Idazoxan, an ??2 Antagonist, Augments Fluphenazine in

Litman, Robert E.; Hong, Walter W.; Weissman, Ellen M.; Su, Tung‐Ping; Potter, William Z.; Pickar, David

doi:10.1097/00004714-199308000-00006

Cited by 34 publications

(11 citation statements)

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“…Our data confirm and extend a previous report by Hertel et al (1999a), and lend further experimental support for the significance of a 2 adrenoceptor blockade in APD efficacy as, for example, reported previously by Litman et al (1993Litman et al ( , 1996, as well as for a favourable EPS profile similar to Clz, that indeed has high affinity for the a 2 adrenoceptor (see Introduction). Furthermore, together with recent data from our laboratory (Marcus et al, 2005), showing that combined treatment with Ida+Rac, similarly to Clz, fully reversed impairment of working memory induced by the NMDA receptor antagonist MK-801 in rats, our present data suggest that adjunctive a 2 adrenoceptor blockade to APDs, lacking appreciable affinity for the a 2 adrenoceptor, may not only offer a reduced DA D 2 receptor occupancy with retained sufficient antipsychotic efficacy, but may possibly also allow for enhanced therapeutic efficacy against some aspects of cognitive impairment in schizophrenia.…”

Section: Discussionsupporting

confidence: 92%

“…Clz is a potent antagonist for a 2 adrenoceptors (Ashby and Wang, 1996), while most other atypical APDs, with the exception of risperidone, have relatively low affinity for this receptor. Clinical studies have previously shown that, compared with antipsychotic treatment alone, adjunctive treatment with the selective a 2 adrenoceptor antagonist idazoxan (Ida) (Dabiré, 1986) significantly augmented the effect of a conventional APD (fluphenazine) in schizophrenic patients, meeting the criteria for treatment resistance, with a reduction of psychosis and negative symptoms, as well as a significant effect on thought disorders and withdrawal retardation (Litman et al, 1993(Litman et al, , 1996. Litman et al also noted that the add-on treatment with Ida to fluphenazine, but not fluphenazine alone, compared favourably with Clz.…”

Section: Introductionmentioning

confidence: 99%

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Enhanced efficacy of both typical and atypical antipsychotic drugs by adjunctive α2 adrenoceptor blockade: experimental evidence

Wadenberg

Wiker

Svensson

2006

Int. J. Neuropsychopharm.

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Enhanced efficacy of both typical and atypical antipsychotic drugs by adjunctive α2 adrenoceptor blockade: experimental evidence

Wadenberg

Wiker

Svensson

2006

Int. J. Neuropsychopharm.

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“…Therefore, these negative symptoms may be attributable to dysfunction of the prefrontal cortex, including hypofunction of the noradrenergic network (Rao and Moller 1994). To support this, idazoxan, a selective ␣2-antagonist, is reported to augment therapeutic effect of typical neuroleptics in treatment of schizophrenia (Litman et al 1993(Litman et al , 1996.…”

Section: Discussionmentioning

confidence: 99%

Clozapine- and Olanzapine-induced Fos Expression in the Rat Medial Prefrontal Cortex is Mediated by β-Adrenoceptors

Ohashi

Hamamura

Lee

et al. 2000

Neuropsychopharmacology

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The atypical neuroleptics, clozapine and olanzapine, have superior therapeutic efficacy against the negative symptoms of schizophrenia, compared with the typical neuroleptics. Recently, it has been suggested that the ability of clozapine and olanzapine to induce Fos expression in the medialClozapine, a prototype atypical antipsychotic compound, is effective not only against the positive, but also against the negative symptoms of schizophrenia (Claghorn et al. 1987;Kane et al. 1988) which are usually resistant to typical neuroleptics. The mechanisms underlying this action, although investigated intensively, remain to be established. Recent studies involving the Fos protein have demonstrated that clozapine induces a much larger increase in the number of neurons that exhibit Fos-like immunoreactivity (LI) in the medial prefrontal cortex (mPFC) than do typical neuroleptics (Deutch and Duman 1996; Fink-Jensen and Kristensen 1994; Fink-Jensen et al. 1995;Guo et al. 1995;Kurokawa et al. 1997;Robertson and Fibiger 1992;Robertson et al. 1994;Wan et al. 1995). This regionally specific clozapine effect sets it apart from typical neuroleptics.Although simple neuronal depolarization or increase in firing rate per se are not enough to induce c-fos in many neurons, other factors such as phenotype of neuronal cell are also required for c-fos expression, Fos protein is thought to be a marker of activated neurons in specified subset of neurons (Sagar et al. 1988; Dragunow and Faull 1989;Grant et al. 1992;Sharp et al. 1993). Therefore, it can be postulate that clozapine may enhance neuronal activity in the mPFC. In connection with the hypothesis that hypofrontality may be responFrom the Department of Neuropsychiatry (KO, TH, YL, HS, SK), Okayama University Medical School, Shikata-cho Okayama, Japan; and Takaoka Hospital (YF), Nishi-imazyuku Himeji, Japan.Address correspondence to: Dr. T. Hamamura, Department of Neuropsychiatry, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama, 700-8558 Japan.Received November 9, 1999; revised February 8, 2000; accepted February 17, 2000. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 23 , NO . 2 Clozapine-and Olanzapine-induced Fos in mPFC 163 sible for the negative or deficit symptoms of schizophrenia (Weinberger 1988), the preferential induction of Fos-LI in the mPFC is postulated to be one of the mechanisms by which clozapine reduces the negative symptoms of schizophrenia (Robertson et al. 1994). If this is the case, it is important to determine the neuropharmacological mechanisms by which clozapine induces Fos expression in the mPFC. Although clozapine is known to have an affinity for various neurotransmitter receptors, such as noradrenergic, dopaminergic, histaminergic, muscarinic and 5-hydroxytryptamine (5-HT) receptors, the precise neuropharmacological action of clozapine that results in the induction of Fos expression in the mPFC is unknown. Since clozapine administration increases the firing rate of noradrenergic cells in the locus coeruleus (LC) and noradrenaline release from...

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“…In this context, it has been suggested that the relatively high α 2 adrenergic antagonist properties of clozapine contribute to its superior clinical profile Nutt 1994;Hertel et al 1999;Kalkman and Loetscher 2003). This hypothesis is supported by clinical reports that co-treatment with the α 2 adrenergic antagonist, idazoxan, enhances the antipsychotic efficacy of the D 2 antagonist, fluphenazine (Litman et al 1993(Litman et al , 1996 and by recent pharmacological studies in rats. Indeed, Hertel et al (1999) demonstrated a pharmacological basis for α 2 adrenergic/D 2 interactions using microdialysis and conditioned avoidance procedures.…”

Section: Introductionmentioning

confidence: 88%

Anticataleptic properties of ?2 adrenergic antagonists in the crossed leg position and bar tests: differential mediation by 5-HT1A receptor activation

et al. 2004

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Idazoxan, an ??2 Antagonist, Augments Fluphenazine in

Cited by 34 publications

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Enhanced efficacy of both typical and atypical antipsychotic drugs by adjunctive α2 adrenoceptor blockade: experimental evidence

Enhanced efficacy of both typical and atypical antipsychotic drugs by adjunctive α2 adrenoceptor blockade: experimental evidence

Clozapine- and Olanzapine-induced Fos Expression in the Rat Medial Prefrontal Cortex is Mediated by β-Adrenoceptors

Anticataleptic properties of ?2 adrenergic antagonists in the crossed leg position and bar tests: differential mediation by 5-HT1A receptor activation

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