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/6 J mice. Microdialysis was used to measure whether BPN engaged kappa-opioid receptor (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 dopamine (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 days did not produce tolerance to these behavioral effects. nor-BNI produced a similar antidepressant-like response in the FST 24 h post-injection 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.

Figure 1. Effects of BPN in the FST and locomotor activity when tested 30 min postadministration

A) Effects of BPN and DMI on immobility, n = 28 for saline group; n = 9–10 per BPN and DMI group. B) Effects of BPN and DMI on locomotor activity, n = 29 for saline group; n = 9–10 per BPN and DMI group. Data are depicted as mean ± SEM (* p < 0.05, ** p < 0.01, *** p < 0.001).

Figure 2. Effects of BPN in the FST and locomotor activity when tested 24 h postadministration

A) Effects of BPN and DMI on immobility in the FST, n = 29 for saline group and n = 9–10 per BPN and DMI groups. B) Effects of BPN and DMI on locomotor activity, n = 29 for saline group; n = 9–10 per BPN and DMI group. Data are depicted as mean ± SEM (* p < 0.05).

Figure 3

Effects of BPN and saline on the latency to approach and ingest food in the novel arena in the NIH test 24 h post-administration, n = 9–10 per group. Data are depicted as mean ± SEM (*** p < 0.001).

Figure 4. Effects of treatment with BPN for 6 days

A) BPN reduced immobility in the FST, n = 9–10 per group. B) BPN reduced the latency to approach and ingest food in the novel arena, n = 9–10 per group. C) BPN did not change locomotor activity, n = 10 per group. Data are depicted as mean ± SEM (*** p < 0.001).

Figure 5. Effects of opioid compounds in the FST and locomotor activity tested 24 h post-administration

A) Treatment with nor-BNI (n = 9) and morphine (n = 10) on immobility in the FST compared with saline control (n = 19). B) Treatment with nor-BNI (n = 10) or morphine (n = 10) did not change locomotor activity compared with saline control (n = 30). Data are depicted as mean ± SEM (*** p < 0.001).

Figure 6

DA levels in the NAchSh in response to systemic administration of U50,488 (n = 5), BPN (n = 6) or in combination (n = 8). Data are expressed as percent change from individual baseline and are presented as mean ± SEM. Significant differences between groups are indicated by the following symbols: a (U50,488 vs. BPN + U50,488, p < 0.001), b (BPN vs. U50,488, p < 0.05), and c (BPN vs BPN + U50,488, p < 0.05).