Overexpression of ASIC1A in the nucleus accumbens of rats potentiates cocaine-seeking behavior

Abstract

Acid-sensing ion channels (ASICs) are abundantly expressed in the nucleus accumbens core (NAcore), a region of the mesolimbocortical system that has an established role in regulating drug-seeking behavior. Previous work shows that a single dose of cocaine reduced the AMPA-to-NMDA ratio in Asic1a^-/- mice, an effect observed after withdrawal in wild-type mice, whereas ASIC1A overexpression in the NAcore of rats decreases cocaine self-administration. However, whether ASIC1A overexpression in the NAcore alters measures of drug-seeking behavior after the self-administration period is unknown. To examine this issue, the ASIC1A subunit was overexpressed in male Sprague-Dawley rats by injecting them with adeno-associated virus, targeted at the NAcore, after completion of 2 weeks of cocaine or food self-administration. After 21 days of homecage abstinence, rats underwent a cue-/context-driven drug/food-seeking test, followed by extinction training and then drug/food-primed, cued, and cued + drug/food-primed reinstatement tests. The results indicate that ASIC1A overexpression in the NAcore enhanced cue-/context-driven cocaine seeking, cocaine-primed reinstatement, and cued + cocaine-primed reinstatement but had no effect on food-seeking behavior, indicating a selective effect for ASIC1A in the processes underlying extinction and cocaine-seeking behavior.

Keywords: abstinence; incubation; reinstatement; self-administration; withdrawal.

Figure 1.

A. Timeline for all experiments. B. Representative immunohistochemistry image showing virus expression in the NAcore. ac, anterior commissure. C. The left panel is a schematic showing the maximum and minimum observed spread of virus, as visualized by immunohistochemistry. The blue shape shows rats (n = 2) with viral spread into the NAshell.

Figure 2.

A. Groups did not differ in the total number of cocaine infusions during the last 3 days of self-administration. B. ASIC1A overexpression in the NAcore increased active lever pressing during the cue-/context-driven cocaine-seeking test after the homecage period. ****, p < 0.0001. C. ASIC1A overexpression increased inactive lever pressing during the cue-/context-driven cocaine seeking. *, p < 0.05. D. ASIC1A-overexpressing rats showed greater lever pressing during the first 90 min of the session. %, p < 0.0001 and #, p < 0.05 for overall between-group difference; &, p < 0.05 for group difference on that day. E. During the extinction of cocaine seeking, ASIC1A overexpression marginally increased active lever pressing and increased inactive lever pressing. @, p < 0.1; #, p < 0.05. F. ASIC1A overexpression increased active lever pressing during cocaine-primed reinstatement. @, p < 0.1 and ***, p < 0.001 relative to extinction baseline; #, p < 0.01 relative to GFP. G. ASIC1A overexpression had no significant effect on active lever pressing during cued reinstatement. **, p < 0.01; and ***, p < 0.001 relative to extinction baseline. H. ASIC1A overexpression increased active lever pressing during cued + cocaine-primed reinstatement. *, p < 0.05 and ***, p < 0.001 relative to extinction baseline; #, p < 0.01 for GFP vs. ASIC1A. I-K. ASIC1A overexpression had no effect on inactive lever presses during reinstatement tests.

Figure 3.

A. Groups did not differ in the number of food pellets earned during the last 3 sessions of self-administration. B. ASIC1A overexpression in the NAcore had no effect on food seeking during the cue-/context-driven food-seeking test after the homecage period. C. ASIC1A overexpression had no effect on active or inactive lever presses during extinction training. D-F. Rats showed significantly increased active lever pressing during food-primed, cued, and cued + food-primed reinstatement tests, respectively, but GFP and ASIC1A overexpressing rats did not differ from one another. *, p < 0.05 and **, p < 0.01 relative to extinction baseline. G-I. No differences existed in inactive lever presses during food-primed, cued, and cued + food-primed reinstatement, respectively.