Extinction and reinstatement to cocaine-associated cues in male and female juvenile rats and the role of D1 dopamine receptor

Abstract

Extinction of behaviors in response to drug-associated cues and prevention of reinstatement are integral for addiction treatment, and can reverse or ameliorate the harmful consequences of drug use. The mechanisms controlling extinction and reinstatement involve prefrontal cortical dopamine receptors, which change in expression and activity during the juvenile and adolescent transitions until they mature in adulthood. Little is known about the role that PFC D1 dopamine receptors play in extinction of drug-paired associations early in life. We used extinction of place preferences for cocaine in juvenile male and female rats following genetic, cell-specific overexpression of D1 on glutamatergic cells in the PFC. All subjects needed to demonstrate cocaine preferences for inclusion in the extinction studies. Here, male juveniles with a preference to 10 mg/kg cocaine took longer to extinguish preferences compared to both male adults and female juveniles. Female juveniles extinguished more rapidly than male juveniles at 20 mg/kg cocaine. Overexpression of D1 in juvenile males significantly facilitated extinction relative to juvenile male controls, whereas D1 prolonged expression of extinction in adults overexpressing D1 and adolescents who naturally have elevated D1 expression. These data suggest that an immature D1 profile in juveniles prevented the learning of new associations, and D1 overexpression may provide sufficient activity to facilitate extinction learning. D1 overexpression reduced reinstatement to a priming dose of cocaine in juvenile males. Together, these data show D1 expression may re-program motivational circuitry to facilitate extinction learning during juvenility that is normally unavailable to juveniles and that sex differences exist.

M5 Muscarinic Receptor Gene Deletion Accelerates Extinction, But Inhibits Reinstatement of Morphine-Conditioned Reward in Mice

“…These results support a role for M5Rs in maintaining and restoring previously learned CPP, possibly through the sustained activation of dopamine neurons by M5Rs [26,[49][50][51]. Previous authors have argued that dopamine neural activity is important in the learning of extinction and spontaneous recovery in different paradigms [52,53].…”

Estrous cycle-induced sex differences in medium spiny neuron excitatory synaptic transmission and intrinsic excitability in adult rat nucleus accumbens core

“…Second, the other relevant experiment employed prepubertal animals (Cao et al 2016). It is possible that activational hormone effects during puberty modulate the excitatory synaptic inputs onto the AcbC, reminiscent of changes in dopamine receptor complement in the AcbC during puberty (Andersen et al 2002;Brenhouse et al 2015;Teicher et al 1995). Furthermore, the properties of excitatory synapse in the nucleus accumbens shell have been shown to be sensitive to the effects of environmental stimuli such as drugs of abuse and stress (Brancato et al 2017;Hodes et al 2015), reminiscent of classical research in the hippocampus (Shors et al 2001).…”

“…Thus, although gonadectomy and the consequent elimination of changes in circulating sex steroid hormones are sufficient for eliminating estrous cycle-induced sex differences in MSN electrophysiology, it remains possible that local hormone synthesis could be playing a role in other aspects of AcbC function. More broadly, given that environmental stimuli such as exposure to drugs of abuse can manipulate other excitatory synapse properties such as NMDA-to-AMPA ratio (Andersen et al 2002;Brenhouse et al 2015;Jedynak et al 2016;Kourrich et al 2007;Rothwell et al 2011;Teicher et al 1995), it is likely that many sex differences in AcbC synaptic physiology remain undiscovered. Collectively, these sex differences and hormone sensitivity may not only set the stage for sex differences in AcbC-influenced behaviors but also prepare this brain region for the rewardrelated activities related to reproduction (Bradley et al 2005).…”

Commentary on the special issue on the adolescent brain: Adolescence, trajectories, and the importance of prevention

“…In this edition, Baker et al (2016) reports on how extinction learning of fear-related stimuli is uniquely impaired during adolescence; prolonged extinction in adolescence relative to other stages is also observed to cocaine-associated environments (Brenhouse and Andersen, 2008), but see Li and Frantz (2009). This process is also related to motivational salience mediated by D1 receptors (Brenhouse et al, 2015). Taken together, these studies imply a period of enhanced learning about environmental factors that are made more salient during adolescence and are further accompanied by reduced extinction.…”