Improved prevention and treatment of drug addiction will require deeper understanding of genetic factors contributing to susceptibility to excessive drug use. Intravenous operant self-administration methods have greatly advanced understanding of behavioral traits related to addiction. However, these methods are not suitable for large-scale genetic experiments in mice. Selective breeding of mice can aggregate 'addiction alleles' in a model that has the potential to identify coordinated effects of multiple genes. We produced mouse lines that orally self-administer high (MAHDR) or low (MALDR) amounts of methamphetamine, representing the first demonstration of selective breeding for self-administration of any psychostimulant drug. Conditioned place preference and taste aversion results indicate that MAHDR mice are relatively more sensitive to the rewarding effects and less sensitive to the aversive effects of methamphetamine, compared to MALDR mice. These results validate the oral route of self-administration for investigation of the motivational effects of methamphetamine and provide a viable alternative to intravenous self-administration procedures. Gene expression results for a subset of genes relevant to addiction-related processes suggest differential regulation by methamphetamine of apoptosis and immune pathways in the nucleus accumbens of MAHDR and MALDR mice. In each line, methamphetamine reduced an allostatic state by bringing gene expression back toward 'normal' levels. Genes differentially expressed in the drug-naïve state, including Slc6a4 (serotonin transporter), Htr3a (serotonin receptor 3A), Rela [nuclear factor κB (NFκB)] and Fos (cFos), represent candidates whose expression levels may predict methamphetamine consumption and susceptibility to methamphetamine reward and aversion.

Abstract3,4-Methylenedioxymethamphetamine (MDMA or Ecstasy) stimulates the transporter-mediated release of monoamines, including serotonin (5-HT). High-dose exposure to MDMA causes persistent 5-HT deficits (e.g., depletion of brain 5-HT) in animals, yet the functional and clinical relevance of such deficits are poorly defined. Here we examine functional consequences of MDMA-induced 5-HT depletions in rats. Male rats received binges of 3 ip injections of MDMA or saline, one injection every 2 h; MDMA was given at a threshold pharmacological dose (1.5 mg/kg × 3, low dose) or at a 5-fold higher amount (7.5 mg/kg × 3, high dose). One week later, jugular catheters and intracerebral guide cannulae were implanted. Two weeks after binges, rats received acute iv challenge injections of 1 and 3 mg/kg MDMA. Neuroendocrine effects evoked by iv MDMA (prolactin and corticosterone secretion) were assessed via serial blood sampling, while neurochemical effects (5-HT and dopamine release) were assessed via microdialysis in brain. MDMA binges elevated core temperatures only in the high-dose group, with these same rats exhibiting ~50% loss of forebrain 5-HT two weeks later. Prior exposure to MDMA did not alter baseline plasma hormones or dialysate monoamines, and effects of iv MDMA were similar in saline and low-dose groups. By contrast, rats pretreated with high-dose MDMA displayed significant reductions in evoked hormone secretion and 5-HT release when challenged with iv MDMA. As tolerance developed only in rats exposed to high-dose binges, hyperthermia and 5-HT depletion are implicated in this phenomenon. Our results suggest that MDMA tolerance in humans may reflect 5-HT deficits which could contribute to further dose escalation. KeywordsEcstasy; serotonin; dopamine; transporter; neuroendocrine; microdialysis (±)-3,4-Methylenedioxymethamphetamine (MDMA, or Ecstasy) is an illicit drug that stimulates transporter-mediated release of monoamines from neurons (White et al., 1996, Address correspondence to: Michael H. Baumann, Ph.D., IRP, NIDA, NIH, DHHS, 333 Cassell Drive, Suite 4500, Baltimore, MD 21224, Tel. 410 550-1754, Fax. 410 550-2997.nih.gov. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2008 May 21. Published in final edited form as:Neuroscience. 2008 March 27; 152(3): 773-784. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript Green et al., 2003). High-dose administration of MDMA to rats causes impairments in central serotonin (5-HT) neurons, including inhibition of tryptoph...

Establishing measurement invariance of tobacco addiction among adolescents remains challenging. In adult smoking cessation trials, poor outcome is predicted by high cigarette consumption and large puff volume at baseline. We examined the predictive value of pretreatment smoking rates and topography variables for abstinence outcomes among 66 adolescents enrolled in a 3-month smoking cessation trial using nicotine replacement and cognitive behavioral therapy. Pretreatment variables included cigarettes per day (CPD), puff volume, puff duration, and several youth-adapted Fagerströ m-derived questionnaire scores. Outcome measures included prolonged abstinence at end of treatment and point-prevalent abstinence 3 months after the end of the trial. Logistic regression controlling for treatment group showed that increases in baseline CPD (odds ratio, 1.438; 95% confidence interval, 1.051-1.967) and average puff volume (odds ratio, 1.168; 95% confidence interval, 1.030-1.326) predicted continued smoking at the end of treatment. Puff volume (P = 0.013), but not CPD, predicted abstinence at the 3-month follow-up. None of the youth-adapted Fagerströ m questionnaires predicted outcome on either abstinence measure. If confirmed in a larger sample, our findings suggest that puff topography, and possibly CPD, might predict cessation outcome better than Fagerström scores in adolescent smokers.

Although extracellular signal-regulated kinase (ERK) activity is essential for the acquisition of a variety of associative learning tasks, its involvement in the acquisition and extinction of ethanol (EtOH)-induced conditioned place preference (CPP) remains unknown. Therefore, in these experiments we examined the effects of the ERK-kinase (MEK)-inhibitor SL327 on acquisition and expression of EtOH-CPP as well as the dose-and time-dependent effects of SL327 on CPP extinction. The parametric findings of Experiment 1 showed that three 30-min (but not 15-or 5-min) non-reinforced trials were required to completely extinguish EtOH-CPP in male, DBA/2J mice. In Experiments 2 & 3, SL327 (30 and 50 mg/kg), administered 30 or 90 min prior to extinction trials, was unable to impair EtOH-CPP extinction. Experiment 4 showed that SL327 (50 mg/kg) had no effect on acquisition of EtOH-CPP or the development of EtOH-induced sensitization during conditioning. When administered prior to testing in Experiments 5 & 6, SL327 did not alter expression of EtOH-CPP but did reduce test activity. Importantly, SL327 significantly reduced pERK protein levels when assessed in the dorsal striatum and motor cortex (Experiment 7). Together, these data suggest that EtOH-related learning and EtOH reward in mice, as assessed with CPP, are not impaired by the systemically administered MEK-inhibitor SL327.