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Author (up) Briggs, C.A.; Gronlien, J.H.; Curzon, P.; Timmermann, D.B.; Ween, H.; Thorin-Hagene, K.; Kerr, P.; Anderson, D.J.; Malysz, J.; Dyhring, T.; Olsen, G.M.; Peters, D.; Bunnelle, W.H.; Gopalakrishnan, M. file  url
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  Title Role of channel activation in cognitive enhancement mediated by alpha7 nicotinic acetylcholine receptors Type Journal Article
  Year 2009 Publication British Journal of Pharmacology Abbreviated Journal Br J Pharmacol  
  Volume 158 Issue 6 Pages 1486-1494  
  Keywords Allosteric Regulation; Animals; Avoidance Learning/drug effects; Azabicyclo Compounds/administration & dosage/*pharmacology; Behavior, Animal/drug effects; Cell Line; Cognition Disorders/drug therapy/physiopathology; Dose-Response Relationship, Drug; Furans/administration & dosage/*pharmacology; Humans; Male; Mice; Nicotinic Agonists/*pharmacology; Oocytes/drug effects/metabolism; Oxadiazoles/administration & dosage/*pharmacology; Pyridazines/pharmacology; Pyrroles/pharmacology; Rats; Receptors, Nicotinic/*drug effects/metabolism; Xenopus laevis; alpha7 Nicotinic Acetylcholine Receptor  
  Abstract BACKGROUND AND PURPOSE: Several agonists of the alpha7 nicotinic acetylcholine receptor (nAChR) have been developed for treatment of cognitive deficits. However, agonist efficacy in vivo is difficult to reconcile with rapid alpha7 nAChR desensitization in vitro; and furthermore, the correlation between in vitro receptor efficacy and in vivo behavioural efficacy is not well delineated. The possibility that agonists of this receptor actually function in vivo as inhibitors via desensitization has not been finally resolved. EXPERIMENTAL APPROACH: Two structurally related alpha7 nAChR agonists were characterized and used to assess the degree of efficacy required in a behavioural paradigm. KEY RESULTS: NS6784 activated human and rat alpha7 nAChR with EC(50)s of 0.72 and 0.88 microM, and apparent efficacies of 77 and 97% respectively. NS6740, in contrast, displayed little efficacy at alpha7 nAChR (<2% in oocytes, < or =8% in GH4C1 cells), although its agonist-like properties were revealed by adding a positive allosteric modulator of alpha7 nAChRs or using the slowly desensitizing alpha7V274T receptor. In mouse inhibitory avoidance (IA) memory retention, NS6784 enhanced performance as did the 60% partial agonist A-582941. In contrast, NS6740 did not enhance performance, but blocked effects of A-582941. CONCLUSIONS AND IMPLICATIONS: Collectively, these findings suggest that a degree of alpha7 nAChR agonist efficacy is required for behavioural effects in the IA paradigm, and that such behavioural efficacy is not due to alpha7 nAChR desensitization. Also, a partial agonist of very low efficacy for this receptor could be used as an inhibitor, in the absence of alpha7 nAChR antagonists with favourable CNS penetration.  
