UC San Diego

Psychostimulant addiction is a chronically relapsing disorder characterized by escalated drug intake and persistent drug craving, which are compulsive behavioral effects due to negative affective states experienced during withdrawal. When endogenous opioid dynorphin binds to kappa-opioid receptors (KORs) in the mesolimbic system, transmission of dopamine to the nucleus accumbens (NAc) is decreased. It is theorized that increased activity of the dynorphin/KOR system mediates the dysphoric component of psychostimulant withdrawal and thus facilitates the transition from occasional psychostimulant use to chronic dependence. This thesis examines two aspects of how upregulation of the dynorphin/KOR system drives the transition toward methamphetamine dependence. Dynorphin activates KORs, which leads to increased activity of transcription factor cyclic adenosine monophosphate response element-binding protein (CREB) within the NAc; in turn, increased CREB activity leads to expression of more dynorphin. Experiment 1 explored the relationship between elevated NAc CREB activity and the compulsive drug--taking behavior associated with extended access to methamphetamine. Immunoreactivity of phospho-CREB within the NAc core and shell was compared to access condition (1 h limited- or 6 h extended-access) and overall escalation of methamphetamine self-administration. The positive correlation between NAc phospho-CREB and methamphetamine intake implicates mesolimbic CREB activity in compulsive methamphetamine-taking behavior. Experiment 2, which examined the effects of KOR antagonist nor-Binaltorphamine (nor-BNI) on re-escalation of drug-taking and reinstatement of drug-seeking, showed that the compulsive behaviors associated with chronic methamphetamine abuse are reversible. The combined results of this thesis preliminarily identify NAc CREB as a potential therapeutic target for treatment of pre-existing methamphetamine addiction