Dopamine D1-like receptors and reward-related incentive learning.

There now is general agreement that dopaminergic neurons projecting from ventral mesencephalic nuclei to forebrain targets play a critical role in reward-related incentive learning. Many recent experiments evaluate the role of dopamine (DA) receptor subtypes in various paradigms involving this type of learning. The first part of this paper reviews evidence from these studies that use antagonists or agonists relatively specific for D1- or D2-like receptors in operant paradigms with food, brain stimulation, self-administered stimulant or conditioned rewards or place conditioning. The focus is on studies that directly compare agents acting at the two DA receptor families, especially those studies where the agents produce differential actions. Results support the conclusion that D1-like receptors play a more critical role in reward-related learning than D2-like receptors. D1-like receptors initiate a cascade of intracellular events including cyclic adenosine monophosphate (cAMP) formation and activation of cAMP-dependent protein kinase (PKA). The final section of this paper reviews evidence from a wide range of neuroscience experiments that implicates the cAMP/PKA pathway in learning in general and in reward-related incentive learning in particular. We conclude that the molecular mechanism underlying DA-mediated incentive learning may involve DA release in association with reward, stimulation of D1-like receptors, activation of the cAMP/PKA cascade and additional intracellular events leading to modification of cortico-striatal glutamatergic synapses activated by stimuli encountered in close temporal contiguity with reward. Thus, when reward-related incentive learning takes place, it may be the action of DA acting at D1-like receptors that leads to plastic changes in the striatum that form the substrate of that learning.