Maladaptive consequences of repeated intermittent exposure to uncertainty

Abstract

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.

Keywords: Amphetamine; Dopamine; Gambling; Glutamate; Sensitization; Uncertainty.

Figure 1.

Animals previously exposed to conditions of Uncertain saccharin reinforcement under VR schedules show enhanced locomotor (A) and NAcc DA (B) responding to a challenge injection of amphetamine (arrow at abscissa), as well as enhanced work output and self-administration of the drug (C) compared to rats previously exposed to Certain reinforcement under FR schedules. Numbers in parentheses indicate n/group. *, p<0.05, **, p<0.01, compared to Certain at specified time. Adapted from Mascia et al. (2019).

Figure 2.

Animals previously exposed to conditions of Uncertain saccharin reinforcement under VR schedules show increased levels of phosphorylation by CaMKII [pGluA1(S831)] (A) and PKC [pNg(S31)] (B) as well as increased protein levels of ΔFosB (C) and decreased protein levels of GLT1 (D) compared to rats previously exposed to Certain reinforcement under FR schedules. These adaptations observed in the NAcc are similar to those observed in animals previously exposed to psychostimulant drugs and are known to modulate AMPA receptor function (A-C) as well as extracellular levels of glutamate (D). NAcc tissues were harvested two weeks following the last saccharin exposure session. Data are shown as group mean (+SEM) % of Certain and normalized to phosphorylation substrate or tubulin as indicated. Numbers in parentheses indicate n/group. *, p<0.05, **, p<0.01, Uncertain vs Certain.

Figure 3.

(A) Expected reinforcement (dashed line) and uncertainty (solid curve) as a function of the probability of reinforcement in a Pavlovian approach. Adapted from Schultz et al. (2008) where uncertainty as used here is labelled risk, denoting the degree of uncertainty inherent in known probability distributions that can be expressed as variance. (B) Median sustained activation of DA neurons as a function of reinforcement probability, indicating that DA tracks uncertainty according to the inverted U function outlined in (A). Adapted from Fiorillo et al. (2003).

Figure 4.

NAcc DA overflow tracks uncertainty in an operant approach. (A) Mathematically derived curves of the variance associated with increasing FR and VR schedules of reinforcement. Variance (a measure of uncertainty) increases exponentially with the increasing VR schedules as these program an increasingly variable relationship between performance of an operant and payout. The variance associated with the different escalating FR schedules remains at 0 as these program a fixed relationship. (B) The patterns of DA overflow assessed in the NAcc with the different schedules showed a notable similarity to the exponential uncertainty (VR) and flat certainty (FR) curves in (A). From Mascia et al. (2019). n/group=4–8. ***, p<0.001, VR compared to FR at the specified ratios.

Figure 5.

Non-DA compounds measured in the NAcc during exposure to uncertainty. Of the several compounds assessed in addition to DA following further analyses of the HPLC-MS/MS results obtained in Mascia et al. (2019), only glutamate (G) and the related excitatory amino acid aspartic acid (C) similarly tracked uncertainty. The extra-synaptically originating modulator adenosine (B) displayed a weaker but significant increase with increasing uncertainty. 5-HT and norepinephrine levels were too low to permit reliable measurement (see text). Data illustration and group affiliation [FR, open circles (Certain conditions); VR, filled circles (Uncertain conditions)] as in Figure 4. n/group=4–8. *, p<0.05, VR compared to FR at the specified ratios.