Hypothalamic control of reinstatement and extinction of drug seeking in the rat

Abstract

Drug addiction is a chronically relapsing condition, and current relapse prevention therapies are not effective. Drug addiction can be considered a disorder of motivation, and the hypothalamus is a structure that is critical for the expression of motivated behaviour. The present series of experiments used an animal model of relapse, context-induced reinstatement, to investigate the role of the hypothalamus in the expression of extinction and reinstatement of drug and reward seeking. The first series of experiments (Chapter 2) demonstrated that functional inactivation of LH blocks context-induced reinstatement of sucrose and alcoholic beer seeking. Furthermore it was shown that activity in an AcbShV → LH pathway is associated with reinstatement, whereas activity in an AcbShDm → LH pathway is associated with extinction, of alcoholic beer seeking. The second series of experiments (Chapter 3) demonstrated that activity in an ilPFC → MDH pathway is associated with extinction expression. The remaining experiments of Chapter 3 demonstrated that MDH mediates the inhibition of reward seeking after extinction training. MDH infusion of CART 55 – 102 were shown to reinstate extinguished sucrose and alcoholic beer seeking in the extinction context. This effect was shown to be pharmacologically specific, anatomically restricted, dose-dependent, and specific to the expression of extinction. Thus it was concluded that MDH mediates the expression of extinction, and MDH infusion of CART 55 – 102 selectively abolished this extinction expression. The final series of experiments (Chapter 4) demonstrated that activity in an MDH → PVT pathway is associated with extinction expression. The majority of these neurons were shown to express prodynorphin, the precursor peptide to endogenous KOR ligands. A final experiment demonstrated that intra-PVT infusion of a KOR agonist attenuated context-induced reinstatement of alcoholic beer seeking. This indicates that activity at KOR in PVT is sufficient to inhibit alcoholic beer seeking. The findings of this thesis demonstrate the hypothalamus mediates bi-directional control over context mediated drug seeking. The functional neurocircuitry experiments demonstrated evidence for distinct reinstatement and extinction circuits. It is proposed that inhibition of drug seeking during extinction is mediated by active inhibition of the reinstatement circuit by the extinction circuit.