Role of the dorsal and ventral prefrontal cortex in cue- and drug-induced reinstatement following extended access to methamphetamine

A. ROCHA,; A. PACCHIONI,; P. W. KALIVAS

Washington DC, USA

Congreso; 38th Annual Meeting of Neurosciences; 2008

Society for Neuroscience

<!-- /* Font Definitions */ @font-face {font-family:"Cambria Math"; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:roman; mso-font-pitch:variable; mso-font-signature:-1610611985 1107304683 0 0 159 0;} @font-face {font-family:Calibri; panose-1:2 15 5 2 2 2 4 3 2 4; mso-font-charset:0; mso-generic-font-family:swiss; mso-font-pitch:variable; mso-font-signature:-1610611985 1073750139 0 0 159 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin-top:0in; margin-right:0in; margin-bottom:10.0pt; margin-left:0in; line-height:115%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-fareast-font-family:Calibri; mso-bidi-font-family:"Times New Roman";} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-size:10.0pt; mso-ansi-font-size:10.0pt; mso-bidi-font-size:10.0pt; mso-ascii-font-family:Calibri; mso-fareast-font-family:Calibri; mso-hansi-font-family:Calibri;} @page Section1 {size:8.5in 11.0in; margin:1.0in 1.0in 1.0in 1.0in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.Section1 {page:Section1;} --> Neuroimaging studies provide evidence of corticolimbic dysregulation in methamphetamine (METH)-dependent individuals. Specifically, fMRI studies show decreased activation of the medial prefrontal cortex (mPFC) in individuals with long-term METH use. In mapping the brain circuitry mediating cue- and drug-induced METH reinstatement, it was postulated that rats trained to self-administer METH would exhibit impaired prefrontal cortical function, with greater impairments in animals exposed to METH for an extended period of time. To assess whether length of daily exposure to METH would be a factor in corticolimbic dysregulation, male Long-Evans were implanted with indwelling jugular catheters as well as cannulae aimed at one of four brain regions (dorsal prefrontal cortex [dPFC], ventral prefrontal cortex [vPFC], nucleus accumbens core [NAcore], nucleus accumbens shell [NAshell]). Animals were trained to self-administer METH i.v. (.06mg/kg) for 1 hr/day for 10 days. Half of the animals continued on a short-access (sha) paradigm for 12 additional days, while half were given 6 hr (long) access to the drug for the same period of time. Animals were then placed on 10 days of extinction training. After extinction, the dPFC,vPFC,NAcore and NAshell were temporarily inactivated with a combination of the GABA-B agonist baclofen and the GABA-A agonist muscimol (B/M) before each animal was reintroduced to cues previously associated with the drug (cue-induced reinstatement) or an i.p. challenge injection of METH (drug-induced reinstatement). Temporary inhibition of the dPFC blocked cue- and drug-induced reinstatement in the long-access (lga) group, whereas inhibition of the vPFC did not alter drug reinstatement in either sha or lga group. These data suggest that, following METH self-administration, the dPFC-NAcore circuitry is intact and glutamatergic projections between these regions are perhaps stronger in lga than sha animals, as evidenced by more pronounced reinstatement in the lga group. In contrast, the vPFC-NAshell circuitry appears to be offline after chronic METH. The levels of dopamine and its metabolites were also assayed in the dPFC, vPFC, NAcore, and NAshell in sha, lga, and yoked-saline control animals, three weeks after the last self-administration trial. No siginficant dopamine depletions were measured in any brain region in the METH treatment groups