Cocaine withdrawal‐induced anxiety in females: Impact of circulating estrogen and potential use of delta‐opioid receptor agonists for treatment

Abstract

Sex differences in cocaine addiction warrants further research focused on examining the growing population of female cocaine addicts. As demonstrated in both clinical and preclinical research, females are more susceptible to drug relapse with anxiety being a contributing factor. In support of this, a recent clinical study from our laboratory highlights the importance of menstrual cycle phase and anxiety at treatment admission for cocaine addiction on treatment retention. In support of these trends in the clinical population, the purpose of the present study was to design an animal model to directly test the role of circulating hormone levels during cocaine withdrawal. To directly measure the influence of estrogen on anxiety-like behavior during early stages of withdrawal, both ovariectomized and intact female rodent models were employed. The elevated-plus maze and elevated-zero maze were used to assess anxiety-like behavior. Recent evidence in male rodents highlights a potential role for the delta opioid-receptor (DOR) system in the modulation of cocaine withdrawal-induced anxiety. In addition to the evaluation of hormonal effects, a potential anxiolytic specific for DOR was tested for its efficacy in females withdrawn from cocaine. Our results support the use of DOR agonists as a potential anxiolytic in females and highlight the importance of estrogen and other circulating hormones during all phases of cocaine addiction.

Chronic alcohol exposure differentially affects activation of female locus coeruleus neurons and the subcellular distribution of corticotropin releasing factor receptors

“…These behaviors are increased with anxiolytic administration, and conversely decreased with anxiogenic drugs (Shepherd et al 1994). All animals were exposed to an EZM for assessment of anxiety-like behaviors as previously described on day 12 of treatment (Carvalho et al 2010b; Ambrose-Lanci et al 2010). As a modified version of the elevated plus maze, the EZM is used extensively to examine anxiety like phenotypes in rodents (Braun et al 2011), particularly after a pharmacological intervention (Kulkarni et al 2007).…”

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

“…Although there is a paucity of data regarding the prevalence of co-morbid anxiety disorders, possibly due to the fact that cocaine is less commonly thought to be consumed in individuals with a pre-disposition for anxiety, a NESARC survey documented that 31% of individuals with cocaine dependence reported lifetime anxiety disorders (Conway, Compton, Stinson, & Grant, 2006) and paranoia has also been documented as occurring in 68% to 84% of patients using cocaine (Morton, 1999). The clinical relevance of this is highlighted by the fact that severity of withdrawal-related anxiety has been found to impact the course, treatment outcome, and prognosis of both syndromes (Naifeh, Tull, & Gratz, 2012; O'Leary et al, 2000) (Sanchez-Hervas & Llorente del Pozo, 2012), particularly in women (Ambrose-Lanci, Sterling, & Van Bockstaele, 2010; Back et al, 2005; Chaplin, Hong, Bergquist, & Sinha, 2008; H. C. Fox & Sinha, 2009).…”

“…Several animal studies have modeled this noradrenergic mediation of anxiety-like behavior which emerges after withdrawal of cocaine, predicts relapse (Ambrose-Lanci et al, 2010; Kampman, Volpicelli, et al, 2001; O'Leary et al, 2000), and is attenuated by alpha2 adrenergic receptor agonists. For example, several recent studies from the animal and human literature have examined the ability of alpha2 adrenergic agonists including guanfacine, clonidine and lofexidine to attenuate stress-induced craving, cocaine-seeking and relapse as well as other negative reinforcing components of the craving state including negative affect and anxiety (R.…”

“…It is likely that such attenuation of stress system arousal may be related to central noradrenergic mediation of anxiety-like behavior which emerges after the withdrawal of cocaine (Buffalari et al, 2012; El Hage et al, 2012; Kampman, Alterman, et al, 2001; Kampman et al, 1998), is associated with craving and relapse factors (Ahmadi, Kampman, & Dackis, 2006; Ahmadi et al, 2009; Erb, 2010; H. C. Fox, Hong, Siedlarz, et al, 2008) and is sensitive to gender (Ambrose-Lanci et al, 2010; Back et al, 2005; Chaplin et al, 2008; H. C. Fox, Hong, Siedlarz, et al, 2008).…”

High anxiety is a predisposing endophenotype for loss of control over cocaine, but not heroin, self-administration in rats

“…Additionally, exposure to, or withdrawal from, cocaine and heroin increases anxiety (Rogerio and Takahashi 1992;Schulteis et al 1998;Zhou et al 2003;Le Merrer et al 2006;Ambrose-Lanci et al 2010;Salas-Ramirez et al 2010).…”