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

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.

Glutamate acts as a key neurotransmitter for itch in the mammalian spinal cord

“…Anterior cingulate cortex (ACC) can be activated by pleasurable events. [65][66][67][68] Interestingly, one brain imaging work reported that the ACC is significantly deactivated after active or passive scratching of itch. 62 Regression analyses of brain activity versus pleasurability ratings showed that areas including the ACC deactivated while actively scratching an itch coincided with areas significantly correlated with pleasurability.…”

The Protective Effect of Social Reward on Opioid and Psychostimulant Reward and Relapse: Behavior, Pharmacology, and Brain Regions

“…• Concurrent Meth SA 1 mating induced higher extinction responding and Meth priming-induced reinstatement than nonconcurrent Meth SA 1 mating (see text for description of the two conditions) • Sex-induced reinstatement was only observed when mating in the concurrent group had occurred in the Meth SA context but not in a nondrug context 15 Kuiper et al, 2020 Meth Male SD rats…”

“…Brain mechanisms. Kuiper et al (2020), using immunohistochemistry and chemogenetic approaches, showed that noncontingent methamphetamine injections and mating coactivated CaMKII-expressing neurons in anterior insular cortex (ACC). Additionally, inhibition of CaMKII-expressing ACC neurons decreased the potentiation effect of concurrent methamphetamine self-administration 1 mating on drug cue-and drug priming-induced reinstatement but not extinction responding.…”