Meth Self-administration Research Articles

Escalation of methamphetamine self-administration in adolescent and adult rats

BackgroundMethamphetamine (METH) use has increased substantially in the last 10 years and poses a serious health concern, especially for young populations. Drug abuse primarily begins during adolescence, when uninhibited and excessive and drug intake is a common occurrence; thus, understanding the developmental patterns of addiction during this critical period is an essential step in its prevention. In the present study, the effect of age on the vulnerability to METH abuse was examined using a rat model of bingeing (i.e., escalation). MethodsAdolescent and adult rats were compared during short (ShA, 2-h) and long-access (LgA, 6-h) to METH self-administration. On postnatal (PN) days 23 (adolescents) and 90 (adults), rats were implanted with i.v. catheters and trained to lever press for infusions of METH (0.05mg/kg) during 2-h sessions. Once the rats reached a steady rate of METH self-administration, they were divided into ShA or LgA groups and allowed to self-administer METH for 15 additional days. ResultsResults indicated that adolescent rats earned significantly more infusions than adults under the LgA condition, but the age groups did not differ during ShA. Adolescents, but not adults, also significantly increased (i.e., escalated) METH self-administration across the 15 days of testing under the LgA condition. Further analysis indicated excessive responding during infusions in the LgA METH-exposed adolescents compared to the other groups, suggesting elevated impulsivity or motivation for drug. ConclusionThese results demonstrate that adolescents are more vulnerable to the escalation of METH than adults during LgA.

Reciprocal inhibitory effects of intravenous d-methamphetamine self-administration and wheel activity in rats

BackgroundSome epidemiological and cessation studies suggest physical exercise attenuates or prevents recreational drug use in humans. Preclinical studies indicate that wheel activity reduces cocaine self-administration in rats; this may, however, require the establishment of compulsive wheel activity. MethodsEffects of concurrent wheel activity on intravenous d-methamphetamine (METH) self-administration were examined in male Wistar and Sprague Dawley rats with negligible prior wheel experience. Wistar rats self-administered METH (0.05mg/kg/inf) under a fixed-ratio 1 (FR1) schedule with concurrent access to an activity wheel during sessions 1–14, 8–21 or 15–21. Control rats which did not self-administer METH had access to an activity wheel during sessions 1–14, 8–21 or 15–28. Sprague Dawley rats self-administered METH (0.1mg/kg/inf) under FR1 for 14 sessions with either concurrent access to a locked or an unlocked activity wheel. ResultsMETH self-administration was lower when the wheel was available concurrently from the start of self-administration training in both strains, even though Sprague Dawley rats self-administered twice as many METH infusions and ran one-sixth as much on the wheel compared to Wistar rats. Wheel access initiated after 7 or 14 days had no effect on METH self-administration in Wistar rats. Wheel activity was significantly reduced in these groups compared with the group with concurrent wheel and METH access for the first 14 sessions. ConclusionsThese data show that METH self-administration is reduced by exercise if initiated from the start of self-administration and that prior METH self-administration experience interferes with the value of exercise as a reinforcer.

Chronic modafinil effects on drug-seeking following methamphetamine self-administration in rats

Acute administration of the cognitive enhancing drug, modafinil (Provigil®), reduces methamphetamine (Meth) seeking following withdrawal from daily self-administration. However, the more clinically relevant effects of modafinil on Meth-seeking after chronic treatment have not been explored. Here, we determined the impact of modafinil on Meth-seeking after chronic daily treatment during extinction or abstinence following Meth self-administration. Rats self-administered intravenous Meth during daily 2-h sessions for 14 d, followed by extinction sessions or abstinence. During this period, rats received daily injections of vehicle, 30, or 100 mg/kg modafinil and were then tested for Meth-seeking via cue, Meth-primed, and context-induced reinstatement at early and late withdrawal time-points. We found that chronic modafinil attenuated relapse to a Meth-paired context, decreased conditioned cue-induced and Meth-primed reinstatement, and resulted in enduring reductions in Meth-seeking even after discontinuation of treatment. Additionally, we determined that only a very high dose of modafinil (300 mg/kg) during maintenance of self-administration had an impact on Meth intake. These results validate and extend clinical and preclinical findings that modafinil may be a viable treatment option for Meth addiction.

