Effects of buprenorphine on behavioral tests for antidepressant and anxiolytic drugs in mice

Abstract

Rationale Buprenorphine (BPN) has been shown to rapidly improve mood in treatment-resistant depressed patients in small clinical studies. However, BPN’s effects in preclinical tests for mood and antidepressant efficacy are largely unexplored. Objective The current study examined the effects of BPN in the forced swim test (FST) and novelty-induced hypophagia (NIH) test as measures of antidepressant and anxiolytic-like effects in C57BL/6J mice. Microdialysis was used to measure whether BPN engaged KORs in the nucleus accumbens shell (NAcSh) at a behaviorally active dose (0.25 mg/kg). Methods BPN was tested in the FST at both 30 min and 24 h post administration. Also measured in the FST at 24 h post administration were the KOR antagonist norbinaltorphimine (nor-BNI), the MOR agonist morphine and the reference antidepressant desipramine. The anxiolytic effects of BPN were examined in the NIH test 24 h after treatment. The effects of acute injection of BPN and the KOR agonist U50,488 were measured on extracellular DA levels in the NAcSh. Results BPN produced significant reductions in FST immobility without changing locomotor activity and reduced approach latencies in the novel environment of the NIH test when tested 24 h after treatment. Repeated daily BPN injections for 6 d did not produce tolerance to these behavioral effects. nor-BNI produced a similar antidepressant-like response in the FST 24 h postinjection but morphine and desipramine were ineffective. BPN (0.25 mg/kg) did not alter DA levels when given alone but prevented the KOR agonist U50,488 from reducing DA levels. Conclusions Acute and subchronic treatment with BPN produced antidepressant and anxiolytic-like responses in mice at doses that engage KORs. These studies support the clinical evidence that BPN may be a novel rapid-acting antidepressant medication and provides rodent models for investigating associated neurochemical mechanisms.

Antidepressant-like Effects of Buprenorphine are Mediated by Kappa Opioid Receptors

“…Our laboratory has shown previously that low doses of BPN produced antidepressant and anxiolytic responses in mice and rats when tested 24 h post administration (Browne et al, 2015;Falcon et al, 2015). The present study further characterizes antidepressant responses to BPN in C57BL/6J mice, a strain that demonstrates a refractory response to SSRIs in the forced swim test (FST) (Balu et al, 2009;Lucki et al, 2001).…”

“…BPN hydrochloride (Sigma, St Louis, MO and NIDA), nor-BNI (Tocris Bioscience, Ellisville, MO) and desipramine hydrochloride (DMI; Sigma) were administered at doses previously found to have antidepressant activity in the FST (Falcon et al, 2015;Lucki et al, 2001;McLaughlin et al, 2003). JTC-801 (Tocris) was administered at 1 mg/kg based on pilot data (unpublished).…”

Targeting opioid receptor signaling in depression: do we need selective κ opioid receptor antagonists?

“…As discussed earlier, buprenorphine on its own has demonstrated clinical efficacy in treatment-resistant depression and has also been shown to reduce depressive and anxiety-like behaviours in rats and mice [58,68,69]. There remains concerns about the non-therapeutic misuse of buprenorphine, because of its partial MOP receptor agonist activity, which appears to be rising among drug users [70].…”

“…There remains concerns about the non-therapeutic misuse of buprenorphine, because of its partial MOP receptor agonist activity, which appears to be rising among drug users [70]. Initially it was believed that buprenorphine's efficacy in treating depressed patients was derived from its partial MOP agonist actions but this has been challenged in recent years with evidence suggesting these behavioural effects of buprenorphine can be attributed to its KOP receptor antagonism [58,69]. Intriguingly, the most recent data indicate that MOP receptors do play a role in buprenorphine's behavioural response where there is a motivational component [63,71] but perhaps not in the way initially envisaged.…”

Fast Effect of Buprenorphine on Opioid-dependent Patients with Suicidal Ideation: A Novel Approach

“…Likewise, buprenorphine is an agonist of µ-receptor; therefore, it lowers the level of depression, suicide, pain, dysphoria, anxiety, and opioid withdrawal symptoms. In addition, buprenorphine is a strong κ-receptor antagonist; hence, it lessens the amount of suicidal tendencies, anxiety, and hostility (15)(16)(17)(18)(19).…”