S32 CHRONIC METHAMPHETAMINE EXPOSURE AND INDUCTION OF LIMBIC PLASTICITY: DEVELOPMENT OF PHARMACOTHEREPEUTIC STRATEGIES T.C. Napier, J. McDaid and L. Harper Department of Pharmacology and Experimental Therapeutics, Loyola University Chicago Medical Center, Maywood, Illinois, USA E-mail: cnapier@lumc.edu Repeatedadministrationofmethamphetamine(meth;1–2.5 mg/kg)inratsinducesenhancedmotorbehavior(sensitization) that persists for weeks. When the drug administration is associated with a specific environment, rats prefer that environment even in a drug-free state (conditioned place preference; CPP). These behaviors reflect meth-induced alterations in brain function. Our studies focus on: (1) neuroanatomical and biochemical substrates that underlie meth-induced motor sensitization (MS) and CPP; (2) involve- ment of 5-HT 2A/2C R in the changes; and (3) whether these processes can be nullified by antagonists to 5-HT 2A/2C R. We observed that particular components of the mitogen-activated protein kinase (MAPK) signaling cascade are differentially regulated by meth, depending on the length of time after treatment(1,3or14days)andbrainregionassayed.Western blotting revealed, for example, decreased pCREB in the nucleusaccumbensandventralpallidum14daysafterthelast meth injection. At this time, FosB was elevated in the ventral pallidum, pERK/ERK were unchanged in either region, and nochangesinexpressionofanymarkeroccurredinthecortex or ventral tegmental area. The role of 5-HT 2A/2C R in these adaptations is also time and region dependent. Mirtazapine (which blocks 5-HT 2A/2C R) at 1mg/kg antagonized the expression of meth-induced conditioned place preference (CPP), but 5mg/kg was needed to antagonize MS expression. Whenmirtazapinewasgivenduringa14-daywithdrawalfrom aconditioningparadigmthatnormallyinducespersistentCPP and MS (three pairings using 1mg/kg meth), the rats neither exhibitedplacepreferencewhendrug-free,orexpressedMSto an acute meth challenge. When given in the drug-paired chamber, the acute challenge would normally serve to ‘recondition’ rats to the meth-paired environment. However, the mirtazapine treatment rendered ineffectual the capacity of this acute meth challenge to reinstate preference. These data indicate clinical utility for 5-HT 2A/2C R antagonists in post- addiction pharmacotherapy. S33 MDMA, METHAMPHETAMINE AND THEIR COMBINATION: COMPARISON OF LONG-TERM BEHAVIOURAL AND NEURAL EFFECTS IN RATS I. McGregor, K. Clemens, J. Cornish, M.Thompson, K. Li and G. Hunt School of Psychology, University of Sydney, Sydney, Australia E-mail: iain@psych.usyd.edu.au 3,4-Methylenedioxymethamphetamine (MDMA) and methamphetamine(METH)aredrugsthatarefrequentlyused at dance parties. In many countries ‘Ecstasy’ tablets often contain METH rather than MDMA, making it likely that many Ecstasy users are unwittingly using both MDMA and METH.Wehaveexaminedtheacuteandlong-termeffectsof MDMA and METH in rats, when given alone or in combination. MDMA given acutely has a strong prosocial effect, increasing social interaction in rats, while METH decreases social interaction. Both drugs increase locomotor activity, but at higher doses METH causes strong stereotypy. MDMA has greater potency than METH in causing hyperthermia.CombiningsmalldosesofMDMAandMETH causes marked stereotypy and hyperthermia, indicating that eachdrugcanpotentiatetheadverseacuteeffectsoftheother. The exact pattern of acute effects can depend upon whether MDMAorMETHisgivenfirst:MDMAgivenbeforeMETH causesgreaterhyperthermiathanviceversa.Formonthsafter brief exposure to MDMA, METH or their combination, profound decreases in social interaction are seen in rats. Chronic increases in anxiety-like behaviour on the emergence test,anddepressive-likesymptomsontheforcedswimtest,are alsoevidentfollowingbriefexposuretoMDMAorMDMA–- METH combinations, but not to METH. MDMA-exposed rats show lasting decreases in serotonin (5-HT) in many brain regions, while equivalent METH exposure causes lasting depletion of dopamine in the striatum and/or prefrontal cortex. When small doses of MDMA and METH are given incombination,lastingdecreasesinboth5-HTanddopamine depletion are seen – an additive effect – and noradrenaline depletion may also be detected. Overall our results suggest a divergent profile of acute and long-term toxic effects with MDMAandMETH,andindicatethelikelihoodofadditive,if notsynergistic,toxicitywhenthetwodrugsaretakentogether. Supported by the NH and MRC. S34 LONG-TERM CHANGES IN SEROTONERGIC FUNCTION FOLLOWING MDMA ADMINISTRATION TO ADOLESCENT RATS K. C. F. Fone 1 , E. J. Bull 1 , M.V. Porkess 1 , M. Rigby 2 and P. H. Hutson 2 1 Institute of Neuroscience, School of Biomedical Sciences, University of Nottingham, Nottingham, United Kingdom and 2 Neuroscience Research Centre, Merk Sharp and Dohme, Harlow, CM20 2QR, United Kingdom E-mail: kevin.fone@nottingham.ac.uk Several groups have shown that treating young rats with ecstasy, 3,4-methylenedioxymethamphetamine (MDMA) pro- duces a long-lasting enhanced anxiogenic response to mildly aversive contexts. The neurochemical mechanisms underlying these changes in social and exploratory behaviour are unknown, but since MDMA causes serotonergic neurotoxi- city in the rat this study evaluated whether there was any accompanyingpersistentchangeinserotoninreceptorfunction. Separate groups of either Wistar or Lister hooded rats receivedMDMAi.p.(5mg/kg4 Â dailyfor2daysor15mg/kg twicedailyfor3days)orsaline(1ml/kg),startingonpost-natal day 28, and the acute effect on locomotion and body temperature was recorded. Following at least 20 days’ abstinence the behavioural response to selected serotonin (5- HT) agonists [the 5-HT 1A agonist, 8-hydroxy-2-(di-n-propyla- mino)tetraline (8-OHDPAT) 0.5mg/kg s.c.; the 5-HT 2C/1B agonist, m-CPP 1–2.5mg/kg i.p.; or the 5-HT 2A/2C agonist DOI 1mg/kg i.p.] was recorded in open field, elevated plus- mazeandsocialinteractionparadigmstoidentifyanylong-term alteration in specific 5-HT receptor functions. MDMA pre- treatment did not alter the behavioural responseto 5-HT 1A or 5-HT 2C receptor activation but specifically attenuated the anxiogenic effect of DOI in the elevated plus-maze. Further- more,MDMApretreatmentwasexaminedontheDOI-induced change in local cerebral glucose utilization (LCGU) in specific brain regions using [ 14 C]2-deoxyglucose. Eight weeks after MDMA, DOI significantly elevated (Po0.05) LCGU in the nucleusaccumbensofMDMAbutnotinsalinepre-treatedrats, but a similar trend in hippocampal regions did not reach significance. Thus, brief exposure of young rats to an MDMA Abstracts of the 11th Biennial EBPS Meeting S11 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.