Hypothalamic regulation of morphine-induced conditioned place preference
Drug addiction is characterized by compulsive drug-taking and drug-seeking and has enormous consequences on addicts as well as on society. Drugs of abuse are rewarding and due to the complexity of drug addiction, the development of pharmacotherapies for the treatment of drug addiction has not yet been successful. Recently, attention has focused on the hypothalamic orexin and oxytocin systems as promising targets for the treatment of drug addiction. To determine whether the orexin and oxytocin systems might modulate the rewarding effects of morphine during the development and maintenance of morphine addiction, I used the conditioned place preference (CPP) procedure. In the present study, morphine (5 mg kg-1; subcutaneous) administration 5 min prior to the conditioning sessions induced preference for the morphine-paired compartment in control animals. The results showed that neither orexin A (10 µg) nor the non-selective orexin receptor antagonist, TCS 1102 (25 µg), affected the acquisition or expression of morphine-induced CPP. Experiments with oxytocin revealed a specific effect on expression but not acquisition of morphine-induced CPP. Neither oxytocin (0.2 µg) nor oxytocin receptor antagonist (OTA) (0.75 µg) administered into the lateral ventricle 5 min before the conditioning sessions affected the acquisition of morphine-induced CPP. By contrast, intracerebroventricular (ICV) administration of oxytocin, but not OTA, 5 min prior to the post-conditioning test increased the expression of morphine-induced CPP without affecting the overall activity of morphine-conditioned rats. To investigate whether the effect of exogenous oxytocin administration on the expression of morphine-induced CPP might be mediated by activation of oxytocin receptors within the nucleus accumbens shell (NAcSh), bilateral intra-NAcSh injections of oxytocin (10 ng in each side) or OTA plus oxytocin (37.5 ng plus 10 ng in each side) were given 5 min prior to the post-conditioning test. The results suggested that there might be some contribution of NAcSh oxytocin receptors to oxytocin enhancement of the expression of morphine-induced CPP by ICV oxytocin. To investigate the effects of ICV oxytocin on the activity of NAcSh neurons, in vivo electrophysiological recordings of the medial NAcSh neurons were made under urethane anaesthesia from morphine-naive rats (no morphine treatment) and morphine-treated rats (given three daily injections of morphine before the day of recording with the same dosing regime as used for induction of CPP). Chronic morphine treatment decreased the spontaneous firing rate of medial NAcSh neurons and increased regularity of firing of these cells, as indicated by a decrease in the coefficient of variation of inter-spike interval. In morphine-naive rats, ICV administration of oxytocin (0.2 µg) caused a transient increase in the firing rate of medial NAcSh neurons that was typically maximal 10 – 15 min after the injection. The oxytocin-induced change in medial NAcSh firing rate was higher in morphine-naive rats than in morphine-treated rats. Nevertheless, a similar proportion of medial NAcSh neurons were excited by oxytocin in morphine-naive and morphine-treated rats. Although the precise mechanisms remain to be established, the oxytocin enhancement of morphine CPP is likely to be driven by oxytocin facilitation of dopamine release within the NAcSh. The decreased oxytocin excitation of the NAcSh neurons in animals previously exposed to morphine might be underpinned by morphine-induced downregulation of NAcSh D1 receptors, leading to reduced excitatory glutamate transmission onto the NAcSh neurons. Because reward-related behaviours are thought to be mediated by decreases in the firing rate of NAc neurons, the relative desensitisation of NAcSh responses by chronic morphine treatment might allow oxytocin actions on other brain areas that express oxytocin receptors to be unmasked. Taken together, these results suggest that oxytocin does not appear to be a promising treatment for morphine addiction.
Advisor: Brown, Colin; Hyland, Brian
Degree Name: Doctor of Philosophy
Degree Discipline: Physiology
Publisher: University of Otago
Keywords: Morphine; Oxytocin; Nucleus accumbens shell; Conditioned place preference; Reward; Addiction; rat; Electrophysiology
Research Type: Thesis