Dopamine Modulation of Emotional Learning in the Medial Prefrontal Cortex

Dopamine (DA) transmission plays a critical role in the processing of emotionally salient information and in associative learning and memory processes. Within the mammalian brain, neurons within the medial prefrontal cortex (mPFC) are involved critically in the encoding, expression, and extinction of emotionally salient learned information. Within the mPFC, DAergic transmission is involved importantly in controlling attention related and motivational processes, particularly within the context of emotionally salient sensory information. Considerable evidence suggests differential roles for DA D1-like versus D2-like receptors, including the D4-receptor subtype, in the regulation of neuronal activity and emotional processing within the mPFC. Using behavioural models of emotional learning and memory in rats, including olfactory fear-conditioning and conditioned place preference assays, we compared the roles of DA D1-receptor versus D4-receptor activation during the encoding and recall phases of emotional learning and memory. We report that specific activation of DA D4-receptors within the mPFC strongly potentiates the salience of normally nonsalient emotional associative fear memories and blocks the encoding of suprathreshold conditioned fear associations and has no effect on memory recall. In addition, the bidirectional effect demonstrated by D4-receptor activation in the mPFC depends upon downstream signaling via CaMKII, cyclic-AMP/PKA, and PP1 substrates In contrast, intra-mPFC D1-receptor activation failed to increase the emotional salience of subthreshold fear stimuli but completely blocked the expression of previously learned aversive and rewarding memories. Interestingly, both intra-PLC D1-receptor mediated block of either fear-related or reward-related associative memories were dependent upon downstream cAMP signaling as both effects were rescued by co-administration of a cAMP inhibitor. Taken together these results demonstrate that DA D4 versus D1 subtype receptor transmission within the mPFC plays distinct functional roles in the processing of emotionally salient versus nonsalient associative information and differentially modulates the encoding versus recall phases of emotional memory within the mPFC through distinct molecular signaling pathways. A clearer understanding of the specific roles of DA D1 and D4 receptor transmission during emotional learning and memory may help elucidate how abnormalities in the mPFC neural circuitry may lead to aberrant associative learning and memory processes in disorders such as schizophrenia, drug addiction, PTSD and ADHD