Environmental enrichment reverses heroin-caused neural and behavioral adaptations in rats - Summary Abstract Heroin use disorder continues to be a serious and growing national health problem that requires an effective solution that produces long-term abstinence and prevents relapse. A major problem in the treatment of substance use disorder is the prevention of relapse, itself triggered by stress, drug cues and drug itself. Addiction treatments are only modestly successful in maintaining long-term abstinence and preventing relapse. However, an emerging effective behavioral treatment is environmental enrichment (EE). We have demonstrated in rat models of relapse that EE administered as a treatment after heroin self-administration training significantly facilitates abstinence and reduces heroin cue-induced reinstatement of drug seeking. In recent years, there has been an increase in the clinical use of EE as treatment for substance use disorder. However, almost nothing is known about the behavioral and neural mechanisms by which EE confers its beneficial effects on abstinence and relapse. A better understanding of these mechanisms not only is valuable in its own right but also would aid in the development of improved neurobiological and behavioral treatments. It is well-established that the relapse trigger—drug cues—activates dopamine (DA) neurons in the ventral tegmental area (VTA) causing DA release in terminal regions of this DA system and that DA release in those regions causes “drug craving” and relapse in humans and animals. EE causes profound changes in behavior, cognition and brain, including in the terminal regions of the VTA DA system. We hypothesize that EE may reduce drug seeking by reversing some of the behavioral and neural adaptations brought about by chronic heroin intake. The proposed studies will investigate this. In Specific Aim 1 we will characterize adaptations in DA release in the terminal regions of the DA system as a result of heroin self-administration and determine if those adaptations are reversed by EE. In Specific Aim 2 we will characterize how heroin self-administration dysregulates addiction-associated receptors in the terminal regions of the DA system and determine if those adaptations are reversed by EE. Drug addiction also is associated with negative affect and anhedonia (diminished capacity for non-drug reward). We propose that those negative states contribute to continued drug seeking and use and, therefore, understanding how to reverse them would aid in the development of improved treatments. We hypothesize that EE confers its beneficial effects on drug seeking by reversing the negative affect and anhedonia associated with chronic drug use. In Specific Aim 3 we will characterize the behavioral adaptations occurring as a result of chronic opioid intake and determine if EE reverses those adaptations. The proposed studies will (1) reveal neural and behavioral adaptations that underlie drug addiction and (2) reveal those adaptions that can be targeted for reversal in order to neurobiologically and behaviorally reduce drug seeking (i.e., relapse), leading to the development of more effective treatments for substance use disorder.
