Neural circuit competition in cocaine-seeking: roles of the infralimbic cortex and nucleus accumbens shell

Abstract

Following cocaine self-administration and extinction training, activity in the infralimbic cortex (IL) suppresses cocaine-seeking behavior. IL inactivation induces cocaine-seeking whereas activation suppresses cocaine-reinstated drug-seeking. We asked how the suppression of cocaine-seeking induced by IL activation integrates with the circuitry promoting reinstated cocaine-seeking. Following cocaine self-administration and extinction training, rats underwent cue-induced reinstatement. In order to activate IL projections, microinjections of PEPA, a positive allosteric modulator of AMPA receptors, were made into the IL in combination with microinjections into a variety of nuclei known to regulate cocaine-seeking. Intra-IL PEPA administration suppressed cue-induced reinstatement without affecting locomotor activity. The suppression of cocaine-seeking was reversed by activating dopamine neurons in the ventral tegmental area with microinjections of the μ-opioid receptor agonist DAMGO, and was partially reversed by dopamine microinjections into the prelimbic cortex or basolateral amygdala. Previous evidence suggests that the nucleus accumbens shell both promotes and suppresses cocaine-seeking. The suppression of cue-induced cocaine seeking by PEPA in the IL was reversed by intra-shell microinjections of either dopamine or the AMPA receptor antagonist CNQX, suggesting that the accumbens shell bidirectionally regulates cocaine-seeking depending on whether dopamine input is mimicked or glutamate input is inhibited. Together, these findings indicate that the IL acts 'upstream' from structures promoting cocaine-seeking, including from the mesolimbic dopamine projections to the prelimbic cortex and basolateral amygdala, and that the accumbens shell may be a crucial point of integration between the circuits that promote (ventral tegmental area) and inhibit (IL) reinstated cocaine-seeking.

Figure 1

Suppression of cue-induced cocaine-seeking by intra-IL microinjections of PEPA. A, Active and inactive lever presses during last 12 days of cocaine self-administration. B, Active lever presses (mean +/− SEM) during extinction and cue-induce reinstatement. Intra-IL microinjections of PEPA immediately prior to a cue-induced reinstatement session suppressed cocaine-seeking behavior. C, Horizontal activity counts (mean +/− SEM) measured in an open-field test. Intra-IL microinjections of PEPA immediately prior to the open-field test did not affect the rats’ locomotor activity. *, p < 0.0001, compared to extinction baseline. +, p < 0.05 compared to extinction baseline and to vehicle group.

Figure 2

Partial reversal of PEPA-induced suppression of cue-induced cocaine-seeking by dopaminergic activation of the PL or BLA. A, Active lever presses (mean +/− SEM) during extinction and cue-induced reinstatement for the IL-PL experiments. Intra-IL microinjections of PEPA suppressed cue-induced reinstatement, whereas rats receiving PEPA into the IL and dopamine into the PL showed significant reinstatement. Rats were counterbalanced across IL microinjections. B, Active lever presses (mean +/− SEM) during extinction and cue-induced reinstatement for the IL-BLA experiments. Intra-IL microinjections of PEPA suppressed cue-induced reinstatement, whereas rats receiving PEPA into the IL and dopamine into the PL showed significant reinstatement. For the IL-BLA experiment, intra-BLA microinjections of dopamine alone immediately prior to an extinction session did not significantly affect cocaine-seeking behavior. Rats were counterbalanced across BLA micrionjections. *, p < 0.05 compared to extinction baseline.

Figure 3

Reversal of PEPA-induced suppression of cue-induced cocaine-seeking by VTA disinhibition, as shown by active lever presses (mean +/− SEM) during extinction and cue-induced reinstatement. Intra-IL microinjections of PEPA suppressed cue-induced reinstatement, an effect that was reversed by intra-VTA microinjections of the μ-opioid receptor agonist DAMGO. Intra-VTA microinjections of DAMGO did not significantly induce reinstatement when given alone prior to an extinction session. Rats were counterbalanced across IL microinjections. *, p < 0.05 compared to extinction baseline. +, p < 0.05 compared to PEPA-DAMGO group.

Figure 4

Regulation of cue-induce cocaine-seeking behavior by the NAshell. A and B, Active and inactive lever presses (mean +/− SEM), respectively, during extinction and cue-induced reinstatement for rats receiving dopamine microinjections into the NAshell. Intra-IL microinjections of PEPA suppressed cue-induced reinstatement, an effect that was reversed by dopamine microinjections into the NAshell. Intra-NAshell microinjections of dopamine alone prior to an extinction session induced a significant increase in active lever presses. Rats were counterbalanced across NAshell microinjections. C, Active lever presses (mean +/− SEM) during extinction and cue- and cocaine prime-induced reinstatement for rats receiving intra-NAshell microinjections of the AMPA receptor antagonist CNQX. Intra-NAshell microinjections of PEPA suppressed cue-induced reinstatement, an effect that was reversed by intra-NAshell microinjections of CNQX. Rats then underwent a cocaine prime-induced reinstatement session in which CNQX or vehicle was administered into the NAshell prior to the session. CNQX administration did not prevent the cocaine prime-induced reinstatement. Rats were counterbalanced across NAshell microinjections. *, p < 0.05 compared to extinction baseline. #, p < 0.08 compared to extinction baseline. +, p < 0.05 compared to PEPA-dopamine or PEPA-CNQX group.

Figure 5

Diagrams showing the microinjector tracks. Figure 5 shows the location of the microinjector tips for the animals whose data were used in the study. A, Diagram showing the location of 20 randomly selected microinjector tips in the IL. Because the same cannulae were used for IL and PL microinjections, there are no separate tip locations for PL injections. Correct PL placement was assumed if the IL placement was correct. B, Diagram showing the location of the microinjector tips in the BLA. C, Diagram showing the location of the microinjector tips in the VTA. D, Diagram showing the location of the microinjector tips in the NAshell. Figures adapted from Paxinos and Watson (2005) and A/P coordinates (in mm) are given relative to Bregma.