pnu-120596 and Memory-Disorders

Alpha7 nicotinic acetylcholine receptor (α7 nAChR) dysfunction plays an important role in schizophrenia. Positive allosteric modulators of α7 nAChR have emerged as a promising therapeutic approach to manage cognitive deficits that are inadequately treated in schizophrenic patients. The aim of the present study was to evaluate the ability of type I (CCMI) and type II (PNU120596) α7 nAChR positive allosteric modulators to counteract MK-801-induced cognitive and sensorimotor gating deficits. The activity of these compounds was compared with the action of the α7 nAChR agonist A582941. CCMI, PNU120596 and A582941 reversed the sensorimotor gating impairment evoked by MK-801 based on the prepulse inhibition of the startle response. Additionally, no MK-801-evoked working memory deficits were observed with α7 nAChR ligand pretreatment as assessed in a discrete paired-trial delayed alternation task. However, these compounds did not affect the rats' attentional performances in the five-choice serial reaction time test. The α7 nAChR agents demonstrated a beneficial effect on sensorimotor gating and some aspects of cognition tested in a rat model of schizophrenia. Therefore, these results support the use of α7 nAChR positive allosteric modulators as a potential treatment strategy in schizophrenia.

Topics: Acetylcholine; Allosteric Regulation; alpha7 Nicotinic Acetylcholine Receptor; Animals; Attention; Cognition; Cognitive Dysfunction; Dizocilpine Maleate; Isoxazoles; Male; Memory Disorders; Memory, Short-Term; Nicotinic Agonists; Phenylurea Compounds; Rats; Rats, Sprague-Dawley; Reflex, Startle; Schizophrenia; Sensory Gating

The α7 nicotinic acetylcholine receptor (nAChR) is highly expressed in different regions of the brain and is associated with cognitive function as well as anxiety. Agonists and positive allosteric modulators (PAMs) of the α7 subtype of nAChRs have been shown to improve cognition. Previously nicotine, which activates both α7 and non-α7 subtypes of nAChRs, has been shown to have an anxiogenic effect in behavioral tests. In this study, we compared the effects of the α7-selective agonist (PNU-282987) and PAM (PNU-120596) in a variety of behavioral tests in Sprague Dawley rats to look at their effects on learning and memory as well as anxiety. We found that neither PNU-282987 nor PNU-120596 improved spatial-learning or episodic memory by themselves. However when cognitive impairment was induced in the rats with scopolamine (1 mg/kg), both PNU-120596 and PNU-282987 were able to reverse this memory impairment and restore it back to normal levels. While PNU-120596 reversed the scopolamine-induced cognitive impairment, it did not have any adverse effect on anxiety. PNU-282987 on the other hand displayed an increase in anxiety-like behavior at a higher dose (10 mg/kg) that was significantly reduced by the serotonin 5-HT₁a receptor antagonist WAY-100135. However the α7 receptor antagonist methyllycaconitine was unable to reverse these anxiety-like effects seen with PNU-282987. These results suggest that α7 nAChR PAMs are pharmacologically advantageous over agonists, and should be considered for further development as therapeutic drugs targeting the α7 receptors.

Topics: Aconitine; alpha7 Nicotinic Acetylcholine Receptor; Animals; Anxiety; Behavior, Animal; Benzamides; Bridged Bicyclo Compounds; Drug Interactions; Isoxazoles; Learning; Male; Memory Disorders; Nicotinic Agonists; Nicotinic Antagonists; Phenylurea Compounds; Piperazines; Rats; Scopolamine; Serotonin 5-HT1 Receptor Antagonists