Alpha7 Nicotinic Receptor Agonist Research Articles

Phencyclidine-Induced Cognitive Deficits in Mice Are Improved by Subsequent Subchronic Administration of the Novel Selective α7 Nicotinic Receptor Agonist SSR180711

Accumulating evidence suggests that alpha7 nicotinic receptor (alpha7 nAChR) agonists could be potential therapeutic drugs for cognitive deficits in schizophrenia. The present study was undertaken to examine the effects of the novel selective alpha7 nAChR agonist SSR180711 on cognitive deficits in mice after repeated administration of the N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). Saline or PCP (10 mg/kg/day for 10 days) was administered to mice. Subsequently, vehicle, SSR180711 (.3 or 3.0 mg/kg/day), SSR180711 (3.0 mg/kg/day) + the selective alpha7 nAChR antagonist methyllycaconitine (MLA; 3.0 mg/kg/day), or MLA (3.0 mg/kg/day) was administered IP for 2 consecutive weeks. Twenty-four hours after the final administration, a novel object recognition test was performed. The PCP-induced cognitive deficits were significantly improved by subsequent subchronic (2-week) administration of SSR180711 (3.0 mg/kg). The effects of SSR180711 (3.0 mg/kg) were significantly antagonized by co-administration of MLA (3.0 mg/kg). Furthermore, Western blot analysis and immunohistochemistry revealed that levels of alpha7 nAChRs in the frontal cortex and hippocampus of the PCP (10 mg/kg/day for 10 days)-treated mice were significantly lower than those of saline-treated mice. These findings suggest that repeated PCP administration significantly decreased the density of alpha7 nAChRs in the brain and that the alpha7 nAChR agonist SSR180711 could ameliorate cognitive deficits in mice after repeated administration of PCP. Therefore, alpha7 nAChR agonists including SSR180711 are potential therapeutic drugs for treating cognitive deficits in schizophrenic patients.

Antiamnestic effect of α7-nicotinic receptor agonist RJR-2403 in middle-aged ovariectomized rats with Alzheimer type dementia

The effects of chronic combined treatment with alpha7-nicotinic cholinergic receptor agonist RJR-2403 (1.0 mg/kg intraperitoneally) or alpha7-nicotinic cholinergic receptor antagonist mecamylamine (1.0 mg/kg intraperitoneally) and 17beta-estradiol (0.5 microg per rat intramuscularly) for 10 days on passive avoidance retention were studied in middle-aged (15 months) ovariectomized rats with experimental Alzheimer type dementia. Chronic treatment with RJR-2403 and 17beta-estradiol had a pronounced antiamnestic effect under conditions of Alzheimer type dementia in middle-aged ovariectomized rats.

The Vagus Nerve and Nicotinic Receptors Modulate Experimental Pancreatitis Severity in Mice

The nervous system, through the vagus nerve, controls inflammation by decreasing the release of tumor necrosis factor-alpha from endotoxin stimulated macrophages. This anti-inflammatory effect is mediated by an interaction of acetylcholine, the principal neurotransmitter of the vagus nerve, with macrophage cholinergic nicotinic receptors expressing the alpha7 subunit. To determine the role of this "nicotinic anti-inflammatory pathway" in experimental pancreatitis, we induced pancreatitis in mice by 12 hourly intraperitoneal injections of cerulein. Pancreatitis was preceded by unilateral left cervical vagotomy or pretreatment with the nicotinic receptor antagonist mecamylamine or by pretreatment with the selective alpha7 nicotinic receptor agonist 3-(2,4-dimethoxybenzylidene) anabaseine (GTS-21). Vagotomy or pretreatment with mecamylamine resulted in an enhanced severity of pancreatitis, as reflected by histology, edema, plasma hydrolases, and interleukin-6 levels. Furthermore, the number of neutrophils migrated to the pancreas was increased in these mice, as shown by myeloperoxidase content and intrapancreatic staining of neutrophils. Conversely, GTS-21 pretreatment strongly decreased the severity of pancreatitis. Pancreatitis-associated pulmonary inflammation was independent of the integrity of the vagus nerve and nicotinic receptors. This study provides the first evidence for a therapeutic potential of the vagus nerve and the "nicotinic anti-inflammatory pathway" in attenuating inflammation and injury during experimental pancreatitis.

