Rationale Modulation of the endocannabinoid system has been found to interfere

Rationale Modulation of the endocannabinoid system has been found to interfere with opiate withdrawal. CB1 antagonists AM4113 and AM6527 (oral) to interfere with establishment of a MWD-induced CPA was investigated. As well the potential of AM251 and AM4113 to interfere with reinstatement of a previously established MWD-induced CPA was investigated. Materials and methods Using a one-trial place conditioning paradigm rats were administered naloxone (1 mg/kg subcutaneous (sc)) 24 h after receiving a high dose of morphine (20 mg/kg sc) and were placed on the conditioning floor. To determine the effect of each pretreatment drug around the establishment of the MWD-induced CPA URB597 (0.3 mg/kg intraperitoneally (ip)) PF-3845 (10 mg/kg ip) AM251 (1 or 2 2.5 mg/kg ip) AM4113 (1 or 2 2.5 mg/kg ip) and AM6527 (5 mg/kg oral) were administered prior to conditioning. Results AM251 (2.5 but not 1 mg/k) AM4113 and AM6527 but not URB597 or PF-3845 interfered with the establishment of the MWD-induced CPA. AM251 and AM4113 did not prevent reinstatement of the CPA. Conclusions Neutral antagonism of the CB1 receptor reduces the aversive affective properties of morphine withdrawal. tests) for two consecutive days. A week Rotigotine HCl following the last extinction trial the rats were tested for reinstatement of the CPA. On reinstatement day 1 they received a saline primary test. On day 2 they Rabbit polyclonal to PDCL. were injected sc with 20 mg/kg morphine in their home cage. On day 3 they received the naloxone-precipitated MWD primary test (1 mg/kg naloxone sc). On both day 1 and day 3 the rats were injected ip with VEH ((1 22 (1 22 (1 46 (4 46 test. Overall rats pretreated with VEH (show … Experiment 3: effect of AM251 and AM4113 on reinstatement of the CPA by a naloxone-precipitated MWD primary The naloxone-precipitated MWD-induced CPAwas reinstated by the primary following extinction; however neither AM251 nor AM4113 interfered with or potentiated the reinstatement of the CPA. Physique 3 presents the floor aversion around the test trials for the naloxone-precipitated MWD-induced CPA. The rats displayed a significant CPA as assessed by paired assessments on test days 1 (indicate a significant difference between the saline- and MWD-paired floors.*(1 45 (1 21 (1 21 test pooled across trials revealed that rats pretreated with VEH (test revealed a significant difference in motor activity between the pretreatment drugs on both the saline conditioning trial indicate a significant difference between the saline- and MWD-paired floors. … Discussion The present findings are the first to show that antagonism of the CB1 receptor is usually capable of interfering with the acquisition of the motivationally aversive state of acute morphine dependence as quantified by the place conditioning paradigm. Specifically rats having received AM251 (at 2.5 but not 1 mg/kg) AM4113 (at both 1 and 2.5 m/kg) or oral AM6527 (at 5 mg/kg) prior to conditioning did not show a one-trial naloxone-precipitated MWD-induced CPA. Only orally administered AM6527 also suppressed Rotigotine HCl locomotor activity during conditioning. These findings are in agreement with prior studies demonstrating the ability of antagonism of the endocannabinoid system to attenuate opioid self-administration (Caille and Parsons 2003; De Vries et al. 2003; Navarro et al. 2001; Solinas et al. 2003) and conditioned place preference (Chaperon et al. 1998; Mas-Nieto et al. 2001; Navarro et al. 2001; Singh et al. 2004). Interestingly however although antagonism of the endocannabinoid system with the CB1 antagonist SR141716 has been Rotigotine HCl shown to block reinstatement of opioid drug-seeking (De Vries et al. 2003; Fattore et al. 2003) the current findings suggest that this phenomenon may be Rotigotine HCl exclusive to the rewarding properties of opioids. Indeed following establishment and extinction of the CPA none of the antagonists tested interfered with (or potentiated) reinstatement of the aversion. The apparent dissociations between reinstatement of CPP and CPA and the establishment and reinstatement of the CPA found in the present study suggest that each of these processes may be engaging unique brain regions or a combination of unique brain regions. Even though manifestation of withdrawal is usually associated with changes in the cyclic adenosine monophosphate (cAMP) pathway (Nestler and Aghajanian 1997) it is unlikely that attenuation of the establishment of the CPA was mediated by an inhibition of intrinsic cellular activity and increased.