Differential involvement of prelimbic and infralimbic medial prefrontal cortex in discrete cue-induced reinstatement of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) seeking in rats

Abstract

Rationale: The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) is a widely abused drug, particularly in adolescent and young adult populations. Although it was shown that MDMA-associated cues reinstate extinguished MDMA seeking in an animal relapse model, there is little information regarding the neural mechanisms underlying this behavior.

Objectives: Because the medial prefrontal cortex (mPFC) plays an important role in relapse to cocaine and methamphetamine seeking, we tested the effects of lidocaine inactivation of prelimbic (PL) and infralimbic (IL) subregions of mPFC on cue-induced relapse to MDMA seeking.

Methods: Rats were trained to respond for MDMA infusions (0.50 mg/kg/infusion, i.v.) paired with a discrete cue in daily 2-h sessions. Responding was reinforced contingent on a modified fixed ratio 5 schedule of reinforcement. Cue-induced reinstatement tests were conducted after responding was extinguished in the absence of MDMA and the conditioned cues. Prior to reinstatement tests, rats received bilateral microinjections of either lidocaine (100 μg/0.5 μl/side) or physiological saline (0.5 μl/side) delivered to either PL or IL mPFC.

Results: Microinjections of lidocaine into PL completely blocked reinstatement of MDMA-seeking behavior compared with saline microinjections into the same region. Lidocaine microinjections did not, however, have an effect on food-maintained responding, ruling out a nonspecific disruption of motor performance. Conversely, lidocaine inactivation of IL had no effect on reinstatement of MDMA seeking or food-maintained responding.

Conclusions: Our results provide direct support for PL activation in reinstatement of MDMA-seeking behavior. Moreover, akin to cocaine seeking, there appears to be differential involvement of PL and IL subregions in this behavior.

Fig. 1

Schematic illustration [modified from Paxinos and Watson (2005)] of coronal sections from the rat brain showing approximate injection sites in mPFC. Open and filled circles represent the PL injection sites in saline and lidocaine groups, respectively, and open and filled diamonds represent the IL injection sites in saline and lidocaine groups, respectively. Inset: Photomicrographs of coronal sections illustrating cannula tracts from animals with PL (top) and IL (bottom) placements. Notches indicate right hemisphere

Fig. 2

(a) Acquisition of MDMA self-administrationin rats assigned to receive intra-PL lidocaine or saline during subsequent reinstatement tests (number of 0.50 mg/kg infusions per 2-hr session).(b) Effect of bilateral microinjections of lidocaine (100 µg/0.5 µl/side) or saline (0.5 µl/side) into PL mPFC on CS-induced reinstatement of MDMA seeking. Open and closed bars indicate data obtained from rats assigned to receive saline and lidocaine injections, respectively, before the reinstatement test. SA indicates the mean number of presses per hour during the last three self-administration sessions. EXT indicates the extinction session before reinstatement. Reinstate indicates the reinstatement session, which was preceded by a saline or lidocaine microinjection into PL mPFC. * Indicates Bonferroni post-test, p < .05. (c) Time course of the effect of intra-PL lidocaine or saline on reinstatement responding. * Indicates difference from lidocaine group, Bonferroni post-test, p < .05. (d) Effect of intra-PL lidocaine or saline on food-reinforced operant responding. All data in figure are represented as mean ± SEM

Fig. 3

(a) Acquisition of MDMA self-administration in rats assigned to receive intra-IL lidocaine or saline during subsequent reinstatement tests.(b) Effect of bilateral microinjections of lidocaine (100 µg/0.5 µl/side) or saline (0.5 µl/side) into IL mPFC on CS-induced reinstatement of MDMA seeking. (c) Time course of the effect of intra-IL lidocaine or saline on reinstatement responding. (d) Effect of intra-IL lidocaine or saline on food-reinforced operant responding. See Fig. 2 for other details