The effects of methamphetamine self-administration on cortical monoaminergic deficits induced by subsequent high-dose methamphetamine administrations

Abstract

Preclinical models suggest that repeated high-dose methamphetamine (METH) exposures, administered in a "binge-like" pattern, acutely decrease norepinephrine (NE), and acutely and persistently decrease serotonin (5-hydroxytryptamine; 5HT) content in the frontal cortex. However, the impact of METH self-administration on this region is unknown. Because of the importance of the monoaminergic neurons in the frontal cortex to a variety of cognitive and addictive processes, effects of METH self-administration on cortical NE and 5HT content were assessed. Results revealed several novel findings. First, METH self-administration decreased cortical NE content as assessed 24 h after last exposure. Consistent with previous preclinical reports after a binge METH regimen, this decrease was reversed 8 days after the final METH exposure. Second, and in contrast to our previous reports involving the hippocampus or striatum, METH self-administration caused persistent decreases in 5HT content as assessed 8 days after the final METH exposure. Of note, the magnitude of this decrease (≈ 20%) was less than that observed typically after a binge METH treatment. Third, prior METH self-administration attenuated METH-induced serotonergic deficits as assessed 7 days, but not 1 h, following a neurotoxic METH regimen. No protection was observed when the binge exposure occurred 15 days after the last self-administration session. Taken together, these data demonstrate important and selective alterations in cortical serotonergic neuronal function subsequent to METH self-administration. These data provide a foundation to investigate complex questions involving "resistance" to the persistent deficits caused by neurotoxic METH exposure and frontal cortical function.

Keywords: cortex; methamphetamine; norepinephrine; self-administration; serotonin.

Figure 1

METH self-administration decreased monoamine content in the cortex (histology represented in Panel A). Rats self-administered METH (0.12 mg/infusion) or saline (10 µl/infusion) for 7 d (8 h/d). Rats were sacrificed 24 h (Panel B; Saline NE: 7.58±0.31 pg/µg protein; Saline 5HT: 7.22±0.50 pg/µg protein) or 8 d (Panel C; Saline NE: 10.16±0.27 pg/µg protein; Saline 5HT: 8.72±0.59 pg/µg protein) after the start of the last self-administration session and cortex monoamines were assessed. *p<0.05 METH vs. Saline; #p<0.10 METH vs. Saline

Figure 2

Prior METH self-administration reduced the persistent but not acute serotonergic deficits in the cortex induced by a binge exposure to METH 1 d after the start of the last self-administration session. No protection was afforded by prior self-administration when the binge exposure occurred 15 d after the last self-administration session. Rats self-administered METH (0.12 mg/infusion) or saline (10 µl/infusion) for 7 d (8 h/d), received a binge exposure to METH 1 d after the start of the last self-administration session, and were sacrificed 7 d (Panel A and D; Panel A- Saline/Saline NE: 9.22±0.47 pg/µg protein; Saline/Saline 5HT: 8.11±0.33 pg/µg protein) or 1 h (Panel B and E; Panel B-Saline/Saline NE: 8.40±0.55 pg/µg protein; Saline/Saline 5HT: 8.73±0.79 pg/µg protein) after the last injection. Rats in Panels C and F self-administered as described above, but received the binge exposure to METH 15 d after the last self-administration session and were sacrificed 7 d later (Panel C- Saline/Saline NE: 8.29±0.66 pg/µg protein; Saline/Saline 5HT: 5.97±0.49 pg/µg protein). *p<0.05 compared to Saline/Saline; **p<0.05 compared to all other groups. Panels D, E, and F are from McFadden et al., 2012B with permission.