BEHAVIORAL PHARMACOLOGY OF OPIATE-LIKE NEUROPEPTIDES

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Converging evidence suggests that endogenons opioid systems (EOS) may play an important role in modulating behavioral responsiveness to stressful situations. However, further progress is limited, in part, because of inadequate or incomplete behavioral characterization of various opioid and stress treatments. In addition, comparison of these effects would be greatly facilitated if the behavioral characterization was carried out under similar experimental conditions. Our behavioral system has been specifically designed for the continuous and concurrent monitoring of a broad spectrum of behavioral responses including various measures of arousal, environmental interaction, and ingestive behaviors. The proposed research represents a systematic progression of studies designed to assess the role of EOS in the various behavioral components associated with different types and degress of stress. The acute and chronic behavioral profiles of putative mu (morphine, methadone), kappa- (ketocyclazocine, ethylcyclazocine), sigma- ((+NANM, PCP), and delta- (D-Ala2-Met5-enkephalinamide) opiate receptor agonists will be characterized in the RACs as will the relatively pure opiate antagonists naloxone, naltrexone, and diprenorphine. Under identical experimental conditions, the effects of restraint, noise, and exposure to a novel environment will be determined. Acute interactions and cross-tolerance/sensitization between opioid and stress effects will be examined to determine the extent to which similar behaviors induced by these treatments are mediated by common underlying mechanisms. Stress-opioid interactions will also be examined with the use of our multicompartment chamber and behavioral pattern monitor, and with startle and social interaction paradigms. We will also assess further the effects of NE dorsal bundle lesions on the response to representative opioid and stress treatments. In addition to the conventional stressors, the role of EOS in the alleged stress component of the acute and chronic response to amphetamine and in the apparent susceptibility of spontaneously hypertensive rats to stress will also be examined. The detailed acute and chronic behavioral characterization of exogenously administered opioids and various stressors should enhance our understanding of the role of EOS in the regulation of responsiveness to stress. The potential clinical value of this research is indicated by the accumulating evidence that stress may be significantly implicated in the pathogenesis of major forms of psychopathology including depression and schizophrenia. In addition, individual differences in responsiveness to stress may be involved in determining predisposition to drug abuse.