Cocaine has been shown to have profound positive and negative actions that adhere closely to the classic """"""""opponent process"""""""" theory of motivated behavior. That theory postulates that dual and opposing systems work in tandem to maintain emotional homeostasis. Indeed, cocaine administration in both humans and animals has been shown to produce an initial euphoric/rewarding action followed in time by an aversive """"""""crash"""""""" that is characterized by states of anhedonia and anxiety. The underlying hypothesis guiding the proposed research is that a thorough understanding of the factors that underlie the initiation, maintenance and reinstatement of cocaine abuse must include an understanding of how these dual and opposing properties of the drug interact to motivate drug-seeking behavior. In this context, three specific aims are proposed:
Specific Aim 1 involves studies intended to assess the relative roles of positive and negative drug-cue associations, and the drug's own direct positive and negative actions, in the reinstatement of cocaine-seeking behavior in both """"""""addicted"""""""" and """"""""non-addicted"""""""" animals following varying periods of drug abstinence.
Specific Aim 2 will test the hypothesis that individual differences in the positive and negative responses to cocaine and cocaine-paired cues predict an animal's """"""""risk"""""""" for drug self-administration.
Specific Aim 3 describes research intended to extend previous results showing that functional lesions of structures within the """"""""extended amygdala"""""""" can prevent the expression of cocaine's negative/anxiogenic properties. Studies will examine the roles of NE, 5-HT and CRF systems within these structures to identify the substrates responsible for cocaine's negative properties, and immunocytochemical studies are planned to link cocaine's dual behavioral effects to patterns of neuronal activation in select brain regions associated with reward and aversion. Each of these aims logically builds upon and extends previous findings from the Principal Investigator's laboratory and each is based upon the view that a) cocaine- seeking behavior (in both addicted and non-addicted animals) ultimately depends upon the balance between the inherent positive and negative properties of the drug, or stimuli associated with the drug, b) that this balance determines the vulnerability for the acquisition and relapse of cocaine-seeking behavior, and c) that the dual actions of cocaine are mediated by separate and identifiable neuronal systems. Two behavioral methods will be employed: a runway model of cocaine self-administration that is uniquely sensitive to cocaine's mixed positive and negative actions in the same animal on the same trial (animal's exhibit approach-avoidance conflict about entering a goal-box associated with cocaine administration) and a modified conditioned place test that permits for the dissociation of the positive and negative properties of the drug (animals come to prefer distinct locations paired with the immediate effects of cocaine while avoiding places associated with the effects present 15-min post IV injection). When used in tandem, these two tests provide a unique and powerful behavioral toolkit for dissociating whether an experimental manipulation alters the positive and/or the negative properties of IV cocaine. The proposed research will therefore employ behavioral, pharmacological and immunocytochemical methodologies to elucidate the behavioral and neurobiological mechanisms underlying the dual opponent properties of cocaine that ultimately interact to motivate rats to seek cocaine and to reinstate cocaine-seeking after a period of drug abstinence.

Public Health Relevance

Cocaine has been shown to have both immediate positive/rewarding and delayed negative/anxiogenic effects in both humans and animals. The current application tests the hypothesis that cocaine-seeking is ultimately a consequence of the balance between these inherent positive and negative properties of the drug. Thus, an elucidation of the behavioral and neurobiological nature of these opponent processes, and how they differ in the non-addicted and addicted organism, will provide a more complete understanding of the factors that result in cocaine abuse.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Lynch, Minda
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University of California Santa Barbara
Schools of Arts and Sciences
Santa Barbara
United States
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Akhiary, Mona; Purvis, Erin M; Klein, Adam K et al. (2018) Methamphetamine self-administration in a runway model of drug-seeking behavior in male rats. Pharmacol Biochem Behav 175:27-32
Purvis, Erin M; Klein, Adam K; Ettenberg, Aaron (2018) Lateral habenular norepinephrine contributes to states of arousal and anxiety in male rats. Behav Brain Res 347:108-115
Klein, Adam K; Brito, Michael A; Akhavan, Sayeh et al. (2017) Attenuation of the anxiogenic effects of cocaine by 5-HT1B autoreceptor stimulation in the bed nucleus of the stria terminalis of rats. Psychopharmacology (Berl) 234:485-495
Shelton, Kerisa; Bogyo, Kelsie; Schick, Tinisha et al. (2016) Pharmacological modulation of lateral habenular dopamine D2 receptors alters the anxiogenic response to cocaine in a runway model of drug self-administration. Behav Brain Res 310:42-50
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
Ettenberg, Aaron; Cotten, Samuel W; Brito, Michael A et al. (2015) CRF antagonism within the ventral tegmental area but not the extended amygdala attenuates the anxiogenic effects of cocaine in rats. Pharmacol Biochem Behav 138:148-55
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

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