Targeting Adrenergic Receptors in the Treatment of Cocaine Withdrawal-Related Anxiety
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.
0758: Developmental biology