Fear Memory Recall Potentiates Opiate Reward Sensitivity through Dissociable Dopamine D1 versus D4 Receptor-Dependent Memory Mechanisms in the Prefrontal Cortex

Abstract

Disturbances in prefrontal cortical (PFC) dopamine (DA) transmission are well established features of psychiatric disorders involving pathological memory processing, such as post-traumatic stress disorder and opioid addiction. Transmission through PFC DA D4 receptors (D4Rs) has been shown to potentiate the emotional salience of normally nonsalient emotional memories, whereas transmission through PFC DA D1 receptors (D1Rs) has been demonstrated to selectively block recall of reward- or aversion-related associative memories. In the present study, using a combination of fear conditioning and opiate reward conditioning in male rats, we examined the role of PFC D4/D1R signaling during the processing of fear-related memory acquisition and recall and subsequent sensitivity to opiate reward memory formation. We report that PFC D4R activation potentiates the salience of normally subthreshold fear conditioning memory cues and simultaneously potentiates the rewarding effects of systemic or intra-ventral tegmental area (VTA) morphine conditioning cues. In contrast, blocking the recall of salient fear memories with intra-PFC D1R activation, blocks the ability of fear memory recall to potentiate systemic or intra-VTA morphine place preference. These effects were dependent upon dissociable PFC phosphorylation states involving calcium-calmodulin-kinase II or extracellular signal-related kinase 1-2, following intra-PFC D4 or D1R activation, respectively. Together, these findings reveal new insights into how aberrant PFC DAergic transmission and associated downstream molecular signaling pathways may modulate fear-related emotional memory processing and concomitantly increase opioid addiction vulnerability. Post-traumatic stress disorder is highly comorbid with addiction. In this study, we use a translational model of fear memory conditioning to examine how transmission through dopamine D1 or D4 receptors, in the prefrontal cortex (PFC), may differentially control acquisition or recall of fear memories and how these mechanisms might regulate sensitivity to the rewarding effects of opioids. We demonstrate that PFC D4 activation not only controls the salience of fear memory acquisition, but potentiates the rewarding effects of opioids. In contrast, PFC D1 receptor activation blocks recall of fear memories and prevents potentiation of opioid reward effects. Together, these findings demonstrate novel PFC mechanisms that may account for how emotional memory disturbances might increase the addictive liability of opioid-class drugs.

Chronic pain, posttraumatic stress disorder, and opioid intake: A systematic review

“…Moreover, it has been found that noradrenergic overstimulation in individuals with PTSD may also increase their predisposition to illicit drug use for self-medication, especially for substances with sedative properties, such as alcohol, opioids, and benzodiazepines[54]. It has been recently demonstrated in a rodent model[55] that abnormal dopamine signals in the prefrontal cortex may underlie the ability of traumatic memories to predispose individuals to addiction by increasing their sensitivity to the rewarding effects of drugs such as opioids.…”

Developmental regulation of fear memories by an obesogenic high-saturated fat/high-sugar diet

“…Several lines of evidence show that dopamine D1 receptors expressed in the NAc, the PFC, hippocampus and the amygdala play a critical role in fear learning and fear extinction (Abraham et al, 2016a;2016b;Borowski and Kokkinidis, 1998;Fadok et al, 2009;Hikind and Maroun, 2008;J. J. Li et al, 2018;Ng et al, 2018).…”

Fear expression is suppressed by tyrosine administration

“…D1 and D2 antagonists block the acquisition of fear memories 3–7 whilst the administration of D1 or D2 agonists increase fear expression 8,9 . Blockade of D3 receptors has, surprisingly, shown to enhance fear acquisition 10 , whilst D4 activation potentiates acquisition 11 . In humans, the effects of a dopamine reuptake blocker (Ritalin) or a dopamine precursor (L-Dopa) have only been investigated with respect to fear extinction and spontaneous recovery 12,13 , but not fear acquisition.…”