The objective of this project is to elucidate the neural substrates by which dynorphin A 2-17 (DYN 2-17) prevents the enhancement of the conditioned reinforcing effects of cocaine which occurs following the repeated intermittent administration of cocaine (e.g. sensitization) and determine whether the acute administration of DYN 2-17 attenuates the positive reinforcing effects of this psychostimulant. This issue will be addressed using three established animal models of drug reinforcement together with the technique of in vivo microdialysis. The three behavioral procedures include conditioned place preference, drug discrimination and self-administration. Our goals are to determine whether: 1) DYN 2-17 prevents the development of sensitization to the conditioned reinforcing effects of cocaine via a k-opioid receptor independent mechanism and if peptides with structural similarities to DYN are also effective in preventing sensitization to cocaine; 2) determine the CNS mechanisms mediating the stimulus effects of DYN 2-17 and the attenuation of the reinforcing effects of cocaine by DYN 2-17 and related peptides; 3) DYN 2-17 modulates basal and NMDA-evoked dopamine (DA) overflow within the NAC as well as alterations in DA and glutamate (GLU) overflow which occurs following the repeated administration of cocaine and; 4) the repeated administration of cocaine increases the expression of DYN 2-17 in the nucleus accumbens and other brain regions comprising the mesocorticolimbic system. All three behavioral paradigms will be used to assess changes in the behavioral effects of cocaine which occur following the administration of DYN and related peptides. Cocaine self-administration will be used to determine whether endogenous peptide levels are increased following repeated cocaine administration. Microdialysis will be used to monitor changes in basal DA and Glu overflow within the NAC as well as NMDA-evoked DA overflow within the NAC which occur following the repeated administration of DYN 2-17 and cocaine. Our overall hypothesis is that: 1) DYN 2-17 suppresses basal and NMDA-evoked DA overflow within the NAC via an opioid receptor independent mechanism and that 2) these actions underlie the efficacy of DYN 2-17 in attenuating the positive rewarding effects of cocaine and the sensitization which develops to the conditioned reinforcing effects of cocaine following repeated cocaine administration.
| Szeto, Hazel H (2003) Dynorphin and the hypothalamo-pituitary-adrenal axis during fetal development. Life Sci 73:749-58 |
| Sankararamakrishnan, R; Weinstein, H (2000) Molecular dynamics simulations predict a tilted orientation for the helical region of dynorphin A(1-17) in dimyristoylphosphatidylcholine bilayers. Biophys J 79:2331-44 |
