Role of α1-GABA_A receptors in the serotonergic dorsal raphe nucleus in models of opioid reward, anxiety, and depression

Background: The serotonin (5-hydroxytryptamine (5-HT))-mediated system plays an important role in stress-related psychiatric disorders and substance abuse. Our previous studies showed that stress and drug exposure can modulate the dorsal raphe nucleus (DRN)-5-HT system via γ-aminobutyric acid (GABA)_A receptors. Moreover, GABA_A receptor-mediated inhibition of serotonergic DRN neurons is required for stress-induced reinstatement of opioid seeking.

Aim/methods: To further test the role of GABA_A receptors in the 5-HT system in stress and opioid-sensitive behaviors, our current study generated mice with conditional genetic deletions of the GABA_A α1 subunit to manipulate GABA_A receptors in either the DRN or the entire population of 5-HT neurons. The GABA_A α1 subunit is a constituent of the most abundant GABA_A subtype in the brain and the most highly expressed subunit in 5-HT DRN neurons.

Results: Our results showed that mice with DRN-specific knockout of α1-GABA_A receptors exhibited a normal phenotype in tests of anxiety- and depression-like behaviors as well as swim stress-induced reinstatement of morphine-conditioned place preference. By contrast, mice with 5-HT neuron-specific knockout of α1-GABA_A receptors exhibited an anxiolytic phenotype at baseline and increased sensitivity to post-morphine withdrawal-induced anxiety.

Conclusions: Our data suggest that GABA_A receptors on 5-HT neurons contribute to anxiety-like behaviors and sensitivity of those behaviors to opioid withdrawal.