GABAB receptors in the ventral tegmental area regulate morphine-induced motor sensitization and accumbal fos expression in C57BL/6 mice
Mesolimbic dopamine (A10) neurons have a central role in mediating opiate-induced motor sensitization and are implicated in drug addiction. This dissertation examines the hypotheses that GABAB receptors are located in the ventral tegmental area (VTA), that morphine sensitization occurs via A10 neuronal activation, and that GABAB receptor activation in the VTA inhibits the development and expression of morphine-induced sensitization. Dopaminergic neurons projecting from the VTA to the nucleus accumbens (NAc) of the forebrain are involved in mediating behavioral sensitization to morphine. GABA B receptor activation in the VTA leads to inhibition of dopaminergic transmission and inhibition of opiate actions. Sensitization is a progressive enhancement in the motor stimulant effect, elicited by repeated, intermittent morphine and subsequent drug challenge. Immunoblotting was performed, and GABAB receptor subtypes R1a, R1b, and R2 were found in the ventral mesencephalon. Mice with indwelling cannulae received repeated morphine (10mg/kg, s.c.) treatment on days 1, 3, and 5, followed by a challenge dose of morphine on day 9. Some of these animals received intra-VTA vehicle or baclofen pretreatment on days 1, 3, and 5 (development group) while others received intra-VTA baclofen only on day 9 (expression group). Following treatment, automated activity monitoring was used to measure ambulatory activity. The results show that mice receiving morphine plus vehicle are sensitized to the motor stimulant effects of morphine, as exhibited by a two-fold increase in ambulatory counts on day 9 versus day l. Intra-VTA injection baclofen treatment produced a significant inhibition of both the development and expression of morphine-induced motor sensitization. Immunohistochemistry was performed, and baclofen treatment significantly blocked morphine-induced increases in Fos immunoreactivity in the shell but not in the core of the NAc. These data suggest that functional GABAB receptors in the VTA inhibit the development and expression of opiate sensitization, perhaps via A10 neurons. Long-lasting neuroadaptive changes leading to sensitization in dopaminergic neural circuits underlie certain aspects of drug addiction such as craving and compulsive drug use. Activation of GABAB receptors could be a potential therapeutic target and a useful treatment of opiate addiction as shown by the inhibitory effects of baclofen in opiate sensitization. ^
Biology, Neuroscience|Health Sciences, Pharmacology
Kimberly Anne Leite-Morris,
"GABAB receptors in the ventral tegmental area regulate morphine-induced motor sensitization and accumbal fos expression in C57BL/6 mice"
Dissertations and Master's Theses (Campus Access).