title: Effects of the nicotinic α7 receptor partial agonist GTS-21 on NMDA-glutamatergic receptor related deficits in sensorimotor gating and recognition memory in rats.
abstract: BACKGROUND
  Disturbances in information processing and cognitive function are key features of schizophrenia. Nicotinic α7 acetylcholine receptors (α7-nAChR) are involved in sensory gating and cognition, thereby representing a viable therapeutic strategy.
  
  
  OBJECTIVE
  We investigated the effects of GTS-21, an α7-nAChR partial agonist, on prepulse inhibition (PPI) of acoustic startle in two pharmacologic impairment models in Wistar male rats: NMDA-glutamate receptor antagonism by MK-801 and dopamine receptor agonism by apomorphine. The cognitive effects of GTS-21 were assessed using the object recognition task (ORT) at short (3 h) and long (48 h) delays in Sprague-Dawley male rats. Pharmacological specificity was assessed by methyllycaconitine (MLA) coadministration with GTS-21.
  
  
  RESULTS
  In the PPI task, GTS-21 (1-10 mg/kg) alone did not alter the PPI response or startle amplitude. Coadministration of GTS-21 with MK-801 (0.1 mg/kg) or apomorphine (0.5 mg/kg) abolished the pharmacologic-induced PPI impairment as did the antipsychotics clozapine (5.0 mg/kg) and haloperidol (0.3 mg/kg). MK-801 alone increased startle amplitude which was blocked by GTS-21. In the ORT, GTS-21 (0.1-10 mg/kg) reversed the MK-801 (0.08 mg/kg)-induced memory deficit at the 3 h delay and enhanced memory at the 48 h delay, an effect abolished by MLA (0.313-5 mg/kg).
  
  
  CONCLUSIONS
  The results extend our preclinical pharmacological understanding of GTS-21 to include the ability of GTS-21 to modulate NMDA-glutamate receptor function, in vivo. Given the role of NMDA-glutamate receptor involvement in schizophrenia, α7-nAChR agonists may represent a novel treatment strategy for the pathophysiological deficits of schizophrenia and other psychiatric disorders.
authors.affiliation: Department of Pharmacology and Toxicology, Small Animal Behavior Core, Georgia Regents University, Augusta, GA, 30912, USA, pcallahan@gru.edu.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Callahan
authors.forename: Alvin V
authors.initials: AV
authors.lastname: Terry
authors.forename: Ashok
authors.initials: A
authors.lastname: Tehim
mesh_terms: D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001597:Benzylidene Compounds / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic / Q000502:physiology; D021641:Recognition, Psychology / Q000187:drug effects*; D013216:Reflex, Startle / Q000187:drug effects*; D055139:Sensory Gating / Q000187:drug effects*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists*
chemical_list: D001597:Benzylidene Compounds; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D018722:Nicotinic Agonists; D011725:Pyridines; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D016291:Dizocilpine Maleate; C088936:3-(2,4-dimethoxybenzylidene)anabaseine; D003024:Clozapine; D006220:Haloperidol; D001058:Apomorphine