Electronic Thesis and Dissertation Repository


Master of Science




Steven R Laviolette


Post-Traumatic Stress Disorder (PTSD) and addiction are strongly comorbid. However, the underlying neural mechanisms by which traumatic memory recall may increase addiction liability are poorly understood. The inability to suppress memory recall related to either stressful or rewarding, drug-related experiences may be an underlying neuropsychological feature capable of triggering both PTSD or addiction-related behaviours. Our previous research has shown that transmission through dopamine (DA) D4 and D1 receptor subtypes (D4R, D1R) within the prefrontal cortex (PFC) strongly modulates emotional memory acquisition and recall (Lauzon et al., 2009). Using olfactory fear conditioning and morphine conditioned place preference (CPP) procedures in rats, combined with molecular protein expression analyses, we examined if 1) associative fear memory recall would increase subjects’ sensitivity and vulnerability to morphine reward salience; 2) if blocking fear memory recall with intra-PFC D1R stimulation may block the potentiation of morphine reward salience; 3) if PFC D4R stimulation would potentiate morphine reward salience by modulating the emotional salience of fear memories during memory acquisition. Furthermore, we concomitantly examined the underlying PFC molecular signaling pathways associated with these behavioural effects. We report that rats receiving supra-threshold (0.8 mA) fear conditioning showed strong associative fear memories and heightened morphine reward sensitivity (with either systemic or intra-ventral tegmental area [VTA] administered morphine). Inhibition of fear memory recall with intra-PFC D1R activation reduced the potentiated morphine CPP through cyclic adenosine monophosphate (cAMP) and extracellular-signal-related kinases 1 and 2 (ERK1/2) dependent molecular pathways. In addition, PFC D1R stimulation selectively increased phosphorylation levels of ERK 1/2. In contrast, PFC D4R activation bi-directionally controlled fear memory acquisition and morphine CPP behaviours through a calcium/calmodulin dependent kinase II (CaMKII)-dependent mechanism wherein D4R activation selectively stimulated phosphorylation of PFC CaMKII. Our findings reveal for the first time a novel DA-receptor dependent mechanism in the mammalian PFC capable of controlling both fear-related associative memory formation and the salience of morphine-related reward memories.