Effect of Chronic Delivery of the Toll-like Receptor 4 Antagonist (+)-Naltrexone on Incubation of Heroin Craving

Abstract

Background Recent evidence implicates toll-like receptor 4 (TLR4) in opioid analgesia, tolerance, conditioned place preference, and self-administration. Here we determined the effect of the TLR4 antagonist (+)-naltrexone (a μ-opioid receptor inactive isomer) on the time-dependent increases in cue-induced heroin seeking after withdrawal (incubation of heroin craving). Methods In an initial experiment, we trained rats for 9 h/day to self-administer heroin (0.1 mg/kg/infusion) for 9 days; lever presses were paired with a 5-sec tone-light cue. We then assessed cue-induced heroin seeking in 30-min extinction sessions on withdrawal day 1; immediately after testing, we surgically implanted rats with Alzet minipumps delivering (+)-naltrexone (0, 7.5, 15, 30 mg/kg/day, s.c.) for 14 days. We then tested the rats for incubated cue-induced heroin seeking in 3-h extinction tests on withdrawal day 13. Results We found that chronic delivery of (+)-naltrexone via minipumps during the withdrawal phase decreased incubated cue-induced heroin seeking. In follow-up experiments, we found that acute injections of (+)-naltrexone immediately before withdrawal day 13 extinction test had no effect on incubated cue-induced heroin seeking. Furthermore, chronic delivery of (+)-naltrexone (15 or 30 mg/kg/day) or acute systemic injections (15 or 30 mg/kg) had no effect on ongoing extended access heroin self-administration. Finally, in rats trained to self-administer methamphetamine (0.1 mg/kg/infusion, 9 h/d, 9 days), chronic delivery of (+)-naltrexone (30 mg/kg/day) during the withdrawal phase had no effect on incubated cue-induced methamphetamine seeking. Conclusions The present results suggest a critical role of TLR4 in the development of incubation of heroin, but not methamphetamine, craving.

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

“…Not all drugs may participate in TLR signaling; for instance, chronic antagonism of TLR4 with (+)-naltrexone during withdrawal does not modify cueinduced drug seeking for methamphetamine (Theberge et al, 2013). These results suggest that methamphetamine may act autonomously from TLR4, or alternatively, these results may be specific to the conditions of the behavioral paradigm (ie, incubation of drug-seeking).…”

“…In rats, self-administration of remifentanil, an ultra-short-acting synthetic opioid, is dose-dependently reduced by (+)-naloxone treatment . In a similar fashion, chronic antagonism of TLR4 with (+)-naltrexone delivered via osmotic minipumps during withdrawal reduces cue-induced heroine self-administration (Theberge et al, 2013). Importantly, a single dose of (+)-naltrexone administered before extinction testing was ineffective at reducing heroin intake, suggesting that TLR4 antagonism may not acutely diminish the reinforcing properties of heroin after repeated exposure but rather influence synaptic remodeling during the withdrawal period.…”

Incubation of Methamphetamine and Palatable Food Craving after Punishment-Induced Abstinence

“…We anesthetized rats with ketamine and xylazine (50 and 5 mg/kg, i.p., respectively) and inserted silastic catheters into the jugular vein, as described previously Theberge et al, 2013). We attached the catheters to a modified 22-gauge cannula that was mounted to the rats' skulls with dental cement.…”

“…The training procedure for methamphetamine self-administration was similar to that used in our studies on incubation of cocaine, methamphetamine, and heroin craving (Koya et al, 2009;Shepard et al, 2004;Theberge et al, 2013). On the first day of training, we brought the rats to the self-administration room where we chronically housed them in the chambers.…”

“…We trained rats to self-administer dl-methamphetamine HCl (NIDA) during three 3-h sessions/day (the sessions were separated by 30 min) over 14 days under a fixed-ratio-1 with 20-s timeout reinforcement schedule; lever presses were accompanied by a 5-s compound tone-light cue. These drug access and reinforcement schedule conditions are based on our previous incubation studies with heroin and methamphetamine Theberge et al, 2013). We trained the rats in seven cycles of 2 days of methamphetamine self-administration and one off day in order to prevent loss of body weight during the training phase (under our training conditions of 6 or 9 h daily sessions, rats lose weight after each training day and regain the lost weight during the off days (Shepard et al, 2004;Theberge et al, 2013)).…”