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  • 1.
    Wadenberg, Marie-Louise
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Fjällström, Ann-Kristin
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Federley, Malin
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Persson, Pernilla
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Stenqvist, Pia
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Effects of adjunct galantamine to risperidone, or haloperidol, in animal models of antipsychotic activity and extrapyramidal side-effect liability: involvement of the cholinergic muscarinic receptor2011In: International Journal of Neuropsychopharmacology, ISSN 1461-1457, E-ISSN 1469-5111, Vol. 14, no 5, p. 644-654Article in journal (Refereed)
    Abstract [en]

    The acetylcholine esterase inhibitor/cholinergic nicotinic receptor (nAChR) allosteric modulator galantamine (Gal) is used against cognitive impairment in Alzheimer’s disease. Negative/cognitive and psychotic symptom improvement in schizophrenia by adjunct Gal to antipsychotic drugs (APDs) has been reported. Cognitive symptoms in schizophrenia may involve brain prefrontal hypo-dopaminergia. Experimental data by others indicate nAChR involvement in animal pro-cognitive effects of Gal. The role of nAChRs in antipsychotic effects by Gal has, however, not been elucidated. Using the conditioned avoidance response (CAR) and the catalepsy tests for antipsychotic activity and extrapyramidal side-effect (EPS) liability, respectively, we here investigated the effects of adjunct Gal (1.25 mg/kg) to the typical APD haloperidol (Hal) (0.05 mg/kg), or the atypical APD risperidone (Ris) (0.2 mg/kg), in rats. Adjunct Gal significantly enhanced APD-like effects by low doses of Hal or Ris, but showed a safe EPS liability profile only in combination with Ris. Pretreatment with the muscarinic receptor (mAChR) antagonist scopolamine, but not the nAChR antagonist mecamylamine, completely reversed the enhancing effects of adjunct Gal to Hal treatment, in the CAR test. While the nAChR-modulating properties of Gal probably contribute to pro-cognitive activity, as shown by others, the present data suggest that any contribution to antipsychotic activity by Gal is mediated primarily via mAChRs. This property combination of Gal may offer a unique, favourable therapeutic profile for schizophrenia treatment.

  • 2.
    Wadenberg, Marie-Louise
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Fjällström, Ann-Kristin
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Karlsson-Federley, Malin
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Persson, Pernilla
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Stenqvist, Pia
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Effects of adjunct galantamine to antipsychotics in animal models of antipsychotic activity and extrapyramidal side effect liability: Cholinergic muscarinic receptor mediation2010In: International Journal of Neuropsychopharmacology, ISSN 1461-1457, E-ISSN 1469-5111, Vol. 13, no Suppl. 1, p. 111-Article in journal (Other academic)
  • 3.
    Wadenberg, Marie-Louise
    et al.
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Wiker, Charlotte
    Svensson, Torgny
    Enhanced efficacy of both typical and atypical antipsychotic drugs by adjunct alpha2 adrenoceptor blockade: experimental evidence.2007In: International Journal of Neuropsychopharmacology, ISSN 1461-1457, E-ISSN 1469-5111, Vol. 10, p. 191-202Article in journal (Refereed)
  • 4.
    Wiker, Charlotte
    et al.
    Karolinska Institutet.
    Schilström, Björn
    Karolinska Institutet.
    Sandbäck, Carina
    Karolinska Institutet.
    Wadenberg, Marie-Louise
    University of Kalmar, School of Pure and Applied Natural Sciences.
    Svensson, Torgny
    Karolinska Institutet.
    Adjunctive galantamine, but not donepezil, enhances the antipsychotic-like effect of raclopride in rats.2008In: International Journal of Neuropsychopharmacology, ISSN 1461-1457, E-ISSN 1469-5111, Vol. 11, no 6, p. 845-850Article in journal (Refereed)
    Abstract [en]

    Acetylcholine (ACh) esterase inhibitors like galantamine and donepezil have been tested as adjunct treatment in schizophrenia. Although ACh esterase inhibition might confer some antipsychotic activity, the role of allosteric potentiation of nicotinic ACh receptors (nAChRs), which is an additional mechanism of galantamine, remains elusive. Therefore, the potential antipsychotic-like effects of galantamine and donepezil, respectively, alone, and in combination with the dopamine D2/3 receptor antagonist, raclopride, were tested in the conditioned avoidance response (CAR) test and extrapyramidal side-effect liability was assessed with the catalepsy test. Neither galantamine nor donepezil alone suppressed CAR selectively. Galantamine, but not donepezil, enhanced the raclopride-induced suppression of CAR, predicting augmentation of antipsychotic activity. In contrast to donepezil, galantamine did not increase catalepsy, alone or combined with raclopride. These data suggest that allosteric potentiation of nAChRs may mediate the antipsychotic-like effect of adjunctive galantamine and provide support for the development of α7 nAChR-selective allosteric potentiators for schizophrenia.

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