Extended access to cocaine self-administration results in reduced glutamate function within the medial prefrontal cortex

Abstract

Previous studies have shown that brief access to cocaine yields an increase in D2 receptor binding in the medial prefrontal cortex (mPFC), but that extended access to cocaine results in normalized binding of D2 receptors (i.e. the D2 binding returned to control levels). Extended-access conditions have also been shown to produce increased expression of the NR2 subunit of the N-Methyl-D-aspartate receptor in the mPFC. These results implicate disrupted glutamate and dopamine function within this area. Therefore, in the present study, we monitored glutamate and dopamine content within the mPFC during, or 24 hours after, cocaine self-administration in animals that experienced various amounts of exposure to the drug. Naïve subjects showed decreased glutamate and increased dopamine levels within the mPFC during cocaine self-administration. Exposure to seven 1-hour daily cocaine self-administration sessions did not alter the response to self-administered cocaine, but resulted in decreased basal dopamine levels. While exposure to 17 1-hour sessions also resulted in reduced basal dopamine levels, these animals showed increased dopaminergic, but completely diminished glutamatergic, response to self-administered cocaine. Finally, exposure to 17 cocaine self-administration sessions, the last 10 of which being 6-hour sessions, resulted in diminished glutamatergic response to self-administered cocaine and reduced basal glutamate levels within the mPFC while normalizing (i.e. causing a return to control levels) both the dopaminergic response to self-administered cocaine as well as basal dopamine levels within this area. These data demonstrate directly that the transition to escalated cocaine use involves progressive changes in dopamine and glutamate function within the mPFC.

Figure 1

Outline of the experimental schedules: Exp. 1 – Panel A; Exp. 2 – Panel B (with the no-net-flux for the 17 1hr group illustrated at the upper part of Panel A).

Figure 2

Cocaine-induced changes in glutamate content within the mPFC during the 1^st, 8^th, and 17^th 1h cocaine self-administration session, and the first hour of the last (i.e. 10^th) 6h session. Panel A – Raw extracellular glutamate content. Inset showing average number of cocaine infusions in subjects, from the four experimental groups, from which measurements of glutamate content were taken; Panel B – Data from A expressed as a percent change from the average baseline values; Panel C – probe location: filled bars = extended access, open ellipses = brief access. Cocaine self-administration started at the 0 time point. Cocaine self-administration induced significant reduction in glutamate content over the 1^st and 8^th h of self-administration.

Figure 3

Cocaine-induced changes in glutamate content within the mPFC over the first and last 6h session. Panel A – Changes in extracellular glutamate content resulting from cocaine self-administration (starting at the 0 time point). Inset showing average number of cocaine infusions in subjects, from the two 6h groups, from which measurements of glutamate content were taken; Panel B – Data from A expressed as a percent change from the average baseline values. Cocaine self-administration induced significant reduction in glutamate content over the first 4 hours of the first extended access session.

Figure 4

Cocaine-induced rise in dopamine content within the mPFC during the 1^st, 8^th, and 17^th lh cocaine self-administration session, and the first hour of the last (i.e. 10^th) 6h session. Panel A – Changes in extracellular dopamine content resulting from cocaine self-administration (starting at the 0 time point). Inset showing average number of cocaine infusions in subjects, from the four experimental groups, from which measurements of glutamate content were taken; Panel B – Data from A expressed as a percent change from the average baseline values. Cocaine self-administration started at the 0 time point.

Figure 5

Cocaine-induced rise in dopamine within the mPFC over the first and last 6h session. Panel A – Changes in extracellular dopamine content resulting from cocaine self-administration (starting at the 0 time point). Inset showing average number of cocaine infusions in subjects, from the two 6h groups, from which measurements of glutamate content were taken; Panel B – Data from A expressed as a percent change from the average baseline values. Cocaine self-administration started at the 0 time point. Inset showing average area under the curve for the two 6h groups (* represents significant difference from 0, or significant increase in DA content p=0.04).

Figure 6

Basal concentration of glutamate (expressed as μM of glutamate at the point of nonet-flux- Y axis) within the mPFC 24 hrs before the first session of cocaine self-administration (PreSA), or 24 hrs after the seventh or seventeenth day of brief access (8-lh and 17-1h, respectively), the first day of extended access (First6h), and the last day of extended access (Last6h). Basal glutamate levels were significantly lower after 10 days of extended access to cocaine. * Represent significant difference from the PreSA group p=0.021. Panel B – probe location: filled bars = extended access, open ellipses = brief access.

Figure 7

Basal concentration of dopamine (expressed as μM of Dopamine at the point of nonet-flux- Y axis) within the mPFC 24 hrs before the first session of cocaine self-administration (PreSA), or 24 hrs after the seventh day or seventeenth day of brief access (8-lh and 17-lh, respectively), the first day of extended access (First6h), and the last day of extended access (Last6h). Basal dopamine levels were significantly lower after 7 or 17 days of brief, or 1 day of extended, access to cocaine. * Represent significant difference from the PreSA group p<0.001. Panel B – probe location: filled bars = extended access, open ellipses = brief access.