Lee Leavitt, University of Utah
Biology
Chronic methamphetamine (METH) abuse leads to structural and functional damage in the brain, which likely contributes to cognitive and behavioral dysfunction. Recent data suggest an association between METH abuse and impaired inhibitory control over behavior; that is an impaired ability to inhibit inappropriate actions or thoughts. However, the extent to which METH-induced neurotoxicity is responsible for such impairment remains to be determined. Previously, we reported that rats with METH-induced partial dopamine (DA) and serotonin (5-HT) loss in striatum and prefrontal cortex (PFC) exhibited impaired response inhibition in the form of perseverative responding. Furthermore, levels of serotonin transporter (SERT) binding in PFC correlated with perseverative responding. Herein, we have examined another dimension of response inhibition impulsive action, which is an inability to withhold a “pre-potent” response in rats with METH-induced neurotoxicity. Rats were trained to perform a stop-signal task (SST). Once rats achieved stable responding (>80% correct response) on both “Go” and “Stop” trials, they were treated with saline (0.9%), a neurotoxic regimen of METH (4 x 10 mg/kg, 2-hr intervals, s.c.) under normal ambient temperature conditions (“neurotoxic” METH group) or the METH regimen under cooling conditions (“normothermic” METH group). One week after the treatment, rats were again tested on the SST. After behavioral tests were done, animals were sacrificed and brains removed for determination of monoamine loss. The results showed: 1) the “neurotoxic” METH-, but not the “normothermic” METH or saline-treated rats, showed a 40-60% loss of SERT and dopamine transporter (DAT) binding in PFC and striatum; 2) the “neurotoxic” METH group showed normal behavioral performance in “Go” trials of the SST relative to the “normothermic” METH group or saline controls; 3) the “neurotoxic” METH group exhibited impaired withholding of a “pre-potent” response, as reflected by increased numbers of errors on the “Stop” trials of the SST. Overall, these data suggest that impaired inhibitory control over behavior (i.e., increased impulsive action) can arise as a consequence of METH-induced neurotoxicity to central dopamine and serotonin systems. Supported by NIH grant DA 024036