Role of obesity-associated neurobiological adaptations on spontaneous morphine withdrawal responses in rodents

Obesity and opioid abuse are two major public health problems plaguing the United States and substantially decrease the lives and well-being of the affected individuals. The objective of this dissertation was to elucidate convergent factors underlying both disorders and ascertain whether obesity- related neurobiological adaptations alter morphine withdrawal responses. We focused primarily on the locus coeruleus (LC)- norepinephrine (NE) system, which has long been implicated in mediating morphine withdrawal symptoms, but its role in obesity has been suggested but largely unexplored. We first characterized alterations in LC neural activity following obesogenic diet and weight gain by assessing in vivo single- unit LC electrophysiological activity in selectively- bred obese prone (OP) and obese resistant (OR) male Sprague Dawley rats following high (45% kcal fat) - or low- fat (10% kcal fat) feeding. OP rats demonstrated significantly higher spontaneous and tonic activity and decreased sensory- evoked LC activity. Analysis of signal- to- noise (evoked/ tonic) revealed significant interacting effects of diet and strain with OR- LFD showing greater activity than OP- LFD and OP- HFD. Given the observed obesity- associated alterations, LC neural responses to morphine withdrawal was evaluated in LFD and HFD-fed male Sprague Dawley rats. Increases in sensory- evoked activity were observed following morphine withdrawal in LFD, but not HFD rats. We next examined whether obesity- related alterations in LC signaling translate to behavioral differences. OP and OR mice were identified based on median split in body weights following 8- weeks of HFD and were subsequently switched to LFD to attenuate the confounding effects of body weight differences. Morphine withdrawal responses were assessed on three consecutive days. Interacting effects of obesity susceptibility and treatment were observed in the open field exploration test, in which OP attenuated morphine withdrawal- induced reduction in locomotor behavior. The effects were more apparent in females, than male, mice. Differences in obesity susceptibility did not alter morphine withdrawal responses during the elevated plus maze or prepulse inhibition. The interactive effects of obesity susceptibility and treatment on expression of noradrenergic and anxiolytic genes in the LC and PVN may have contributed to the observed behavioral differences. No expression differences were observed in the selected genes in the PFC and central amygdala regions. Taken together, our findings suggest neurobiological alterations associated with obesity may have implications in morphine withdrawal responses.Ph.D.Includes bibliographical reference