  Call Number Serial 1881  
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Author (up) Fudala, P.J.; Iwamoto, E.T. file  url
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  Title Further studies on nicotine-induced conditioned place preference in the rat Type Journal Article
  Year 1986 Publication Pharmacology, Biochemistry, and Behavior Abbreviated Journal Pharmacol Biochem Behav  
  Volume 25 Issue 5 Pages 1041-1049  
  Keywords Animals; Avoidance Learning/drug effects; Behavior, Animal/*drug effects; Conditioning (Psychology)/*drug effects; Cotinine/pharmacology; Dose-Response Relationship, Drug; Lobeline/pharmacology; Male; Motor Activity/drug effects; Motor Skills/drug effects; Nicotine/*pharmacology; Rats; Rats, Inbred Strains; Time Factors  
  Abstract Rats received subcutaneous (SC) injections of either nicotine (NIC, 0.001 to 2.0 mg/kg) or saline (SAL, 1 ml/kg) immediately prior to conditioning sessions in a conditioned place preference (CPP) paradigm. NIC was paired for 3 conditioning sessions with one environment of a 3 compartment CPP apparatus; SAL was paired with another environment. The animals were then tested for place preference by determining the proportion of time spent in each compartment during a 15 min test session. A dose-response curve was obtained for the place conditioning effect of nicotine as measured by its ability to alter baseline preferences calculated from control rats. NIC's place preference, but not place aversion, effect was linearly correlated with respect to dosage within the range of 0.1 to 0.8 mg/kg. NIC, 0.8 mg/kg, induced a place preference when it was administered immediately prior to conditioning sessions, but not when administered 20, 60 or 120 min prior to the sessions. Three repeated conditioning and testing cycles, or the daily administration of NIC for 2 weeks between conditioning and testing cycles had little or no effect on NIC place conditioning. Lobeline (2, 10 and 20 mg/kg) or cotinine (1 to 50 mg/kg) failed to condition a place preference. NIC, 0.1 or 1.2 mg/kg SC, administered to rat pups on postnatal days 5 through 8, did not alter subsequent place preference (induced by 0.8 mg/kg of NIC) measured at approximately 40 and 70 days of age. Periodic measurements of spontaneous motor activity, forelimb grip strength and negative geotaxis were unaltered by the perinatal exposure to nicotine.  
  Call Number Serial 233  
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Author (up) Schmatz, R.; Mazzanti, C.M.; Spanevello, R.; Stefanello, N.; Gutierres, J.; Correa, M.; da Rosa, M.M.; Rubin, M.A.; Chitolina Schetinger, M.R.; Morsch, V.M. file  url
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  Title Resveratrol prevents memory deficits and the increase in acetylcholinesterase activity in streptozotocin-induced diabetic rats Type Journal Article
  Year 2009 Publication European Journal of Pharmacology Abbreviated Journal Eur J Pharmacol  
  Volume 610 Issue 1-3 Pages 42-48  
  Keywords Acetylcholinesterase/*metabolism; Animals; Avoidance Learning/drug effects; Behavior, Animal/drug effects; Blood Glucose/analysis; Cholinesterase Inhibitors/*pharmacology; Diabetes Mellitus, Experimental/blood/*enzymology; Dose-Response Relationship, Drug; Memory/drug effects; Memory Disorders/chemically induced/enzymology/*prevention & control; Random Allocation; Rats; Stilbenes/*pharmacology; Streptozocin/pharmacology  
  Abstract The objective of the present study was to investigate the effect of the administration of resveratrol (RV) on memory and on acetylcholinesterase (AChE) activity in the cerebral cortex, hippocampus, striatum, hypothalamus, cerebellum and blood in streptozotocin-induced diabetic rats. The animals were divided into six groups (n=6-13): Control/saline; Control/RV 10 mg/kg; Control/RV 20 mg/kg; Diabetic/saline; Diabetic/RV 10 mg/kg; Diabetic/RV 20 mg/kg. One day after 30 days of treatment with resveratrol the animals were submitted to behavioral tests and then submitted to euthanasia and the brain structures and blood were collected. The results showed a decrease in step-down latency in diabetic/saline group. Resveratrol (10 and 20 mg/kg) prevented the impairment of memory induced by diabetes. In the open field test, no significant differences were observed between the groups. In relation to AChE activity, a significant increase in diabetic/saline group (P<0.05) was observed in all brain structures compared to control/saline group. However, AChE activity decreased significantly in control/RV10 and control/RV20 (P<0.05) groups in cerebral cortex, hippocampus and striatum, while no significant differences were observed in diabetic/RV10 and diabetic/RV20 groups in all brain structures compared to control/saline group. Blood AChE activity increased significantly in diabetic/saline group (P<0.05) decreased in control/RV10, control/RV20 and diabetic/RV20 groups (P<0.05) compared to control/saline group. In conclusion, the present findings showed that treatment with resveratrol prevents the increase in AChE activity and consequently memory impairment in diabetic rats, demonstrating that this compound can modulate cholinergic neurotransmission and consequently improve cognition.  
  Call Number Serial 323  
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