Guanfacine effects on stress, drug craving and prefrontal activation in cocaine dependent individuals: preliminary findings

Abstract

Cocaine dependence is associated with increased stress and drug cue-induced craving and physiological arousal but decreased prefrontal activity to emotional and cognitive challenge. As these changes are associated with relapse risk, we investigated the effects of α2 receptor agonist guanfacine on these processes. Twenty-nine early abstinent treatment-seeking cocaine dependent individuals were randomly assigned to either daily placebo or guanfacine (up to 3 mg) for four weeks. In a laboratory experiment, all patients were exposed to three 10-min guided imagery conditions (stress/stress, drug cue/drug cue, stress/drug cue), one per day, consecutively in a random, counterbalanced order. Subjective craving, anxiety and arousal as well as cardiovascular output were assessed repeatedly. Brain response to stress, drug cue and relaxing imagery was also assessed during a functional magnetic resonance (fMRI) imaging session. In the current study, guanfacine was found to be safe and well-tolerated. Lower basal heart rate and blood pressure was observed in the guanfacine versus placebo group. Guanfacine lowered stress and cue-induced nicotine craving and cue-induced cocaine craving, anxiety and arousal. The guanfacine group also showed increased medial and lateral prefrontal activity following stress and drug cue exposure compared with placebo. Data suggest further exploration of guanfacine is warranted in terms of its potential for reducing stress-induced and cue-induced drug craving and arousal.

Sex Differences in Guanfacine Effects on Drug Craving and Stress Arousal in Cocaine-Dependent Individuals

“…Consistent with our initial laboratory project assessing the effects of guanfacine on stress-and cue-induced cocaine craving (Fox et al, 2012), the current dosing schedule was shown to be safe and well tolerated in both males and females. Side effects were reported in 46.7% of guanfacine males, 66.7% of guanfacine females, 85.7% of placebo females, and 33.3% of placebo males.…”

“…Similarly, in humans, lofexidine has been shown to decrease stress-and drug cue-related opiate craving in opiate dependent individuals also treated with naltrexone (Sinha et al, 2007b). Moreover, in a recent preliminary study, we showed that guanfacine decreased cue-related cocaine craving, anxiety, and arousal in individuals with cocaine dependence (Fox et al, 2012).…”

β-Adrenergic Receptor Mediation of Stress-Induced Reinstatement of Extinguished Cocaine-Induced Conditioned Place Preference in Mice: Roles for β1 and β2 Adrenergic Receptors

“…In rodent and nonhuman primate models, central delivery of norepinephrine (Brown et al, 2011) or activation of central noradrenergic neurotransmission via antagonism of ␣ 2 adrenergic receptors (Lee et al, 2004;Feltenstein and See, 2006) reinstates extinguished cocaine seeking. Likewise, functional antagonism of noradrenergic neurotransmission through the administration of ␣ 2 adrenergic receptor agonists blocks stress-induced reinstatement in preclinical models (Erb et al, 2000) and attenuates stress-induced craving in human cocaine addicts (Jobes et al, 2011;Fox et al, 2012).…”

Adrenaline Rush: The Role of Adrenergic Receptors in Stimulant-Induced Behaviors

“…Because prazosin, on its own, had no effect on cue-induced reinstatement in rodents, the lack of effect in the monkey cocaine 1 cue reinstatement paradigm is not entirely surprising. The only human studies germane to this subject found that clonidine and guanfacine decreased stress-or cue-induced craving for cocaine (Jobes et al, 2011;Fox et al, 2012).…”

“…On the basis of recent studies implicating NE in relapse-like behavior, interest in the contribution of this neurotransmitter to addictive processes has reemerged (Weinshenker and Schroeder, 2007;Gaval-Cruz and Weinshenker, 2009). Some noradrenergic compounds have already shown promise in human laboratory studies and initial clinical trials (Gaval-Cruz and Weinshenker, 2009;Fox et al, 2012;Haile et al, 2012;Newton et al, 2012;Shorter et al, 2013;K. Cunningham, personal communication).…”