Evidence for β(1)-adrenergic receptor involvement in amygdalar corticotropin-releasing factor gene expression: implications for cocaine withdrawal

We previously showed that betaxolol, a selective β(1)-adrenergic receptor antagonist, administered during early phases of cocaine abstinence, ameliorated withdrawal-induced anxiety and blocked increases in amygdalar β(1)-adrenergic receptor expression in rats. Here, we report the efficacy of betaxolol in reducing increases in gene expression of amygdalar corticotropin-releasing factor (CRF), a peptide known to be involved in mediating ‘anxiety-like’ behaviors during initial phases of cocaine abstinence. We also demonstrate attenuation of an amygdalar β(1)-adrenergic receptor-mediated cell signaling pathway following this treatment. Male rats were administered betaxolol at 24 and 44 hours following chronic cocaine administration. Animals were euthanized at the 48 hour time-point and the amygdala was micro-dissected and processed for quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and/or Western blot analysis. Results showed that betaxolol treatment during early cocaine withdrawal attenuated increases in amygdalar CRF gene expression and cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) regulatory and catalytic subunit (nuclear fraction) protein expression. Our data also reveal that β(1)-adrenergic receptors are on amygdalar neurons which are immunoreactive for CRF. The present findings suggest that the efficacy of betaxolol treatment on cocaine withdrawal-induced anxiety may be related, in part, to its effect on amygdalar β(1)-adrenergic receptor, modulation of its downstream cell signaling elements and CRF gene expression.