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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    733—Cocaine Reinforcement, Seeking, and Reinstatement I

    Wednesday, November 13, 2013, 8:00 am - 12:00 noon

    733.15: Enhanced cocaine-seeking behavior after optogenetic stimulation of the accumbens shell to lateral hypothalamic (AcbSh-LH) pathway

    Location: Halls B-H

    *E. B. LARSON, A. M. WISSMAN, D. W. SELF;
    Psychiatry, UT Southwestern, Dallas, TX

    Abstract Body: Pharmacological or molecular activation of the nucleus accumbens shell (AcbSh) facilitates extinction of cocaine-seeking behavior (Sutton et al. 2003; Peters et al. 2008). However, over-expression of CREB, which increases excitability of AcbSh neurons (Dong et al. 2006), enhances cocaine-seeking behavior (Larson et al. 2011). These discrepancies may reflect activity in differential AcbSh outputs, including those to the lateral hypothamus (LH), a target region known to influence drug-related behavior (Marchant et al. 2012). Interestingly, while general inhibition of the AcbSh can directly reinstate alcohol-seeking behavior (Millian et al. 2010), reinstatement of alcohol seeking also is associated with activation, rather than inhibition, of AcbSh projections to the LH (Marchant et al. 2009). Presently, it is unknown if there is a causal link between altered activity in the AcbSh-LH pathway and changes in cocaine-seeking behavior. Therefore, in this study, we used an optogenetics approach to stimulate AcbSh nerve terminals expressing channelrhodopsin2 (ChR2) within the LH for comparison with generalized stimulation of cell bodies in the AcbSh. Rats were infused with an AAV-ChR2 viral vector in the AcbSh, and fiber optic cannula were positioned ~0.5 mm above the LH or AcbSh to allow for blue-light (473 nm) stimulation of AcbSh-LH terminals or cell bodies in the AcbSh, respectively. After recovery, rats self-administered cocaine (0.5 mg/kg, FR1) for 3 weeks, and were withdrawn from cocaine for 3 days. Rats were then given optogenetic stimulation over a 30 min pretreatment period (20 Hz, 200 pulses/min, 5 ms/pulse), and the subsequent motivation for cocaine was assessed using a progressive ratio test. In addition, the propensity for relapse to cocaine seeking was assessed after an additional week of withdrawal using the extinction-reinstatement test. We found that stimulation of the AcbSh-LH pathway enhanced the motivation to self-administer cocaine in progressive ratio testing, and facilitated cocaine-seeking behavior during withdrawal. Interestingly, global optogenetic stimulation of cell bodies within the AcbSh produced the opposite effect, and reduced both the motivation to self-administer cocaine and cocaine-seeking in withdrawal. These data suggest that the behavioral effects of LH terminal stimulation are not due to antidromic activation of AcbSh cell bodies, and suggest that different AcbSh outputs may play very different roles in the regulation of drug-seeking behavior. Together these findings suggest that the AcbSh produces highly complex and pathway-specific modulation of drug-seeking behavior.

    Lay Language Summary: Our research indicates that selective activation of discrete brain circuits can have profound effects on addictive behavior. Addiction is a devastating disorder with serious medical, social, and economic consequences. Decades of research have identified several key regions of the brain that are altered by chronic exposure to addictive drugs. One region that undergoes major modification after chronic drug exposure is the nucleus accumbens shell (AcbSh). The AcbSh mediates the rewarding effects of addictive drugs, but also is involved in translating incoming emotional input into appropriate behavioral outputs. Several drug-induced changes in the AcbSh lead to alterations in how easily the AcbSh brain cells are stimulated. Therefore, it is possible that drugs cause addictive behavior by altering the ability of AcbSh brain cells to communicate with output target brain regions: the ventral tegmental area, the ventral pallidum, and the lateral hypothalamus. Presently, however, little is known about how altering the activity of these AcbSh outputs might influence addictive behavior.
    To study this, we utilized a technique called optogenetics to artificially stimulate AcbSh brain cells prior to behavioral tests of addictive behavior. We chose to examine two stimulation conditions - either activate AcbSh neurons globally (alters all three target outputs), or to selectively activate a single target. For the latter, we chose to activate the AcbSh output to the lateral hypothalamus, as there is relatively little known about the role of this projection in addictive behavior. To measure addictive behavior in rats, we used the intravenous drug self-administration procedure to determine the rats’ motivation to obtain cocaine, as well as the amount of craving and propensity for relapse withdrawal. In these tests, rats have voluntary control over their drug intake, and must press a lever to receive the intravenous cocaine infusions. The cost of cocaine is initially low (one lever press per infusion), and rats self-administered cocaine in daily sessions until their drug use became regular.
    Once drug use was regular, rats were given optogenetic stimulation to activate AcbSh outputs, and were then tested to see how hard they would work (in lever presses) to receive a single cocaine infusion. We found that when we globally activated AcbSh outputs prior to this motivational test, rats tended to work less than control (un-stimulated) rats. Surprisingly, when we selectively stimulated the AcbSh-lateral hypothalamus output alone, we found the opposite effect: the rats now worked much harder for cocaine. A similar dichotomy was found when rats were tested for how intensely they sought out cocaine after a drug-free period. When returned to the drug-taking environment, rats that had selective activation of the AcbSh-lateral hypothalamus output showed greater cocaine-seeking behavior, while cocaine-seeking was reduced when all of the AcbSh outputs were activated non-discriminately.
    Our ability to unmask these opposing influences of global AcbSh and selective AcbSh-lateral hypothalamus stimulation on addictive behavior is important, as it demonstrates that altered activity in different AcbSh outputs can have very different or even opposite consequences on addictive behavior. This suggests that increases in the excitability of certain AcbSh brain cells is actually protective against further drug use, while others are maladaptive and facilitate the drive for drugs. These findings, along with others in the field, are beginning to open our eyes to the complexity of information that can be transmitted from one brain region to another, and they help to increase our understanding of how these circuits communicate with one another to regulate motivated behavior. These findings also suggest that a better understanding of aberrant communication amongst these circuits after chronic drug use might lead to the development of circuit-specific (and possibly symptom specific) treatments that reduce addictive behavior.