The extinction of drug seeking: a role for the nucleus accumbens shell

Relapse following abstinence from drug use remains the major impediment for the treatment of addiction. Major advances have been made in understanding the brain systems that promote relapse. Much less is known about the brain systems that promote abstinence. The focus of the present dissertation was to investigate the brain systems that promote abstinence by examining the neural substrates underlying the extinction of reward seeking in rats. The first series of experiments (Chapter 3) studied the role of the nucleus accumbens shell (AcbSh) and its interactions with lateral hypothalamus (LH) in mediating the extinction of alcoholic beer seeking. These experiments demonstrated that functional inactivation of the AcbSh prevented the expression of extinction and so reinstated previously extinguished alcoholic beer seeking. It had no effect on the acquisition of extinction. Moreover, the reinstatement produced by AcbSh inactivation was associated with c-Fos expression in hypothalamus, including in orexin- and CART-containing neurons in LH. It was also shown that concurrent inactivation of LH blocked reinstatement produced by AcbSh inactivation. Finally, contralateral but not ipsilateral disconnection of AcbSh from anterior LH prevented expression of extinction, suggesting that serial AcbSh→LH communication is necessary for extinction of reward seeking. The second series of experiments (Chapter 4) studied the role of AcbSh AMPA type-glutamate receptors and interactions with the basolateral amygdala (BLA) in mediating extinction of alcoholic beer seeking. These experiments demonstrated that intra-AcbSh infusions of the AMPA receptor antagonist, NBQX, attenuated the expression of extinguished responding. This effect was dose-dependent and specific to the behavioural expression of extinction; it had no effect on measures of non-extinguished responding, including context-induced reinstatement, initial extinction acquisition, and responding on a progressive ratio schedule. This chapter also reported that contralateral but not ipsilateral disconnection of the BLA from AcbSh prevented the expression of extinction, suggesting that serial BLA→AcbSh communication is necessary for the extinction of reward seeking. However, in the final experiment, reversible inactivation of the BLA failed to prevent the expression of extinction. Together, the findings from this thesis suggest that a circuit involving BLA→AcbSh and AcbSh →LH actively promotes expression of extinction of reward seeking in rats