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. 2016 Jun;26(6):2895-904.
doi: 10.1093/cercor/bhw051. Epub 2016 Mar 5.

Role of Dopamine 2 Receptor in Impaired Drug-Cue Extinction in Adolescent Rats

Isabel C Zbukvic  1 , Despina E Ganella  1 , Christina J Perry  1 , Heather B Madsen  1 , Christopher R Bye  1 , Andrew J Lawrence  1 , Jee Hyun Kim  1
Affiliations

Role of Dopamine 2 Receptor in Impaired Drug-Cue Extinction in Adolescent Rats

Isabel C Zbukvic et al. Cereb Cortex. 2016 Jun.

Abstract

Adolescent drug users display resistance to treatment such as cue exposure therapy (CET), as well as increased liability to relapse. The basis of CET is extinction learning, which involves dopamine signaling in the medial prefrontal cortex (mPFC). This system undergoes dramatic alterations during adolescence. Therefore, we investigated extinction of a cocaine-associated cue in adolescent and adult rats. While cocaine self-administration and lever-alone extinction were not different between the two ages, we observed that cue extinction reduced cue-induced reinstatement in adult but not adolescent rats. Infusion of the selective dopamine 2 receptor (D2R)-like agonist quinpirole into the infralimbic cortex (IL) of the mPFC prior to cue extinction significantly reduced cue-induced reinstatement in adolescents. This effect was replicated by acute systemic treatment with the atypical antipsychotic aripiprazole (Abilify), a partial D2R-like agonist. These data suggest that adolescents may be more susceptible to relapse due to a deficit in cue extinction learning, and highlight the significance of D2R signaling in the IL for cue extinction during adolescence. These findings inspire new tactics for improving adolescent CET, with aripiprazole representing an exciting potential pharmacological adjunct for behavioral therapy.

Keywords: adolescence; aripiprazole; dopamine; extinction; infralimbic cortex.

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Figures

Figure 1.
Figure 1.
Experimental design. (A) Adult and adolescent rats underwent cue-paired cocaine self-administration. In the first experiment only, rats underwent a single PR session prior to the final day of self-administration. Rats then received lever extinction in absence of the cue. Rats were divided into groups for handling (No Cue Ext) or cue extinction (Cue Ext). Rats were tested the next day for cue-induced reinstatement. (B) Adolescent rats underwent cocaine self-administration and lever extinction as per the first experiment. Prior to cue extinction, rats received an infusion of vehicle or quinpirole (5 μg per hemisphere) into the infralimbic cortex (IL). Rats were tested the next day for cue-induced reinstatement. (C) Adolescent rats underwent cocaine self-administration and lever extinction as per the first two experiments. Prior to cue extinction, rats received a systemic injection of either vehicle or aripiprazole (5 mg/kg). Rats were tested the next day for cue-induced reinstatement.
Figure 2.
Figure 2.
Cocaine self-administration was similar for adult and adolescent rats. Responding occurred on a FR 1 for the first 5 days, and increased to FR3 for the final 5 days of self-administration (broken line). (A) Mean (±SEM) daily lever responses. Responding on the active lever increased for both age groups over self-administration days (P < 0.05), while responding on the inactive lever remained low. (B) Mean (±SEM) daily rewards, that is, cocaine infusions (0.3 mg/kg per infusion) increased for both age groups over self-administration days (P < 0.05). (C) Once stable cocaine self-administration was established responding on a PR of reinforcement was similar across age groups, with adult and adolescent rats showing a similar number of maximum consecutive active lever presses to obtain a cocaine infusion (breakpoint). (D) Mean (±SEM) active lever responses decreased over lever extinction days (P < 0.05), with no difference between age groups by final lever extinction day. Inactive lever responding remained low relative to active lever responding across days. Adult n = 24; adolescent n = 18.
Figure 3.
Figure 3.
Age differences in cue-induced reinstatement following cue extinction. (A) Mean (+SEM) active lever responses made over one hour cue-induced reinstatement differed depending on age (*P < 0.05, main effect of Age, significant interaction of Age and Cue Extinction). There was no effect of day or cue extinction on inactive lever responding for both adults and adolescents. (B) Compared with the final day of lever extinction, adults that did not receive cue extinction (No Cue Ext) significantly reinstated cocaine seeking behavior following re-exposure to a drug-associated cue the next day (*P < 0.05, effect of Day in the No Cue Ext group) while adults that received cue extinction training did not. Adult No Cue Ext n = 13; adult Cue Ext n = 11. (C) Adolescents reinstated to the cue regardless of whether cue extinction training was received or not (*P < 0.05, main effect of Day). Adolescent No Cue Ext n = 9; adolescent Cue Ext n = 9.
Figure 4.
Figure 4.
Enhancing D2R signaling at the time of cue extinction reduces cue-induced reinstatement in adolescent rats the next day. (A) Coronal sections illustrating intracranial cannula placements show that 14 rats had successful cannula tips within the infralimbic cortex (hits; filled circles) (misses; empty circles) (Paxinos and Watson 2013). (B) Analyses of mean active lever responses (+SEM, left panel) indicate that adolescent rats that received vehicle at the time of cue extinction showed reinstatement the next day (*P < 0.05), while rats that received quinpirole (5 μg per hemisphere) did not. Mean responses on the inactive lever (+SEM, right panel) remained low for both vehicle- and quinpirole-treated rats across final lever extinction and reinstatement test. Vehicle n = 8; quinpirole n = 6. (C) Adolescent rats that received vehicle at the time of cue extinction displayed cue reinstatement the next day (*P < 0.05), whereas rats that received aripiprazole (5 mg/kg) did not. Responding on the inactive lever remained low for both vehicle- and aripiprazole-treated rats over final lever extinction and reinstatement days. Vehicle n = 9; aripiprazole n = 7.
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