The Role of Guanfacine as a Therapeutic Agent to Address Stress-Related Pathophysiology in Cocaine-Dependent Individuals

Abstract

The pathophysiology of cocaine addiction is linked to changes within neural systems and brain regions that are critical mediators of stress system sensitivity as well as behavioral processes associated with the regulation of adaptive goal-directed behavior. This is characterized by the up-regulation of core adrenergic and corticotrophin releasing factor (CRF) mechanisms which sub-serve negative affect and anxiety and impinge upon intracellular pathways in the prefrontal cortex underlying cognitive regulation of stress and negative emotional state. Not only are these mechanisms essential to the severity of cocaine withdrawal symptoms, and hence the trajectory of clinical outcome, but they may also be particularly pertinent to the demography of cocaine dependence. The ability of guanfacine to target overlapping stress, reward and anxiety pathophysiology suggests that it may be a useful agent for attenuating the stress and cue-induced craving state in women especially, but also in men. This is supported by recent research findings from our own laboratory. Additionally, the ability of guanfacine to improve regulatory mechanisms that are key to exerting cognitive and emotional control over drug seeking behavior also suggest that guanfacine may be an effective medication for reducing craving and relapse vulnerability in many drugs of abuse. As cocaine dependent individuals are typically polydrug abusers, and women may be at a greater disadvantage for compulsive drug use than men, it is plausible that medications which target catecholaminergic fronto-striatal inhibitory circuits and simultaneously reduce stress system arousal may provide added benefits for attenuating cocaine dependence.

α2A‐Adrenergic receptor polymorphisms and mRNA expression levels are associated with delay discounting in cocaine users

“…In line with our findings, a recent review highlights the potential of guanfacine as a therapeutic agent to attenuate stress‐induced and cue‐induced craving in cocaine‐dependent individuals (Fox & Sinha ). The authors further propose that guanfacine may be an effective medication to reduce craving and relapse vulnerability in other forms of addiction as well, because of its ability to improve cognitive and emotional control over drug‐seeking behavior (Fox & Sinha ).…”

The bed nucleus of the stria terminalis in drug-associated behavior and affect: A circuit-based perspective

“…Clinical data has suggested that the non-specific beta-adrenergic receptor antagonist propranolol and the alpha 2a agonist guanfacine may decrease cocaine-withdrawal induced anxiety, and lower cocaine-craving (Fox and Sinha, 2014; Fox et al, 2012, 2008; Kampman et al, 2011, 2001). Similar data was obtained in a preclinical setting in which antagonism of the beta receptors within the BNST blocks anxiety like behavior following an immobilization stressor (Cecchi et al, 2002).…”

Noradrenergic signaling in the VTA modulates cocaine craving

“…Understanding the neurobiological mechanisms that underlie cue‐induced craving is critical to the development of effective treatment. It has been demonstrated that α 2 ‐AR agonists decrease cue‐induced drug craving in humans (Jobes et al ; Sinha et al ; Fox & Sinha ), pointing to a potential role of noradrenergic signaling in relapse prevention. In addition, noradrenergic signaling has been implicated in cocaine‐evoked conditioned place preference (Jasmin et al ), escalated cocaine intake by self‐administration (Zhang & Kosten ; Wee et al ), cocaine subjective effects (Newton et al ) and reinstatement of cocaine seeking (Zhang & Kosten ; Smith & Aston‐Jones ; Schroeder et al ) in rats.…”