Alpha 7
nicotinic acetylcholine receptors (α7-nAChRs) have generated great interest as targets of new pharmacological treatments for
cognitive dysfunction in
schizophrenia. One promising recent approach is based on the use of positive allosteric modulators (PAMs) of α7-nAChRs, which demonstrate several advantages over direct agonists. Nevertheless, the efficacy of these newly introduced α7-nAChR agents has not been extensively characterised in animal models of
schizophrenia. The aim of the present study was to evaluate the efficacy of type I and II PAMs, N-(5-chloro-2,4-dimethoxyphenyl)-N'-(5-methyl-3-isoxazolyl)urea (PNU-120596) and N-(4-chlorophenyl)-[[(4-chlorophenyl)amino]methylene]-3-methyl-5-isoxazoleacet-
amide (CCMI), respectively, and
galantamine, an
acetylcholinesterase inhibitor (AChE) that also allosterically modulates nAChRs, against
ketamine-induced cognitive deficits and social withdrawal in rats. The orthosteric α7-nAChR agonist octahydro-2-methyl-5-(6-phenyl-3-pyridazinyl)-pyrrolo[3,4-c]
pyrrole (A-582941) was used as a positive control. Additionally, the
antipsychotic activities of the tested compounds were assessed using the conditioned avoidance response (CAR) test.
PNU-120596, CCMI,
galantamine and
A-582941 reversed
ketamine-induced cognitive inflexibility, as assessed in the attentional set-shifting task (ASST). The tested compounds were also effective against
ketamine-induced impairment in the novel object recognition task (NORT).
PNU-120596, CCMI, and
A-582941 ameliorated
ketamine-induced social interaction deficits, whereas
galantamine was ineffective. Moreover, all tested compounds selectively suppressed the CAR. The positive allosteric modulation of α7-nAChRs demonstrates preclinical efficacy not only against
schizophrenia-like cognition impairments but also positive and negative symptoms. Therefore, the use of α7-nAChR PAMs as a potential treatment strategy in
schizophrenia is supported.