Overexpression of CREB in the Nucleus Accumbens Shell Increases Cocaine Reinforcement in Self-Administering Rats

Abstract

Chronic exposure to addictive drugs enhances cAMP response element binding protein (CREB)-regulated gene expression in nucleus accumbens (NAc), and these effects are thought to reduce the positive hedonic effects of passive cocaine administration. Here, we utilized viral-mediated gene transfer to produce short- and long-term regulation of CREB activity in NAc shell of rats engaging in volitional cocaine self-administration. Increasing CREB expression in NAc shell markedly enhanced cocaine reinforcement of self-administration behavior, as indicated by leftward (long-term) and upward (short-term) shifts in fixed-ratio dose-response curves. CREB also increased the effort exerted by rats to obtain cocaine on more demanding progressive ratio schedules, an effect highly correlated with viral-induced modulation of BDNF protein in the NAc shell. CREB enhanced cocaine reinforcement when expressed either throughout acquisition of self-administration or when expression was limited to post-acquisition tests, indicating a direct effect of CREB independent of reinforcement-related learning. Down-regulating endogenous CREB in NAc shell by expressing an shRNA reduced cocaine reinforcement in similar tests, while over expression of a dominant negative CREBS133A mutant had no significant effect on cocaine self-administration. Finally, increasing CREB expression after withdrawal from self-administration enhanced cocaine-primed relapse, while reducing CREB levels facilitated extinction of cocaine seeking, but neither altered relapse induced by cocaine cues or footshock stress. Together, these findings indicate that CREB activity in NAc shell increases the motivation for cocaine during active self-administration or after withdrawal from cocaine. Our results also highlight that volitional and passive drug administration can lead to substantially different behavioral outcomes.

The Nucleus Accumbens: A Comprehensive Review

“…While a number of the other neurotransmitters, including norepinephrine [266], serotonin [267,268], and GABA [269], are likely involved, the role of glutamate is perhaps the most well studied [251,252,270,271,272,273,274,275,276]. On a molecular level, these changes are likely mediated by a host of transcription factors, but three in particular - the cyclic-AMP response element-binding protein (CREB) [277,278,279,280,281], ΔFosBand [282,283,284,285,286,287], and CaMKII [288,289,290,291,292] - have often been implicated in addiction (for review, see [293,294]).…”

Roles of Nucleus Accumbens CREB and Dynorphin in Dysregulation of Motivation

“…Potential explanations for these effects are that elevated CREB in the NAc enhances the anxiogenic effects of cocaine or somehow reduces the strength or duration of cocaine reward, which at low doses might result in an acute withdrawal state that becomes associated with the drug chamber in place conditioning studies. CREBmediated reductions in cocaine reward together with increases in aversive or stressful withdrawal signs might help to explain why the same viral vector treatment causes increases in cocaine intake in a drug self-administration paradigm (Larson et al 2011), reflecting negative reinforcing effects (Koob and Le Moal 2008). Importantly, CREB overexpression in the NAc increases local levels of prodynorphin mRNA, and pretreatment with the long-acting KOR antagonist nor-binaltorphimine (norBNI) restores the rewarding effects of cocaine (Carlezon et al 1998).…”

FoxO6 regulates memory consolidation and synaptic function

“…For example, the activitydependent transcription factor CREB plays an important role in regulating a gene expression program important for synaptic function (Tao et al 1998), synaptic plasticity (Barco et al 2002), and reward and addiction behaviors (Carlezon et al 1998;Larson et al 2011). Furthermore, MEF2, another activity-dependent transcription factor, is important for synaptic function (Flavell et al 2006;Shalizi et al 2006), learning and memory (Barbosa et al 2008), and behavioral plasticity in response to drugs of abuse (Pulipparacharuvil et al 2008).…”