Antidepressant-like effects of buprenorphine in rats are strain dependent

Abstract

The prevalence of major depressive disorder and the limited efficacy of conventional drug treatments provide significant impetus to develop novel and more rapidly acting antidepressants for individuals with treatment resistant forms of depression. The primary goal of these studies was to ascertain whether buprenorphine (BPN), a medically available drug with mixed effects at opioid receptors, was effective in behavioral tests using the Wistar Kyoto (WKY) rat strain, a rodent model of exaggerated depressive and anxiety behaviors that demonstrates resistance to certain antidepressants. As WKY rats are maintained by different sources, we assessed the behavioral effects of BPN using the modified rat forced swim test (FST) and the emergence test in WKY rat colonies obtained from different vendors. BPN dose-dependently reduced immobility and increased swimming behavior in the FST and reduced emergence latencies in two WKY lines (Charles River (WKY/NCrl) and Harlan laboratories (WKY/NHsd)) that also showed high baseline immobility in the FST. WKY rats from Taconic (WKY/NTac) did not show high baseline immobility in the FST or anxiety as had been previously reported, suggesting a drift in the phenotype of rats from this supplier. Furthermore, BPN did not reduce immobility in the FST or reduce latencies in the emergence test in WKY rats from Taconic. BPN also failed to produce antidepressant-like effects in Wistar and Sprague-Dawley rats. These results indicate a striking strain-selectivity for the effects of BPN, producing antidepressant and anxiolytic-like responses in WKY/NCrl and WKY/NHsd lines but not in the normosensitive control Wistar and Sprague-Dawley strains.

Keywords: Buprenorphine; Emergence test; FST; Treatment-resistant depression; Wistar Kyoto rat.

Fig 1

Performance in the emergence test compared between WKY substrains, WKY/NCrl, WKY/NHsd and WKY/NTac. WKY/NTac rats exhibited a low level of anxiety in this task; their latency to emerge was significantly lower than WKY/NCrl and WKY/NHsd rats. The symbol ### indicates p<0.001, where a significant difference exists between the WKY/NCrl or WKY/NHsd and the WKY/NTac vehicle groups. BPN significantly decreased the time to emerge 24 h post treatment in WKY/NCrl and WKY/NHsd rats. The symbol ** indicates p<0.01, where a significant effect of treatment was observed in WKY/NCrl rats. The symbol *** indicates p<0.001, where a significant effect of treatment was observed in WKY/NHsd rats.

Fig 2

Comparison of behaviors in the FST between WKY substrains, WKY/NCrl, WKY/NHsd and WKY/NTac. A significant difference in baseline behavior was observed between the WKY/NTac and the other WKY strains. The symbol ### indicates p<0.001, where a significant difference exists between the WKY/NCrl or WKY/NHsd and the WKY/NTac vehicle groups. BPN significantly decreased immobility and increased swimming behavior 24 h post treatment. The symbol * indicates p<0.05, where a significant effect of treatment was observed in WKY/NCrl rats. The symbol *** indicates p<0.001, where a significant effect of treatment was observed in WKY/NHsd rats.

Fig 3

Comparison of FST performance from videotapes for a cohort of WKY/NTac rats tested in 2007, 2010 and 2013 under identical conditions. The WKY/NTac rats tested in 2013 exhibited a significant decrease in immobility and increased climbing behavior compared to WKY/NTac rats tested in 2007 and 2010 [32]. The symbol *** indicates p<0.001, and the symbol ** indicates p<0.01, and the symbol * indicates p<0.05, where a significant difference is observed between either the 2007 and 2010 cohort and WKY/NTac rats tested in 2013normo.

Fig 4

Effects of BPN in the emergence test in a) WKY/NCrl, b) Crl: WI and c) Crl: SD rats. BPN significantly decreased the latency to emerge in WKY rats, but not in Crl:SD or Crl:WI rats 24 h post treatment. The symbol ** indicates p<0.01, where 2.25 mg/kg BPN-treated WKY rats exhibited a decreased latency to emerge compared to the vehicle animals.

Fig 5

Performance in the FST and the effects of BPN treatment compared between WKY/NCrl, Crl:WI and Crl:SD rats. The symbol * indicates p<0.05, where a significant effect of treatment exists between BPN-treated and vehicle-treated WKY rats. The symbol *** indicates p<0.05, where a significant effect of treatment exists between BPN-treated and vehicle-treated WKY rats.

Fig 6

Locomotor activity of WKY/NCrl, Crl:WI and Crl:SD rats. Crl:WI rats exhibited higher locomotor activity over the 15-minute test compared to WKY rats. No significant difference was observed between Wistar and SD rats. BPN had no effect on locomotor activity 24 h post treatment in any of the three strains investigated.