Evaluation of neuroprotection and behavioral recovery by the kappa-opioid, PD117302 following transient forebrain ischemia.
The effects of the selective kappa-opioid, PD117302 ((+/-)-trans-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzo[b]thiophene-4-acetamide), on transient (15 min) global forebrain ischemia, induced by four-vessel occlusion, was evaluated using a multiple fixed-ratio, fixed-interval schedule of food presentation in rats. The schedule produced distinctive patterns of responding in the fixed-ratio and fixed-interval components. Ischemia produced CA1 hippocampal necrosis and prolonged suppression of responding under both schedule components. When responding resumed, the pattern of responding rapidly returned. Response disruption and CA1 hippocampal necrosis were minimal or nonexistent in sham-occluded rats. Behavioral recovery time under both components of the schedule of reinforcement correlated with CA1 necrosis. On average, CA1 necrosis was less, and behavioral recovery time was shorter, in rats treated with PD117302 postocclusion as compared with vehicle-treated rats. The difference, however, did not reach statistical significance. These results demonstrate the utility of schedule-controlled responding for evaluating potentially therapeutic compounds for the treatment of ischemic injury. These results also further characterize the neuroprotective actions of kappa opioids.
Genovese
R F
RF
Department of Medical Neurosciences, Walter Reed Army Institute of Research, Washington, DC 20307.
Moreton
J E
JE
Tortella
F C
FC
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects*; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000523:psychology; D008297:Male; D016548:Prosencephalon / Q000098:blood supply*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000187:drug effects*; D012055:Reinforcement Schedule; D013876:Thiophenes / Q000494:pharmacology*
D011758:Pyrroles; D017473:Receptors, Opioid, kappa; D013876:Thiophenes; C054718:PD 117302