Abstract
We previously showed that betaxolol, a selective β1-adrenergic receptor antagonist, administered during early phases of cocaine abstinence, ameliorated withdrawal-induced anxiety and blocked increases in amygdalar β1-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 β1-adrenergic receptor-mediated cell-signaling pathway following this treatment. Male rats were administered betaxolol at 24 and 44 h following chronic cocaine administration. Animals were euthanized at the 48-h time point and the amygdala was microdissected and processed for quantitative reverse transcriptase-polymerase chain reaction 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-dependent protein kinase regulatory and catalytic subunit (nuclear fraction) protein expression. Our data also reveal that β1-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 β1-adrenergic receptor, modulation of its downstream cell-signaling elements and CRF gene expression.
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Abbreviations
- BLA:
-
basolateral nucleus of the amygdala
- BSA:
-
bovine serum albumin
- cAMP:
-
cyclic adenosine monophosphate
- CNA:
-
central nucleus of the amygdala
- CREB:
-
cAMP response element-binding protein
- CRF:
-
corticotropin-releasing factor
- GAPDH:
-
glyceraldehyde-3-phosphate-dehydrogenase
- PB:
-
phosphate buffer
- PBS:
-
phosphate-buffered saline
- pCREB:
-
phosphorylated CREB
- PKA:
-
cyclic AMP-dependent protein kinase
- qRT-PCR:
-
quantitative reverse transcriptase-polymerase chain reaction
- TS:
-
tris-saline buffer
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Acknowledgements
This work was supported by a predoctoral fellowship, NIH, National Institute on Drug Abuse (NIDA), Ruth L Kirschstein National Research Service Award (F31DA019311) to CR and DA15395 and DA009082 to EVB We thank Kristen Smith and Sarah Kidd for technical assistance.
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DISCLOSURE/CONFLICT OF INTEREST
The authors would like to state that no prior, current, or pending conflict of interest exists for any of the authors (Carla A Rudoy, Arith-Ruth S Reyes, and Elisabeth J Van Bockstaele) pertaining to the research contained in the present paper submission. Furthermore, the authors declare that except for income received from their primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.
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Rudoy, C., Reyes, AR. & Van Bockstaele, E. Evidence for β1-Adrenergic Receptor Involvement in Amygdalar Corticotropin-Releasing Factor Gene Expression: Implications for Cocaine Withdrawal. Neuropsychopharmacol 34, 1135–1148 (2009). https://doi.org/10.1038/npp.2008.102
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DOI: https://doi.org/10.1038/npp.2008.102
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