RESUMEN
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.
Asunto(s)
Agonistas de Receptores de Cannabinoides/administración & dosificación , Dronabinol/administración & dosificación , Motivación , Refuerzo en Psicología , Síndrome de Abstinencia a Sustancias/psicología , Sacarosa/farmacología , Animales , Conducta Animal/efectos de los fármacos , Antagonistas de Receptores de Cannabinoides/administración & dosificación , Femenino , Indoles/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/antagonistas & inhibidores , Rimonabant/administración & dosificación , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Tiofenos/administración & dosificaciónRESUMEN
Recently, multiple compounds have been synthesized that target the allosteric binding site(s) of CB1. These CB1 positive allosteric modulators may capture the benefits of cannabinoid receptor activation without unwanted psychoactive effects, such as sedation. For example, ZCZ011 blocks neuropathic pain, absent the catalepsy, sedation, and hypothermia caused by CB1 orthosteric modulators, including Δ9-tetrahydrocannabinol (THC). The primary goal of the present study was to evaluate the potential of ZCZ011 to attenuate somatic signs of cannabinoid withdrawal in mice. Mice were repeatedly administered THC (10â¯mg/kg, s.c.) or vehicle, and withdrawal was either precipitated using the CB1 antagonist rimonabant (3â¯mg/kg, i.p.) or elicited spontaneously via THC abstinence. ZCZ011 (≥10â¯mg/kg, i.p.) significantly attenuated somatic signs of withdrawal, including head twitches and paw tremors, but had no effect on locomotor activity or conditioned place preference. We next tested the antiulcerogenic properties of CB1 positive allosteric modulation. Mice were fasted for 22â¯h, administered ZCZ011, and gastric hemorrhages were induced with the nonsteroidal anti-inflammatory drug diclofenac sodium (100â¯mg/kg, p.o.). ZCZ011 alone had no effect on gastric ulceration, but ZCZ011 (≥10â¯mg/kg) blocked ulcer formation when combined with a subthreshold MAGL inhibitor (JZL184; 1â¯mg/kg, i.p.). Thus, CB1 positive allosteric modulation is a novel approach to treat cannabinoid dependence and gastric inflammation.