Neuropsychopharmacology (2011) 36, S324–S449 & 2011 American College of Neuropsychopharmacology. All rights reserved 0893-133X/11 S324 www.neuropsychopharmacology.org Poster Session III 2. Long-Term, 96-hour Methamphetamine Self-Administration Wednesday, December 7, 2011 5:30 PM – 7:30 PM in Rats: A Preclinical Model Of Human Methamphetamine Addiction Nicholas E. Goeders*, Glenn F. Guerin, Elyse M. Cornett 1. BK Channel b1 Subunit Modulates Ethanol Drinking and LSU Health Sciences Center, Shreveport, USA Behavioral Adaptations to Chronic Ethanol Exposure Candice Contet*, David Le, Amanda J. Roberts, Steven N. Background: In 2009, the economic cost of methamphetamine Treistman, George F. Koob use to society was estimated at $16.2 - $48.3 billion. Chronic methamphetamine use is also associated with crime, aggression, The Scripps Research Institute, Committee on the Neurobiology of and violent, deviant and risky sexual behaviors. Human metham- Addictive Disorders, La Jolla, USA phetamine addicts typically follow a ‘‘binge-pattern’’ of use, with Background: Alcohol abuse disorders have devastating health and 3-15 days of continual drug use followed by a ‘‘crash’’ period of societal consequences. Development of more efficient alcoholism 1-3 days, often consisting of continuous sleep. They then usually treatments requires a better understanding of the molecular repeat this cycle if methamphetamine is available. These binges mechanisms mediating the intoxicating and motivational effects of continuous methamphetamine use may underlie the develop- of ethanol. One of the well-established molecular targets of ethanol ment of many of the deviant behaviors observed in long- is the large conductance calcium-activated potassium (BK) term methamphetamine addicts. However, in the preclinical channel. BK channels are highly expressed in the brain and play laboratory, methamphetamine addiction is typically modeled a key role in several aspects of neuronal physiology. Ethanol is a using non-contingent drug injections and/or self-administration potent activator of BK channel gating, but in vivo evidence for a sessions under daily 2- or 6-hour access conditions. While these causal relationship between BK channel potentiation and ethanol’s models have increased our understanding of both the molecular behavioral effects is scarce. Interestingly, association of the and behavioral intricacies of chronic methamphetamine exposure, auxiliary b1 subunit with the pore-forming a subunit precludes they could be improved by more closely modeling human drug ethanol-induced potentiation of BK currents in vitro. In the usage, which was the goal of these experiments. Of additional present study, we investigated how deficiency in BK b1 subunit importance are potential gender differences associated with affects ethanol intoxication, tolerance, dependence and drinking long-term methamphetamine use since there are few reports in mice. of the effects of methamphetamine on female rats, especially Methods: Adult male BK b1 wild-type, heterozygous and knockout using a binge paradigm. Therefore, we studied the effects of mice were trained and tested following the injection ofa low dose 96-hour methamphetamine self-administration in both male and of ethanol (1.5 g/kg) in the accelerating rotarod assay of motor female rats. coordination. The hypnotic effect of a high dose of ethanol (4 g/kg) Methods: Male and female adult Wistar rats were implanted with was measured in the loss-of-righting-reflex test, along with jugular catheters and allowed to recover from surgery. The rats hypothermia. Mice were exposed to chronic intermittent ethanol were placed into operant chambers and trained to self-administer vapor in inhalation chambers for 3 cycles of 8-h intoxication / 16-h methamphetamine (0.06 mg/kg/infusion) for 96 consecutive withdrawal, and a time-course of handling-induced convulsions hours. The rats had free access to water during the session and was conducted to evaluate dependence. Ethanol-induced ataxia, were fed once per day with standard lab chow to maintain weights. sedation, and hypothermia were measured approximately 26 h into After 96 hours, the rats were returned to their home cages for 72 withdrawal to assess the development of tolerance. An indepen- hours (withdrawal), which was followed by another 96-hour self- dent cohort of mice was subjected to a limited-access (2 h /day, administration session. Blood samples were drawn before, during starting 3 h into the dark phase) two-bottle choice model of and after the self-administration sessions to monitor corticoster- voluntary ethanol drinking. one, ACTH and testosterone. Estrous cycle fluctuations were also Results: We found that sensitivity to ethanol-induced ataxia, monitored in female rats. sedation and hypothermia was similar between BK b1 wild-type, Results: The patterns of self-administration evolved during the heterozygous and knockout male mice. Chronic intermittent course of this experiment in both male and female rats. The rats exposure to ethanol vapor produced tolerance to these effects in initially self-administered more methamphetamine during their wild-type mice, but the extent of tolerance was reduced in active cycles, maintaining regular active and inactive periods of knockout mice. Moreover, knockout and heterozygous mice drug intake. Over time, however, the rats displayed dramatic shifts experienced an earlier and more intense physical withdrawal in their circadian rhythms, self-administering more and more syndrome than wild-type counterparts. We also found that methamphetamine during their normally inactive periods com- knockout and heterozygous mice self-administered less ethanol pared to their active periods, often binging nonstop for up to 72 than their wild-type littermates. hours. Plasma corticosterone decreased in both male and female Discussion: These findings suggest that the b1 subunit may be rats during methamphetamine exposure but increased back to recruited upon chronic intoxication to dampen ethanol-induced baseline during withdrawal. Similar effects were seen with plasma potentiation of BK currents, thereby minimizing behavioral ACTH in female rats. Male rats exhibited a similar effect on plasma responses to ethanol. Absence of the b1 subunit in knockout mice testosterone, with decreases during methamphetamine exposure may, on the other hand, promote counter-adaptive changes that increased back to baseline during withdrawal. No changes in downstream of BK channel overstimulation by ethanol and plasma testosterone were seen in female rats. However, female exacerbate withdrawal. Decreased drinking in BK b1 deficient rats displayed disruptions of the estrous cycle by the second mice suggests a key role of BK channels in the initial exposure to the 96-hour methamphetamine sessions, which is neuroadaptations to ethanol within the reward system. consistent with human female menstrual cycle disruption reported Disclosure: C. Contet: None. D. Le: None. A. Roberts: None. S. with methamphetamine use. Finally, both male and female rats Treistman: None. G. Koob: Part 1: Addex Pharmaceuticals displayed increasingly violent, aggressive and self-injurious Alkermes Arkeo Pharmaceuticals Casa Palmera Embera Neuro- behaviors during the course of this experiment, all consistent with Therapeutics GlaxoSmithKline Lilly Psychogenics. human methamphetamine use. ACNP 50th Annual Meeting Abstracts S325 Discussion: These data suggest that our 96-hour binge model of 4. A Preclinical Examination of Behavioral and Neurotransmitter methamphetamine self-administration may be useful as a novel Specific Roles for the Ventral Tegmental Area in Reinforcer- preclinical model to more closely mimic human methamphet- Seeking and Drinking. amine-taking behavior and perhaps to further contribute to Cristine L. Czachowski* elucidating gender differences in methamphetamine use and addiction. Indiana University, Indianapolis, USA Disclosure: N. Goeders: None. G. Guerin: None. E. Cornett: None. Background: The ventral tegmental area (VTA) is a pivotal relay site within the brain’s reinforcement circuit that has been shown to play a role in alcohol-motivated behaviors. The primary dopamine 3. Essential Role for Fragile-X Mental Retardation Protein projection neurons within this system originate in the VTA and (FMRP) in Normal Behavioral and Neuronal Morphological innervate several areas including the nucleus accumbens (NAc) Adaptations following Repeated Cocaine Administration and prefrontal cortex (PFC). In addition, the PFC has afferent Laura N. Smith, Makoto Taniguchi, Karen C. Dietz, Miles R. glutamate projections to the VTA and the NAc. The following Fontenot, Benjamin C. Zirlin, Kimberly M. Huber, Christopher W. studies utilized two different operant behavior paradigms, one Cowan* focusing on reinforcer-seeking and one on reinforcer self- administration, (both with an alcohol and a sucrose reinforcer UT Southwestern Medical Center, Dallas, USA solution) to elucidate regulation of these behaviors by the VTA, Background: Repeated exposure to cocaine produces sensitized and the specific roles of dopamine and glutamate in this region. locomotion and reward-associated learning (conditioned place Methods: The present experiments assessed the effects of preference; CPP) in rodents. We previously reported that microinjections of the glutamate (AMPA/kainate) antagonist expression of active myocyte enhancer factor 2 (MEF2), a CNQX and the dopamine D1-like antagonist SCH23390 into the transcription factor family that promotes