Methamphetamine self‐administration alters gene expression in the rat striatum

Striatum plays a critical role in the development of METH addiction but the molecular adaptations in the striatal neurons caused by METH exposure remain poorly understood. In the present study, we used an extended METH self‐administration model to study changes in gene expression in the rat striatum. Animals self‐administered METH (0.1 mg/kg/injection, i.v.) during 15‐hour sessions for 8 consecutive days. A yoked control group received passive injections of saline. The drug intake for the METH group reached 14.8 mg/kg/day. Rats were euthanized at 2 and 24 hours after the cessation of self‐administration. Transcriptional changes caused by METH were examined in the striatum using Illumina 22K Rat microarrays and validated by qRT‐PCR. METH self‐administration caused upregulation in the expression of transcription factors c‐fos, c‐jun, Nurr1, Nptx1 and neuropeptides cholecystokinin, neurotensin and neuromedin U. METH also induced increases in the expression of BDNF, synaptophysin, synaptotagmin II, syntaxin, cholinergic, glutamate and GABA receptors involved in the regulation of synaptic plasticity. Our results show that METH self‐administration causes changes in the expression of genes known to trigger persistent neuroadaptations in the mammalian brain. Some of these changes might contribute to METH‐related habit learning and development of METH addiction.

Methamphetamine Self-Administration Is Associated with Persistent Biochemical Alterations in Striatal and Cortical Dopaminergic Terminals in the Rat

Methamphetamine (meth) is an illicit psychostimulant that is abused throughout the world. Repeated passive injections of the drug given in a single day or over a few days cause significant and long-term depletion of dopamine and serotonin in the mammalian brain. Because meth self-administration may better mimic some aspects of human drug-taking behaviors, we examined to what extent this pattern of drug treatment might also result in damage to monoaminergic systems in the brain. Rats were allowed to intravenously self-administer meth (yoked control rats received vehicle) 15 hours per day for 8 days before being euthanized at either 24 hours or at 7 and 14 days after cessation of drug taking. Meth self-administration by the rats was associated with a progressive escalation of daily drug intake to 14 mg/kg per day. Animals that self-administered meth exhibited dose-dependent decreases in striatal dopamine levels during the period of observation. In addition, there were significant reductions in the levels of striatal dopamine transporter and tyrosine hydroxylase proteins. There were also significant decreases in the levels of dopamine, dopamine transporter, and tyrosine hydroxylase in the cortex. In contrast, meth self-administration caused only transient decreases in norepinephrine and serotonin levels in the two brain regions, with these values returning to normal at seven days after cessation of drug taking. Importantly, meth self-administration was associated with significant dose-dependent increases in glial fibrillary acidic protein in both striatum and cortex, with these changes being of greater magnitude in the striatum. These results suggest that meth self-administration by rats is associated with long-term biochemical changes that are reminiscent of those observed in post-mortem brain tissues of chronic meth abusers.

Immune responses to methamphetamine by active immunization with peptide-based, molecular adjuvant-containing vaccines

Vaccines to methamphetamine (meth) were designed by covalently attaching a meth hapten (METH) to peptide constructs that contained a conformationally biased, response-selective molecular adjuvant, YSFKPMPLaR (EP54). Rats immunized with EP54-containing meth vaccines generated serum antibody titers to authentic meth, an immune outcome that altered meth self-administration. Immunization increased meth self-administration suggesting pharmacokinetic antagonism. The ability of immune sera to bind a METH-modified target protein dramatically decreased during and shortly after the meth self-administration assay, suggesting effective sequestration of free meth. However, the binding ability of immune sera to the METH-modified target protein was recovered 34 days after meth-free clearance time.