The role of signaling molecules in reward-related incentive learning

Abstract

Reward-related incentive learning involves the acquisition by neutral stimuli of an enhanced ability to elicit approach and other responses. Previous studies have shown that both dopamine (DA) and glutamate (Glu) play critical roles in this type of learning. Signaling molecules are intracellular messengers that participate in the influence of transmitter-receptor events on intracellular function including transcription in the nucleus. In recent years studies have begun to implicate signaling molecules in incentive learning. Thus, inhibition of cyclic adenosine monophosphate-dependent protein kinase (PKA) in the nucleus accumbens (NAc), that is activated by DA acting at D1-like receptors, blocks the acquisition of conditioned approach responses, lever pressing for food, conditioned place preference (CPP) based on NAc injections of amphetamine or cocaine, and conditioned activity based on NAc injections of amphetamine. Similar effects have been observed with PKA inhibition in the basolateral amygdala or medial prefrontal cortex. If animals were trained prior to testing with PKA inhibitors in NAc, no effect was seen suggesting that PKA is more important for acquisition than expression of incentive learning. Inhibition of calcium-dependent protein kinase or mitogen-activated protein kinases in NAc similarly has been shown to block the acquisition of incentive learning. Results support a model of DA-Glu synaptic interactions that form the basis of incentive learning.

Opposing Regulation of Pair Bond Formation by cAMP Signaling within the Nucleus Accumbens Shell

“…Because cAMP signaling is primarily mediated through binding PKA, manipulating cAMP binding sites on PKA is a widely accepted method to study cAMP transmission Baldwin et al, 2002;Beninger and Gerdjikov, 2004;Lynch and Taylor, 2005). The typical "cAMP antagonist," Rp-cyclic adenosine 3Ј,5Ј-phosphorothioate (Rp), is a competitive inhibitor for cAMP binding sites on PKA which maintains PKA in its inactive state (Schwede et al, 2000).…”

Dopamine Receptor Stimulation Modulates AMPA Receptor Synaptic Insertion in Prefrontal Cortex Neurons

“…The D 1 -PKA signaling pathway also contributes to learning and memory processes in other brain regions, including the hippocampus and the striatal complex (Berke and Hyman, 2000;Jay, 2003;Beninger and Gerdjikov, 2004;Kelley, 2004). Facilitation of synaptic GluR1 insertion may contribute to D 1 receptor effects in these regions, based on the PKA dependence of AMPA receptor externalization in hippocampus (see above) and our results showing that D 1 receptor stimulation accelerates AMPA receptor externalization in nucleus accumbens neurons (Chao et al, 2002;Mangiavacchi and Wolf, 2004).…”

Expression of Transcripts for Myelin Related Genes in Postmortem Brain from Cocaine Abusers

“…Interestingly, the changes of mesolimbic neurocircuitry appear similar to those associated with experience-dependent plasticity. Accordingly, chronic drug addiction including sensitization has been suggested to represent an extreme form of learning, and has been proposed as a model to study cellular mechanisms of plasticity [4,8]. In addition to the biochemical changes in NAc and VTA, extended periods of drug use likely progress to include changes in other brain areas, including prefrontal cortex and hippocampus, as well as additional involvement of the basal ganglia including dorsal areas of the striatum [9].…”