LAUSR

Humans have long ingested opioids. In 1797, an opium-induced dream inspired Samuel Taylor Coleridge’s famous poem “Kubla Khan”. 100 years later, Arthur Conan Doyle’s Sherlock Holmes and Dr. Watson meet unexpectedly in an opium den in “The Man with the Twisted Lip” (1891), where Sherlock accuses Watson of assuming the worst (but Sherlock was searching for information, not opium). Recently, opioid misuse has escalated, resulting in what we now refer to as the “opioid overdose crisis,” a period of time characterized by rates of overdose-induced deaths unprecedented in modern history. Opioid use disorders afflict males and females, but females are more likely to use prescription opioids, and opioid-related death are increasing more rapidly among females [1]. Neuroimaging studies document hyperactivity of medial prefrontal cortical regions in response to heroin-related cues in heroin-addicted individuals, and hypoactivity in basal states (discussed in ref. [2]). Similar phenomena are reported in (mostly male) rodents selfadministering cocaine (discussed in ref. [2]). In this issue, a new, comprehensive report by Anderson et al. [2] dives deeply into the neurobiological consequences of opioid self-administration on prefrontal cortical physiology and function, investigating effects across time and sexes. The investigators trained male and female mice to selfadminister remifentanil, an opioid used clinically to treat pain. Mice self-administered for 10–16 days, which I will refer to as “moderate exposure,” or 25–30 days, referred to as “extended exposure.” Following self-administration, the mice received a 14–21-day or longer washout period. Control mice received saline infusions paired with Ensure to promote the acquisition of operant responding and control for effects of motor activity. In initial experiments using moderate remifentanil exposure, females developed basal hypoactivity of layer 5/6 pyramidal neurons in the prelimbic prefrontal cortex (PL). Meanwhile, males exhibited hyperactivity despite similar patterns of drug intake. With extended exposure, both males and females developed hypoactivity. Thus, remifentanil self-administration decreases the basal activity of PL neurons. This effect develops more rapidly in females and is unexpectedly preceded by a period of hyperactivity in males. The investigators next measured patterned spike firing, revealing increased firing with more depolarized potentials following moderate remifentanil exposure in females. This pattern again developed only with extended exposure in males. And interestingly, basal hypoexcitability and modestly elevated firing capacity were evident in females even following a prolonged washout period. Thus, remifentanil-induced hypoactivity and elevated firing capacity of PL neurons develop more rapidly and are more persistent in female mice. The authors then reveal through pharmacological manipulations that hypoactive basal states in females are associated with decreased AMPA-mediated excitatory drive. Meanwhile, hyperactive and hypoactive states in males are instead associated with GABAB signaling. If one were to attempt to treat opioid misuse using novel disease-modifying strategies, these findings are rather impactful—suggesting that treatments in males and females should fundamentally differ. The authors also tested the capacity of remifentanil selfadministering mice to perform an attentional set-shifting task, conceptually similar to the Wisconsin Card Sort task in humans. In striking parallel with physiological patterns, females struggled to perform extradimensional shifts (task phases with the greatest complexity) and generated errors after only moderate remifentanil exposure. Meanwhile, males required extended exposure to develop the same deficits. Finally, the authors turned to Gq-coupled designer receptors exclusively activated by designer drugs (DREADDs). Gq-DREADD stimulation in the PL restored performance in the attentional setshifting task following remifentanil, implicating opioid-induced PL hypoactivity in poor cognitive function. Anderson et al. thus clearly connect drug-induced neuromodulations with cognitive deficits, and in particular cognitive deficits associated with the PL. Another key function of the PL is linking actions and outcomes, a process necessary for goal-directed behavior—selecting actions likely to be rewarded with desirable outcomes [3]. Some argue that addictive drugs degrade this ability and cause organisms to favor habit-based behaviors, which are stimulus-elicited and insensitive to outcomes. Notwithstanding debates regarding whether habitual behavior directly contributes to addiction, it