of neurocognitive measures, some consistencies emerged. The most consistent finding was that verbal memory was associated with all types of functional outcome. Vigilance was related to social problem solving and skill acquisition. Card sorting predicted community functioning but not social problem solving. Negative symptoms were associated with social problem solving but not skill acquisition. Notably, psychotic symptoms were not significantly associated with outcome measures in any of the studies reviewed. Verbal memory and vigilance appear to be necessary for adequate functional outcome. Deficiencies in these areas may prevent patients from attaining optimal adaptation and hence act as "neurocognitive rate-limiting factors." On the basis of this review of the literature, a series of hypotheses are offered for follow-up studies.
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            Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia.

            Abnormalities of prefrontal cortical function are prominent features of schizophrenia and have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular mechanisms of prefrontal function. A potential susceptibility mechanism involves regulation of prefrontal dopamine, which modulates the response of prefrontal neurons during working memory. We examined the relationship of a common functional polymorphism (Val(108/158) Met) in the catechol-O-methyltransferase (COMT) gene, which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefrontal cortical physiology. In 175 patients with schizophrenia, 219 unaffected siblings, and 55 controls, COMT genotype was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance (P = 0.001) in frequency of perseverative errors. Consistent with other evidence that dopamine enhances prefrontal neuronal function, the load of the low-activity Met allele predicted enhanced cognitive performance. We then examined the effect of COMT genotype on prefrontal physiology during a working memory task in three separate subgroups (n = 11-16) assayed with functional MRI. Met allele load consistently predicted a more efficient physiological response in prefrontal cortex. Finally, in a family-based association analysis of 104 trios, we found a significant increase in transmission of the Val allele to the schizophrenic offspring. These data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology, and by this mechanism slightly increases risk for schizophrenia.
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              Serotonin receptors: their key role in drugs to treat schizophrenia.

              Serotonin (5-HT)-receptor-based mechanisms have been postulated to play a critical role in the action of the new generation of antipsychotic drugs (APDs) that are usually referred to as atypical APDs because of their ability to achieve an antipsychotic effect with lower rates of extrapyramidal side effects (EPS) compared to first-generation APDs such as haloperidol. Specifically, it has been proposed by Meltzer et al. [J. Pharmacol. Exp. Ther. 251 (1989) 238] that potent 5-HT2A receptor antagonism together with weak dopamine (DA) D2 receptor antagonism are the principal pharmacologic features that differentiate clozapine and other apparent atypical APDs from first-generation typical APD. This hypothesis is consistent with the atypical features of quetiapine, olanzapine, risperidone, and ziprasidone, which are the most common treatments for schizophrenia in the United States and many other countries, as well as a large number of compounds in various stages of development. Subsequent research showed that 5-HT1A agonism may be an important consequence of 5-HT2A antagonism and that substitution of 5-HT1A agonism for 5-HT2A antagonism may also produce an atypical APD drug when coupled with weak D2 antagonism. Aripiprazole, the most recently introduced atypical APD, and a D2 receptor partial agonist, may also owe some of its atypical properties to its net effect of weak D2 antagonism, 5-HT2A antagonism and 5-HT1A agonism [Eur. J. Pharmacol. 441 (2002) 137]. By contrast, the alternative "fast-off" hypothesis of Kapur and Seeman [Am. J. Psychiatry 158 (2001) 360] applies only to clozapine and quetiapine and is inconsistent with the "slow" off rate of most atypical APDs, including olanzapine, risperidone and ziprasidone. 5-HT2A and 5-HT1A receptors located on glutamatergic pyramidal neurons in the cortex and hippocampus, 5-HT2A receptors on the cell bodies of DA neurons in the ventral tegmentum and substantia nigra and GABAergic interneurons in the cortex and hippocampus, and 5-HT1A receptors in the raphe nuclei are likely to be important sites of action of the atypical APDs. At the same time, evidence has accumulated for the important modulatory role of 5-HT2C and 5-HT6 receptors for some of the effects of some of the current APDs. Thus, 5-HT has joined DA as a critical target for developing effective APDs and led to the search for novel drugs with complex pharmacology, ending the exclusive search for single-receptor targets, e.g., the D3 or D4 receptor, and drugs that are selective for them.
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                Author and article information

                Journal
                Neuropsychiatr Dis Treat
                Neuropsychiatric Disease and Treatment
                Neuropsychiatric Disease and Treatment
                Dove Medical Press
                1176-6328
                1178-2021
                September 2005
                : 1
                : 3
                : 253-260
                Affiliations
                Section for Neuropsychopharmacology, Department of Physiology and Pharmacology, Karolinska Institutet Stockholm, Sweden
                Author notes
                Correspondence: Torgny H Svensson Section of Neuropsychopharmacology, Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz väg 2, S-171 77, Stockholm, Sweden Tel +46 8 5248 7921 Fax +46 8 308 424 Email Torgny.Svensson@ 123456fyfa.ki.se
                Article
                2416756
                18568103
                © 2005 Dove Medical Press Limited. All rights reserved
                Categories
                Original Research

                Neurology

                typical antipsychotic drugs, adjunctive mianserin, prefrontal cortex, dopamine, atypicality

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