Abstract
Individual variance in vulnerability to develop addictions is influenced by social factors. Specifically, drug-taking in a sexual context appears to enhance further drug-seeking behavior in human users, as these users identify the effects of drugs to enhance sexual pleasure as a primary reason for continued drug use. Methamphetamine (Meth) is commonly used in this context. Similarly, male rats that self-administered Meth immediately followed by sexual behavior display enhanced drug-seeking behavior, including attenuation of extinction and increased reinstatement to seeking of Meth-associated cues. Hence, drug-taking in a sexual context enhances vulnerability for addiction. However, the neural mechanisms by which this occurs are unknown. Here the hypothesis was tested that medial prefrontal cortex is essential for this effect of Meth and sex when experienced concurrently. First it was shown that CaMKII neurons in the anterior cingulate area (ACA) were co-activated by both Meth and sex. Next, chemogenetic inactivation of ACA CaMKII cells using AAV5-CaMKIIa-hM4Di-mCherry was shown not to affect Meth-induced locomotor activity or sexual behavior. Subsequently, chemogenetic inactivation of ACA CaMKII neurons during Meth self-administration followed by sexual behavior was shown to prevent the effects of Meth and sex on enhanced reinstatement of Meth-seeking but did not affect enhanced drug-seeking during extinction tests. These results indicate that ACA CaMKII cell activation during exposure to Meth in a sexual context plays an essential role in the subsequent enhancement of drug-seeking during reinstatement tests.
Highlights
Substance use disorders are a severe threat to public health and influenced by social experiences (Heilig et al, 2016; Lacy et al, 2016; Robinson et al, 2016, 2017; de Wit and Sayette, 2018; Venniro et al, 2018, 2019)
The current studies demonstrate that activity of anterior cingulate area (ACA) CaMKII neurons and their targets contributes to enhanced drug-seeking behavior in male rats following Meth exposures in a sexual context
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)
Summary
Substance use disorders are a severe threat to public health and influenced by social experiences (Heilig et al, 2016; Lacy et al, 2016; Robinson et al, 2016, 2017; de Wit and Sayette, 2018; Venniro et al, 2018, 2019). 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. Concurrent Meth and sex-treated animals responded significantly more on the drug-paired lever during extinction sessions and during reinstatement tests where drug-seeking was triggered by Meth-associated discrete cues, Meth administration, or by mating in the absence of Meth, compared to male rats exposed to non-concurrent Meth self-administration and sex (Kuiper et al, 2019)
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