Drug-taking in a socio-sexual context enhances vulnerability for addiction in male rats

Abstract

Vulnerability to develop addiction is influenced by numerous factors, including social behavior. Specifically, in human users, drug taking in a socio-sexual context appears to enhance further drug-seeking behavior. Users report heightened sexual pleasure as a motivation for further drug use and display risk behaviors even when tested in drug-free state. Here, using a preclinical model of limited voluntary drug use in rats, the hypothesis was tested that methamphetamine (Meth)-taking concurrently with socio-sexual experience increases vulnerability to addiction. Male Sprague Dawley rats were socially housed and underwent limited-access Meth self-administration (maximum 1 mg/kg/session). Meth-taking was either concurrent or non-concurrent with sexual behavior: concurrent animals were mated with a receptive female immediately after each session, while non-concurrent animals gained equivalent sexual experience the week prior. Next, drug-seeking behaviors were measured during cue reactivity, extinction, and reinstatement sessions using different extinction and reinstatement protocols in 4 separate studies. Both groups equally acquired Meth self-administration and did not differ in total Meth intake. However, drug-seeking behavior was significantly higher in concurrent animals during cue reactivity tasks, extinction sessions, and cue-or Meth-induced reinstatement tests. In addition, sexual behavior in the absence of Meth triggered reinstatement of drug-seeking in concurrent animals. These results indicate that Meth-taking in a socio-sexual context significantly enhances vulnerability for drug addiction in male rats. This preclinical paradigm of drug self-administration concurrent with socio-sexual behavior provides a useful model for studying the underlying neurobiology of socially driven vulnerability to drug addiction.Neuropsychopharmacology (2019) 44:503-513; https://doi.

Enhancement of Drug Seeking Following Drug Taking in a Sexual Context Requires Anterior Cingulate Cortex Activity in Male Rats

“…Results fit with the overall framework that mPFC is involved in formation and consolidation of context-response associations, including a role for ACA in working memory for response-outcome associations (Kesner and Churchwell, 2011). Here, findings support a role for ACA in forming associations between an intrinsic context of Meth exposure while engaging in emotional reward behavior, which in this study consisted of sexual reward behavior (see Kuiper et al (2019) for additional detailed discussion). Studies have also shown that inactivation of mPFC immediately after a learning task causes memory impairments (Carballo-Marquez et al, 2007).…”

“…CNO was not administered during the remainder of the experiment (Figure 3B), hence any differences between the CNO and vehicle concurrent groups were the result of inhibition of ACA CaMKII cells during the concurrent Meth and sex exposure and were not caused by differences in prior Meth taking or sex experience. Replicating previous findings (Kuiper et al, 2019), the vehicletreated concurrent group responded more on the active lever than the vehicle non-concurrent group during session 1 of extinction training [t (14) = 1.7, p = 0.045] and both concurrent groups responded more on the active lever than vehicle nonconcurrent males during session 2 of extinction training [t (14) = 1.7, p = 0.020-0.025]. However, prior CNO treatment had no effect on this enhanced drug-seeking behavior as vehicle and CNO-pretreated concurrent males did not differ ( Figure 3D; see Table S6 for all statistical analyses).…”

“…Previous studies utilized rat models to investigate increased vulnerability for drug addiction and hypersexuality in rats that were administered methamphetamine (Meth) immediately followed by sexual behavior. This has been termed concurrent Meth and sex in our previous publications (Frohmader et al, 2010c(Frohmader et al, , 2011Kuiper and Coolen, 2018;Kuiper et al, 2019), as sexual behavior is experienced while brain Meth levels are high (Riviere et al, 2000). It was demonstrated that concurrent Meth and sexual behavior leads to maladaptive sexual behavior persisiting for weeks (Frohmader et al, 2010a(Frohmader et al, , 2011.…”

“…Users identify increased sexual pleasure as a reason for drug use and relapse (Saw et al, 2018 ). Moreover, drug addiction is highly comorbid with compulsive sexual behavior, suggesting a shared neural basis for drug and non-drug addictions (Frohmader et al, 2010b ; Tull et al, 2011 ; Ahmadi et al, 2017 ; Berry and Johnson, 2018 ; Kuiper and Coolen, 2018 ; Kuiper et al, 2019 ).…”

“…Likewise, exposure to Meth in the sexual context increased drug-seeking behaviors in male rats measured by conditioned place preference (CPP) (Frohmader et al, 2011 ). Subsequent studies utilized operant drug self-administration paradigms in which male rats were restricted to a relatively low dose of Meth during limited numbers of daily sessions (Kuiper et al, 2019 ) in order to model the initial recreational use of human users (Cho et al, 2001 ). Following this limited Meth self-administration, animals were subsequently tested for drug-seeking behaviors in extinction sessions during which animals were placed back into the original Meth-taking environment but received no drug infusions or received no drug-associated cues nor infusions, and in reinstatement sessions, where drug-seeking was triggered by Meth-associated discrete cues, Meth administration, or by mating in the absence of Meth.…”