P.6.c.004 Transdermal cannabidiol: long-lasting attenuation of relapse vulnerability in animal models of drug seeking, anxiety, and impulsivity

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  • P.6.c. Addiction Drugs (basic) S567

    P.6.c.004 Transdermal cannabidiol: long-lastingattenuation of relapse vulnerability inanimal models of drug seeking, anxiety, andimpulsivity

    F. Weiss1 , G. Gonzales-Cuevas1, A.L. Stinchcomb2 1TheScripps Research Institute, Cellular and Molecular NeuroscienceDepartment (SP302120), La Jolla CA, USA; 2AllTranz Inc.,Lexington KY, USA

    Drug addiction is a chronically relapsing disorder. Susceptibility torelapse can be traced to multiple factors including craving elicitedby drug-related cues, drug-induced neuroadaptation responsiblefor heightened anxiety and hypersensitivity to stress, as well asdrug-induced impairments in impulse control as a risk factor forrelapse. Given that addicted individuals enter vulnerability statesfor multiple reasons, treatment drugs that target more than asingle factor or vulnerability state for relapse are likely to offersignificant clinical advantages. An agent with an emerging profileof actions suggestive of potential to offer such a wide spectrumof actions is cannabidiol (CBD), the main non-psychoactive andnon-addictive component of the Cannabis sativa plant. A factorlimiting the therapeutic potential of CBD is the drugs low oralbioavailability in man due to a major first-pass effect.Therefore, to provide for translational relevance in understand-

    ing CBDs behavioral profile, the transdermal route of adminis-tration that eliminates the first pass effect and reduces bioavail-ability variability was employed. An initial experiment establishedthat a transdermal CBD gel preparation (tCBD) produces dose-dependent significant and sustained plasma CBD levels with littlevariability. The effects of tCBD then were examined in animalmodels of relapse, anxiety, and impulsivity. Male Wistar rats witha history of ethanol or cocaine self-administration were treatedwith tCBD (gel volume: 640ml/kg = 15mg/kg) at 24h intervals for7 days. In repeated reinstatement tests conducted during this time,tCBD significantly reduced ethanol and cocaine seeking inducedby drug-related cues, the pharmacological stressor yohimbine, orfootshock stress, without producing tolerance. Remarkably, bothstress- and cue-induced reinstatement remained fully attenuatedin tests conducted as late as 138 days after termination of tCBDtreatment. In tests of anxiety conducted 2 days post-tCBD, allrats showed significantly reduced anxiety-like behavior on theelevated plus maze. To study tCBDs effects on impulse control,rats were subjected to a 7d ethanol intragastric intoxication pro-cedure during which they were treated at 24h intervals with tCBD(15mg/kg). In subsequent delay discounting tests, rats with anintoxication history showed significantly reduced preference forlarge delayed reward. This profile of high impulsivity was fullyreversed in tCBD-treated rats. In tests of nonspecific behavioraleffects, tCBD neither interfered with reinstatement motivated bya palatable sweet solution, nor altered spontaneous locomotoractivity. Although presently limited to a single dose, the resultsare consistent with the hypothesis that tCBD has therapeuticpotential for multiple vulnerability states underlying relapse risk.Particularly significant was the observation that cue- and stress-induced ethanol seeking remained effectively reduced as late as5 months (138 days) post-treatment. This observation, pairedwith the finding that tCBD attenuates impulsivity in rats with asevere ethanol intoxication history, is of substantial interest bothfrom a medication development and neurobiological perspective inthat it is suggestive of diverse neuroregulatory actions that restore

    normal function to brain circuitries regulating reward, incentivemotivation, impulsivity, stress and anxiety.Support: NIH/ NIAAA AA018010 and NIH/NIDA DA07348

    (FW); Fulbright MECD-2008 (GGC).

    P.6.c.005 Exposure to caffeine and sucrose changeslocomotor behaviour, neurobiology andresponse to acute methamphetaminechallenge

    J.L. Franklin1 , M. Mirzaei2, M.K. Sauer1, T.A. Wearne1,A.K. Goodchild2, P.A. Haynes3, J.L. Cornish1 1MacquarieUniversity, Psychology, Sydney, Australia; 2Macquarie University,Australian School of Advanced Medicine, Sydney, Australia;3Macquarie University, Chemistry and Biomolecular Sciences,Sydney, Australia

    Purpose: Caffeine is a psychostimulant that is commonly con-sumed by adults often in combination with high levels of sugar.There is evidence to suggest that caffeine treatment can change thepsychostimulant response, in adult animals, to cocaine, nicotineor alcohol [1].Sucrose exposure has also been shown to change reward pro-

    cessing [2].Here we examined whether extended exposure to caffeine,

    sucrose or their combination altered the behavioral response to anacute methamphetamine (METH) challenge, as this drug is one ofthe highest abused substances in Australia and worldwide. In ad-dition to behavioural changes, the effect of chronic treatment withcaffeine and or sucrose on protein expression in the orbitofrontalcortex (OFC) was examined. This brain region plays a critical rolein decision making processes, with a number of neurodegenerativeconditions linked to disruption of OFC function.Importantly, the OFC regulates impulse control and addictive

    disorders [3].Method: Adult male Sprague Dawley (SD) rats, (n = 12 per

    group), were treated for 26 days with either water, caffeine(0.6g/L), 10% sucrose, caffeine (0.6g/L)+10% sucrose (C+S full)or caffeine (0.3g/L)+5% sucrose (C+S half) in their drinkingwater. Locomotor behaviour was measured on the first and lastday of treatment, then again one week after treatment. Animalswere then challenged with either saline (1ml/kg, i.p.) or METH(1mg/kg, i.p.) and their locomotor activity was measured for2 hours prior to rapid removal of brain tissue; snap frozen inliquid nitrogen and then stored at 80 until label free quantitativeshotgun proteomic analysis of the OFC was conducted.Results: When tested drug free and challenged with saline

    the caffeine pretreated animals were significantly more activethan control and all other treatment groups (p< 0.05). Unex-pectedly caffeine pretreatment did not cross-sensitize the animalsto METH, as the hyperactivity produced by METH was simi-lar in control rats compared to caffeine treated rats. However,hyperactivity produced by METH was significantly reduced inrats pretreated with combined caffeine and sucrose (full dose)when compared to those pretreated with caffeine alone (p = 0.035).Proteomic analyses of the OFC determined that 158 and 251proteins were differentially expressed in caffeine and sucroserats, respectively, when compared to control treated rats. The topfunctional networks associated with changed proteins in caffeinerats were nervous system function, cellular compromise and mi-tochondrial dysfunction, and in sucrose treated rats were nucleicacid metabolism, signaling, energy production and DNA repair.


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