Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Neuroscience

First Advisor

Rita J. Valentino

Abstract

There are sex differences in disease susceptibility, time of onset of symptoms, and drug responses. Notably, sex differences are particularly prominent in pain and opioid analgesic responses, with females being less sensitive to opioid analgesia. A major site of action of opioids in the brain is the locus coeruleus (LC)-norepinephrine (NE) system. LC neurons express mu-opiate receptors (MOR), and MOR-agonists potently inhibit LC neuronal activity. Evidence suggests that endogenous opioids are released during stress, to restrain LC activation and to facilitate LC recovery when the stressor ends. On the basis of these observations, this dissertation tested the hypothesis that the opioid regulation of the LC is decreased in females relative to males. By implementing electrophysiological, biochemical, and behavioral approaches, sex differences in MOR regulation of the LC-NE system were examined. MOR mRNA was greater in male compared to female LC as indicated by quantitative PCR. This translated to an increased level of MOR protein in male compared to female LC tissue as detected by Western blot analysis. Consistent with sex differences in MOR expression in the LC, recordings of single unit LC activity in anesthetized rats demonstrated that the maximal magnitude of inhibition produced by intracoerulear injection of a MOR agonist, DAMGO, was greater in males. The decreased response of female LC neurons to MOR activation was expressed as a diminished response in upstream targets. Thus, intra-LC DAMGO increased synchronization of local field potential activity in male but not female medial prefrontal cortex (mPFC). Notably, the LC-NE system affects cognitive function through its projections to the mPFC. The molecular and cellular sex differences in MOR regulation of the LC were associated with sexually distinct effects on cognitive processing in an operant strategy-shifting task. Intra-LC DAMGO increased the duration to complete the task and the total number of errors, selectively in males. DAMGO increased premature responses, regressive and random errors in males, and perseverative errors in females. The sex-specific effects of LC-MOR activation on cognitive processing may contribute to an early onset of opioid abuse in males, and susceptibility to opioid relapse in females. Ultimately, given the role of endogenous opioids in restraining the stress response of the LC system, decreased opioid sensitivity in females could enhance female vulnerability to stress.

Files over 3MB may be slow to open. For best results, right-click and select "save as..."

Share

COinS