Facilitation of glutamate release by nicotine involves the activation of a Ca2+/calmodulin signaling pathway in rat prefrontal cortex nerve terminals

The effect of nicotine on evoked glutamate release from isolated nerve terminals (synaptosomes) from rat prefrontal cortex was examined. We found that nicotine significantly potentiated 4-aminopyridine (4AP)-evoked glutamate release, and this potentiatory effect was mimicked by the selective alpha7 nicotinic receptor agonist choline and was blocked by the selective alpha7 nicotinic receptor antagonist methyllycaconitine, indicating its mediation by alpha7 nicotinic receptors. Examination of the effect of nicotine on cytosolic [Ca(2+)] revealed that the potentiation of glutamate release was associated with an increase in voltage-dependent Ca(2+) influx through N- and P/Q-type Ca(2+) channels. The potentiatory effect of nicotine on Ca(2+) influx seems to be attributed to its increasing synaptosomal excitability because nicotine significantly increased depolarization-evoked increase in the intrasynaptosomal free Na(+) concentration and 4AP-evoked depolarization of the synaptosomal plasma membrane potential. Also, Ca(2+) ionophore ionomycin-induced glutamate release was enhanced by nicotine, and this action was blocked by methyllycaconitine. These results suggest that nicotine exerts its potentiatory effect presynaptically, likely through the activation of alpha7 nicotinic receptors, resulting in Na(+) influx and local depolarization, which subsequently enhances the Ca(K+) entry through voltage-dependent N-and P/Q-type Ca(2+) channels as well as the vesicular release machinery to cause an increase in evoked glutamate release from rat prefrontocortical nerve terminals. Moreover, in this release potentiation may involve an activation of Ca(2+)/calmodulin signaling pathway as nicotine-mediated potentiation of 4AP- and ionomycin-evoked glutamate release were significantly attenuated by KN62, a selective inhibitor of Ca(2+)/calmodulin-dependent kinase II.

A chiral synthesis of (-)-spiro[1-azabicyclo[2.2.2]octane-3,5'- oxazolidin-2'-one]: a conformationally restricted analogue of acetylcholine that is a potent and selective alpha7 nicotinic receptor agonist.

A direct, short chiral synthesis of the selective alpha7 nicotinic receptor agonist (-)-spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin-2'-one] (AR-R17779) is presented. The key step utilized attack of the dianion of the (R)-HYTRA ester [(R)-(+)-2-hydroxy-1,2,2-triphenylethyl acetate] on quinuclidin-3-one, followed by a selective precipitation of the diasteriomeric tertiary alcohol that led to (S)-(-)-AR-R17779 in two additional steps.

Alpha-7 nicotinic receptor agonists: potential new candidates for the treatment of schizophrenia.

Auditory sensory gating, a biological measurement of the ability to suppress the evoked response to the second of two auditory stimuli, is diminished in people with schizophrenia. Deficits in sensory gating are associated with attentional impairment, and may contribute to cognitive symptoms and perceptual disturbances. This inhibitory process, which involves the alpha(7) nicotinic receptor mediated release of gamma-aminobutyric acid (GABA) by hippocampal interneurons, represents a potential new target for therapeutic intervention in schizophrenia. This paper will review several lines of evidence implicating the nicotinic-cholinergic, and specifically, the alpha(7) nicotinic receptor system in the pathology of schizophrenia and the evidence that alpha(7) nicotinic receptor agonists may ameliorate some of these deficits. Impaired auditory sensory gating has been linked to the alpha(7) nicotinic receptor gene on the chromosome 15q14 locus. Single nucleotide polymorphisms of the promoter region of this gene are more frequent in people with schizophrenia. Although nicotine can acutely reverse diminished auditory sensory gating in people with schizophrenia, this effect is lost on a chronic basis due to receptor desensitization. Clozapine is able to reverse auditory sensory gating impairment, probably through an alpha(7) nicotinic receptor mechanism, in both humans and animal models with repeated dosing. The alpha(7) nicotinic agonist 3-2,4 dimethoxybenzylidene anabaseine (DMXBA) can also enhance auditory sensory gating in animal models. DMXBA is well tolerated in humans and improves several cognitive measures. Alpha-7 nicotinic receptor agonists appear to be reasonable candidates for the treatment of cognitive and perceptual disturbances in schizophrenia.

The DBA/2J strain and prepulse inhibition of startle: a model system to test antipsychotics?

Prepulse inhibition (PPI) of the startle response in mice is increasingly used as a paradigm of sensory gating with potential predictive and construct validity towards schizophrenia. Establishment of a mouse PPI paradigm in which typical and atypical antipsychotic drugs directly improve a low performance PPI. Three strains of mice--C57Bl/6J, 129S6/SvEvTac and DBA/2J--were tested in a startle paradigm with three prepulse intensities, 2, 4 and 8 dB above background. Under these conditions, risperidone (0, 0.25, 0.5 and 1 mg/kg i.p.) and clozapine (0, 1, 3 and 9 mg/kg i.p.) improved PPI in all three strains, with order of effect in DBA/2J > 129S6SvEvTac > C57Bl/6J. The DBA/2J strain showed larger PPI-enhancing effects, without disturbing the basal startle response. Two alpha7 nicotinic receptor agonists, GTS-21 (1-10 mg/kg i.p.) and AR-R17779 (1-10 mg/kg i.p.) were inactive in the PPI procedure in DBA/2J mice. DBA/2J mice were very sensitive to the antipsychotic-like effects of atypical (clozapine) and typical (risperidone) antipsychotics, and this strain is proposed as a model to directly measure sensory gating properties of drugs. Alpha7 Nicotinergic receptor agonists were ineffective in this PPI paradigm.