Abstract/Details

Targeting Adrenergic Receptors in the Treatment of Cocaine Withdrawal-Related Anxiety


2008 2008

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Abstract (summary)

Anxiety has been indicated as a key symptom of the cocaine withdrawal syndrome and is considered to be one of the most important factors in cultivating the repetitive cycle of chronic cocaine abuse. Cocaine use and withdrawal from cocaine causes alterations in norepinephrine transmission and an associated vulnerability to anxiety. As alterations in noradrenergic transmission in limbic areas underlie withdrawal for many drugs of abuse, the initial goal of the present study sought to determine the effect of cocaine withdrawal on adrenergic receptor expression in the amygdala.

Male Sprague Dawley rats were administered intraperitoneal (i.p.) injections of cocaine (20 mg/kg) once daily for 14 days and underwent either a no, short-term (2 days) or intermediate-term (12 days) withdrawal period. Amygdala brain regions were micro-dissected from all of these animals and processed for Western blot analysis. Results from these experiments showed that â1–adrenergic receptor expression is significantly increased in amygdala extracts of animals following short-term withdrawal compared to controls. This finding motivated further experiments toward determining whether treatment with betaxolol, a selective β1–adrenergic receptor antagonist, could ameliorate cocaine withdrawal-induced anxiety. Therefore, in additional studies, at 24 and then 44 hours following chronic cocaine administration, animals were administered betaxolol (5 mg/kg, i.p.) and anxiety-like behavior in the animals was evaluated on the elevated plus maze test approximately 2 hours following the last betaxolol injection. Animals treated with betaxolol while undergoing withdrawal from chronic cocaine displayed a significant attenuation of anxiety-like behavior characterized by increased open arm exploration compared to control animals.

Corticotropin releasing factor (CRF), a peptide neurotransmitter, has also been implicated in mediating the ‘anxiety-like’ behavior that is observed during the initial phase of cocaine abstinence and an increase in amygdalar CRF gene expression has been found to specifically occur during short-term cocaine withdrawal. Using quantitative reverse transcriptase-polymerase chain reaction, our studies confirmed these findings. Additionally, our anatomical data indicates direct inputs of noradrenergic afferents to CRF neurons in the amygdala and the presence of β1-adrenergic receptors on these neurons.

Modulation of adrenergic receptors eventually culminates in alterations in downstream signal transduction elements and using Western blot analysis, we also found alterations in a β1-adrenergic receptor-mediated cell signaling pathway during early cocaine withdrawal. Betaxolol treatment during early withdrawal blocked increases in CRF gene expression and reversed alterations in the signaling elements to control levels. Together, data from these studies suggest that the effect of betaxolol on ameliorating cocaine withdrawal-induced anxiety may be related to its effect on blocking amygdalar β 1-adrenergic receptors that are upregulated during early phases of drug withdrawal and hence, modulating downstream cell signaling elements and ultimately CRF gene expression.

Indexing (details)


Subject
Cellular biology;
Developmental biology
Classification
0379: Cellular biology
0758: Developmental biology
Identifier / keyword
Health and environmental sciences; Biological sciences; Adrenergic receptors; Anxiety; Cocaine withdrawal; Drug abuse treatment
Title
Targeting Adrenergic Receptors in the Treatment of Cocaine Withdrawal-Related Anxiety
Author
Rudoy, Carla Ann
Number of pages
220
Publication year
2008
Degree date
2008
School code
0272
Source
DAI-B 72/03, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9781124430904
Advisor
Bockstaele, Elisabeth J. Van
Committee member
Menko, Sue; Schneider, Jay; Unterwald, Ellen
University/institution
Thomas Jefferson University
Department
Cell and Developmental Biology
University location
United States -- Pennsylvania
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3438779
ProQuest document ID
848967269
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/848967269
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