The primary long-term goal of this project is to employ behavioral pharmacological methods to investigate neura1 substrates underlying the self-administration of opiate and stimulant drugs of abuse. Toward this end, three specific aims are described each of which is intended to build upon and extend the work completed during the first nine years of this project. These are; 1) to continue investigations of the putative reward-attenuating actions of dopamine antagonist drugs on opiate- and stimulant-reinforced behaviors; 2) to further examine the role of drug-paired stimuli in drug self-administration and drug relapse; and 3) to continue investigations of the anxiogenic side effects of chronic cocaine. The hypothesis driving this work is that central dopaminergic (DA) systems are responsible for the reinforcing properties of both opiate and stimulant drugs. While this position is hardly unique, the methodological approach taken in this project is novel in a number of ways: I) while traditional lever-press procedures examine the behavior of drugged animals working to maintain their drug plasma levels, the current project examines IV drug reinforcement using an operant runway where animals received only one drug injection per day. In this context, the speed with which Ss traverse the alley for drug reinforcement has operationally provided a reliable index of the undrugged animals' motivation to obtain the reinforcer; ii) by testing only one trial per day, the resulting data are devoid of potential confounding and nonspecific effects produced by the drug reinforcers themselves; iii) a response reinstatement test is used to examine the factors that result in the reinstatement of operant runway behavior after a prolonged period of abstinence, and hence serves as a viable model of human drug relapse; and iv) in each of the studies, the putative reinforcement-attenuating actions of antagonist drugs are assessed at a time when the drug's direct pharmacological effects are no longer present (i.e., on the first post-treatment trial 24 hrs post-injection). This permits conclusions about antagonist effects on operant behavior that are not confounded by the sedative arrd motoric side-effects of these test agents. In summary, the work proposed in this application is intended to provide important new information about the nature and neurobiology of both the positive and negative factors that together determine the nature and extent of human drug self-administration behaviors.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Lynch, Minda
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University of California Santa Barbara
Schools of Arts and Sciences
Santa Barbara
United States
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Ettenberg, Aaron; Fomenko, Vira; Kaganovsky, Konstantin et al. (2015) On the positive and negative affective responses to cocaine and their relation to drug self-administration in rats. Psychopharmacology (Berl) 232:2363-75
Wenzel, Jennifer M; Cotten, Samuel W; Dominguez, Hiram M et al. (2014) Noradrenergic ?-receptor antagonism within the central nucleus of the amygdala or bed nucleus of the stria terminalis attenuates the negative/anxiogenic effects of cocaine. J Neurosci 34:3467-74
Su, Zu-In; Santoostaroam, Ashley; Wenzel, Jennifer et al. (2013) On the persistence of cocaine-induced place preferences and aversions in rats. Psychopharmacology (Berl) 229:115-23
Kerstetter, Kerry A; Su, Zu-In; Ettenberg, Aaron et al. (2013) Sex and estrous cycle differences in cocaine-induced approach-avoidance conflict. Addict Biol 18:222-9
Wenzel, Jennifer M; Su, Zu-In; Shelton, Kerisa et al. (2013) The dopamine antagonist cis-flupenthixol blocks the expression of the conditioned positive but not the negative effects of cocaine in rats. Pharmacol Biochem Behav 114-115:90-6
Su, Zu-In; Kichaev, Gleb; Wenzel, Jennifer et al. (2012) Weakening of negative relative to positive associations with cocaine-paired cues contributes to cue-induced responding after drug removal. Pharmacol Biochem Behav 100:458-63
Ettenberg, Aaron; Ofer, Oren A; Mueller, Carl L et al. (2011) Inactivation of the dorsal raphe nucleus reduces the anxiogenic response of rats running an alley for intravenous cocaine. Pharmacol Biochem Behav 97:632-9
Wenzel, Jennifer M; Waldroup, Stephanie A; Haber, Zachary M et al. (2011) Effects of lidocaine-induced inactivation of the bed nucleus of the stria terminalis, the central or the basolateral nucleus of the amygdala on the opponent-process actions of self-administered cocaine in rats. Psychopharmacology (Berl) 217:221-30
Su, Zu-In; Wenzel, Jennifer; Baird, Rebeccah et al. (2011) Comparison of self-administration behavior and responsiveness to drug-paired cues in rats running an alley for intravenous heroin and cocaine. Psychopharmacology (Berl) 214:769-78
Moscarello, J M; Ben-Shahar, O; Ettenberg, A (2010) External incentives and internal states guide goal-directed behavior via the differential recruitment of the nucleus accumbens and the medial prefrontal cortex. Neuroscience 170:468-77

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