Maladaptive consequences of repeated intermittent exposure to uncertainty.

Recently we reported that nucleus accumbens (NAcc) dopamine (DA) tracks uncertainty during operant responding for non-caloric saccharin. We also showed that repeated intermittent exposure to this uncertainty, like exposure to drugs of abuse, leads to sensitization of the locomotor and NAcc DA effects of amphetamine and promotes the subsequent self-administration of the drug. Here we review these findings together with others showing that NAcc glutamate signaling is similarly affected by uncertainty. Extracellular levels of glutamate in this site also track uncertainty in a task in which nose poking for saccharin on an escalating variable ratio schedule of reinforcement is associated with progressively increasing variance between performance of the operant and payout. Furthermore, sensitized behavioral responding to and for amphetamine following exposure to uncertainty is accompanied by increased levels of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC) phosphorylation as well as altered protein levels of the transcription factor ∆FosB (increased) and glutamate transporter 1 (GLT1; decreased) in NAcc tissues. Notably, phosphorylation by CaMKII and PKC regulates AMPA receptor trafficking and function in this site, is elevated following psychostimulant exposure, and is necessary for the expression of enhanced drug taking. Increased ∆FosB and decreased GLT1 levels are observed following psychostimulant exposure, are associated with increased drug taking and seeking, and are known to modulate AMPA receptors and extracellular glutamate levels respectively. These adaptations in glutamate transmission as well as those observed with DA following repeated intermittent exposure to uncertainty are similar to those produced by exposure to abused drugs. Together, they point to the recruitment of both DA and glutamate signaling pathways in the NAcc in both drug and behavioral addictions. As uncertainty is central to games of chance, these findings have particular relevance for gambling disorders known to exhibit comorbidity with drug abuse.