title: Alpha7 nicotinic acetylcholine receptor agonists and PAMs as adjunctive treatment in schizophrenia. An experimental study.
abstract: Nicotine has been found to improve cognition and reduce negative symptoms in schizophrenia and a genetic and pathophysiological link between the α7 nicotinic acetylcholine receptors (nAChRs) and schizophrenia has been demonstrated. Therefore, there has been a large interest in developing drugs affecting the α7 nAChRs for schizophrenia. In the present study we investigated, in rats, the effects of a selective α7 agonist (PNU282987) and a α7 positive allosteric modulator (PAM; NS1738) alone and in combination with the atypical antipsychotic drug risperidone for their utility as adjunct treatment in schizophrenia. Moreover we also investigated their utility as adjunct treatment in depression in combination with the SSRI citalopram. We found that NS1738 and to some extent also PNU282987, potentiated a subeffective dose of risperidone in the conditioned avoidance response test. Both drugs also potentiated the effect of a sub-effective concentration of risperidone on NMDA-induced currents in pyramidal cells of the medial prefrontal cortex. Moreover, NS1738 and PNU282987 enhanced recognition memory in the novel object recognition test, when given separately. Both drugs also potentiated accumbal but not prefrontal risperidone-induced dopamine release. Finally, PNU282987 reduced immobility in the forced swim test, indicating an antidepressant-like effect. Taken together, our data support the utility of drugs targeting the α7 nAChRs, perhaps especially α7 PAMs, to potentiate the effect of atypical antipsychotic drugs. Moreover, our data suggest that α7 agonists and PAMs can be used to ameliorate cognitive symptoms in schizophrenia and depression.
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Marcus
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden.
authors.forename: Carl
authors.initials: C
authors.lastname: Björkholm
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Malmerfelt
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden.
authors.forename: Annie
authors.initials: A
authors.lastname: Möller
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden.
authors.forename: Ninni
authors.initials: N
authors.lastname: Påhlsson
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Konradsson-Geuken
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden.
authors.forename: Kristin
authors.initials: K
authors.lastname: Feltmann
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden.
authors.forename: Kent
authors.initials: K
authors.lastname: Jardemark
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Schilström
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden. Electronic address: Torgny.Svensson@ki.se.
authors.forename: Torgny H
authors.initials: TH
authors.lastname: Svensson
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D015283:Citalopram / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D008297:Male; D016202:N-Methylaspartate / Q000378:metabolism / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018967:Risperidone / Q000494:pharmacology; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism; D012565:Schizophrenic Psychology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists* / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D015283:Citalopram; D004298:Dopamine; D018690:Excitatory Amino Acid Agonists; D016202:N-Methylaspartate; D018722:Nicotinic Agonists; D010671:Phenylurea Compounds; D018967:Risperidone; D017367:Selective Serotonin Reuptake Inhibitors; D064569:alpha7 Nicotinic Acetylcholine Receptor; C523981:1-(5-chloro-2-hydroxyphenyl)-3-(2-chloro-5-trifluoromethylphenyl)urea; C498513:PNU-282987
keywords: Antidepressants; Antipsychotics; Cognition; Dopamine; Electrophysiology; Nicotine