Basic brain mechanisms underlying drug addiction, craving, and relapse

National Institute On Drug Abuse

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Abstract

During the present reporting period, we continued our prior work mainly on three projects. One was to further study the involvement of cannabinoid system in drug self-administration, another one was to explore the neuronal mechanisms underlying the inhibitory effects of clonidine on oxycodone-motivated behaviors, the third was to further explore the roles of appetite hormonal system in drug reward and motivation. Our findings from these three projects are summarized in three separate paragraphs below. We previously reported as well as reported by others that either blocking CB1 receptors or activation of CB2 receptors in rodents significantly inhibits drug rewarding and motivational effects of most abuse drugs such as psychostimulants, opioids and nicotine. We assumed compounds such as LY2828360 which acts as both CB1 antagonist and CB2 agonist should be more effective than either selective CB1 antagonist or CB2 agonist. We therefore systematically explored the role of LY2828360 in oxycodone-motivated behaviors and found that LY2828360 significantly inhibited oxycodone self-administration under either FR-1 or PR schedule of reinforcement at a dose of 5 mg/kg, but not at other doses (2.5, 10 and 200. Ly2828360 also significantly inhibits oxycodone-induced reinstatement of drug-seeking at this specific dose only. The mechanisms underlying this specific dose effect remain to be elucidated. Our early studies demonstrated that clonidine significantly inhibited oxycodone self-administration under both varying unit doses (0.1 or 0.025 mg/kg/infusion) of oxycodone infusion and under different reinforcement schedules (FR and PR). Most importantly, we found that clonidine treatment potently accelerated the extinction of drug-seeking behaviors in oxycodone-trained rats. Coadministration of clonidine at behavioral relevant dose (50 g/kg) with oxycodone (1 mg/kg) significantly potentiates and prolongs the antinociceptive effects of oxycodone. Clonidine pretreatment at doses that significantly decrease oxycodone-motivated behaviors showed no effects on optogenetic brain stimulation reward,but inhibits such stimulation reward at a higher dose (100 g/kg (i.p ). Clonidine conditioning did not produce either CPP or CPA in either oxycodone-nave rats or in oxycodone self-administration trained rats that are conditioned immediately following the completion of self-administration (acute withdrawal phase) or following the subsequent extinction test sessions with repeated clonidine treatments (0-25 g/kg). Blockade of beta-adrenergic receptors also dose-dependently inhibited oxycodone self-administration. Our findings suggest clonidine as an effective agent at reducing opioid use and motivation for opioid, accelerating the extinction of drug-seeking behaviors and increasing the effectiveness in pain management with opioid. Decreased beta-adrenergic action is likely one of the mechanisms underlying such effects of clonidine. The lack of any conditioning effects of clonidine and the lack of the potentiating effects of clonidine on BSR indicates that clonidine may not have any intrinsic rewarding properties at least under the present treatment regimen. We have recently found in male rats that elevation of ghrelin by either cocaine or oxycodone plays a critical role in maintenance of drug self-administration and drug-seeking motivated by drug-conditioned stimuli and acquisition of either cocaine or oxycodone self-administration upregulates VTA ghrelin receptor mRNA levels. Ghrelin signaling is also significantly involved in BSR and in reinstatement of cocaine-seeking triggered by either cocaine or yohimbine in behaviorally extinguished animals with a history of cocaine self-administration. We extended this study by assessing whether such effects of ghrelin can be generalized to female rats, by exploring the potential intracellular signaling processes associated with such effects of ghrelin and the brain loci at which ghrelin exerted these behavior effects. We found that female rats acquired oxycodone self-administration significantly faster than their male littermates tested at 0.1 mg/kg/infusion unit dose. Genetic deletion of GHS-R (GHS-R knockout) tended to slow the acquisition of oxycodone self-administration in both male and female rats. In male rats, acquisition of oxycodone self-administration was associated with significantly higher locomotor activity induced by systemic injection of oxycodone (1 mg/kg. i.p.) in GHS-R knockout rats compare to wildtype littermates while no significant differences were found in female rats. Pretreatments with JMV 2959 significantly decreased oxycodone self-administration in both male and female rats, and significantly inhibited reinstatement of oxycodone seeking triggered by oxycodone (1 mg/kg, i.p.) in female wildtype rats after extinction of drug-taking behaviors. JMV2929 had no effect on oxycodone-motivated behaviors in either male or female GHS-R knockout rats. These findings reveal a critical role for GHS-R in controlling oxycodone-motivated behaviors in Wistar rats regardless of sex. Using western blot assay, we found that cocaine but not oxycodone self-administration in drug-trained rats significantly elevates GHS-R and phospho-CamK2 levels in the VTA. Acquisition of oxycodone but not cocaine self-administration significantly decreases VTA Phospho-CREB levels. Acquisition of oxycodone but not cocaine self-administration decreases phospho-ERK protein levels in the NAS while other measured protein levels are not significantly affected. In the hypothalamus, acquisition of cocaine but not oxycodone self-administration decreases -arrestin protein levels. Collectively, these findings revealed a regional specific response of ghrelin-related intracellular signaling proteins to oxycodone and cocaine and suggest that distinct ghrelin signaling process within the tested brain regions may have been comprised during acquisition of oxycodone and cocaine taking behaviors. With intracranial microinjection, we identified VTA as one of critical loci at which ghrelin drives oxycodone self-administration. Other potential brain loci and other neurotransmitter systems through which ghrelin modulates drug addictive behaviors are currently under investigation.