Dataset Information

Precipitated Δ9-THC withdrawal reduces motivation for sucrose reinforcement in mice.

ABSTRACT: Withdrawal from Δ⁹-tetrahyrocannibidol (THC) is associated with a host of dysphoric symptoms that increase probability of relapse. To date, many animal models of THC withdrawal rely on withdrawal-induced somatic withdrawal signs leaving withdrawal-suppressed behavior relatively unexplored. As compared with withdrawal-induced behaviors, ongoing behavior that is suppressed by withdrawal is a useful behavioral endpoint because it 1) more effectively models the subjective aspects of withdrawal and 2) identifies pharmacotherapies that restore behavior to baseline levels, rather than eliminate behavior induced by withdrawal. The current study assessed effects of spontaneous and rimonabant-precipitated THC withdrawal in mice responding on a progressive-ratio (PR) schedule of sucrose water reinforcement. Once behavior stabilized, male and female mice were administered THC (10 mg/kg, s.c.) or vehicle for five or six days. THC was either discontinued and behavior monitored for three days during abstinence, or the CB₁ antagonist rimonabant (2 mg/kg, i.p.) was used to precipitate withdrawal. Whereas spontaneous THC withdrawal had no effect on PR performance, THC-treated mice were differentially sensitive to rimonabant administration via large decreases in break point, overall response rate, and run rate relative to vehicle-treated mice. Importantly, pretreatment with the CB₁ positive allosteric modulator ZCZ011 (10 mg/kg, i.p.) did not prevent precipitated-withdrawal-induced behavioral impairment. These extend findings of earlier studies suggesting operant baselines are useful tools to study subjective effects of cannabinoid withdrawal. Additionally, operant baselines allow withdrawal pharmacotherapies to be tested in a restoration-of-function context, which may be more sensitive, selective, and clinically relevant.

SUBMITTER: Eckard ML

PROVIDER: S-EPMC7415667 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Cannabis is the most frequently used federally illicit substance in the United States. However, there are currently no FDA-approved pharmacotherapies to mitigate the withdrawal symptoms associated with cessation in heavy users. A promising, readily available, non-cannabinoid therapy are the gabapentinoids. Although currently approved for epilepsy and neuropathic pain, gabapentinoids are increasingly used for their "off-label" efficacy in treating various psychiatric conditions and substance abuse. Gabapentin (GBP) synergizes with cannabinoid agonism in neuropathic pain models, substitutes for Δ9-tetrahydrocannabinol (THC) in drug discrimination procedures, and reduced withdrawal symptoms in an outpatient clinical trial. However, there are limited data on the biological plausibility of the therapeutic action of gabapentinoids in cannabinoid withdrawal in preclinical models. The purpose of the current study was to determine the efficacy of GBP on attenuating THC withdrawal in mice, using an array of tests targeting withdrawal-induced and withdrawal-suppressed behaviors. Separate cohorts of male and female mice were administered THC (10 mg/kg, s.c.) or vehicle for 5.5 days, and withdrawal was precipitated by the CB1 antagonist rimonabant (2 or 3 mg/kg, i.p.) on the sixth day. GBP (≥10 mg/kg) reduced somatic signs of withdrawal (i.e., paw tremors and head twitches), but had no effect in locomotor activity or conditioned place preference. GBP (50 mg/kg) also restored withdrawal-suppressed responding on a progressive ratio reinforcement schedule. However, GBP (50 mg/kg) had no effect in withdrawal-suppressed marble burying or tail suspension struggling and did not normalize the stress response induced by THC withdrawal, as indicated by plasma corticosterone. These data suggest gabapentin may be effective at treating cannabinoid withdrawal symptoms including somatic and affective symptoms but may act independently of endocrine stress activation.

Project description:Δ(9)-Tetrahydrocannbinol (THC), the primary active constituent of Cannabis sativa, has long been known to reduce opioid withdrawal symptoms. Although THC produces most of its pharmacological actions through the activation of CB(1) and CB(2) cannabinoid receptors, the role these receptors play in reducing the variety of opioid withdrawal symptoms remains unknown. The endogenous cannabinoids, N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonylglycerol (2-AG), activate both cannabinoid receptors but are rapidly metabolized by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. The objective of this study was to test whether increasing AEA or 2-AG, via inhibition of their respective hydrolytic enzymes, reduces naloxone-precipitated morphine withdrawal symptoms in in vivo and in vitro models of opioid dependence. Morphine-dependent mice challenged with naloxone reliably displayed a profound withdrawal syndrome, consisting of jumping, paw tremors, diarrhea, and weight loss. THC and the MAGL inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) dose dependently reduced the intensity of most measures through the activation of CB(1) receptors. JZL184 also attenuated spontaneous withdrawal signs in morphine-dependent mice. The FAAH inhibitor N-(pyridin-3-yl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)benzyl)-piperdine-1-carboxamide (PF-3845) reduced the intensity of naloxone-precipitated jumps and paw flutters through the activation of CB(1) receptors but did not ameliorate incidence of diarrhea or weight loss. In the final series of experiments, we investigated whether JZL184 or PF-3845 would attenuate naloxone-precipitated contractions in morphine-dependent ilea. Both enzyme inhibitors attenuated the intensity of naloxone-induced contractions, although this model does not account mechanistically for the autonomic withdrawal responses (i.e., diarrhea) observed in vivo. These results indicate that endocannabinoid catabolic enzymes are promising targets to treat opioid dependence.

Dataset Information

Precipitated Δ9-THC withdrawal reduces motivation for sucrose reinforcement in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets