Prolonged exposure to drugs of abuse trigger persistent changes, or adaptations, throughout the brain’s “reward system,” which are believed to cause core features of addiction, such as craving and relapse. Growing evidence suggests that chronic drug exposure diminishes the function of the prefrontal cortex (PFC) – a component of the reward system – which is believed to cause cognitive and behavioral impairments that lead to the loss of inhibitory control over drug-seeking and drug-taking behaviors. 

Head of the Department of Pharmacology, Kevin Wickman, PhD, is a member of the Medical Discovery Team on Addiction, a professor and Frederick and Alice Stark Endowed Chair. He and four other researchers are studying this phenomena in detail. Their work, “Impact of Acute and Persistent Excitation of Prelimbic Pyramidal Neurons on Motor Activity and Trace Fear Learning” was recently published in the Journal of Neuroscience. 

This particular study builds upon prior work from the Wickman Lab, demonstrating that repeated cocaine exposure triggers an adaptation in a neuron type within the mouse medial prefrontal cortex (mPFC), a subregion of the PFC. As the behavioral implications of this cocaine-induced adaptation remain unknown, the researchers used state-of-the-art techniques in neuroscience to model this specific adaptation in the mPFC of drug-naive mice, and then assessed its impact on behaviors relevant to addiction.

Two behavioral “hallmarks” of chronic cocaine exposure in mice include disrupted associative learning and increased sensitivity to the psychomotor effect of cocaine. It’s these two behavioral outcomes that have been implicated in decision-making deficits and cravings that promote relapse, and the Wickman Lab found that this specific adaptation mimicked both behavioral outcomes.

Since neurons in the mPFC project to multiple brain regions, with each projection shaping behavior in a distinct manner, the researchers sought to identify which projection(s) were involved in these behavioral effects. They found that selective manipulation of the mPFC projection to the ventral tegmental area (VTA) – a small brain region with well-established roles in addiction-related behaviors – could recreate both behavioral outcomes. Taken together, their work suggests that this cocaine-induced adaptation in mPFC neurons, particularly those that project to the VTA, controls specific cognitive and behavioral impairments associated with chronic cocaine intake. 

Next, the researchers will assess the impact of this adaptation on the rewarding properties of cocaine using a preclinical model of addiction known as “conditioned place preference.” They will also determine if manipulations targeting the mPFC-to-VTA projection can counteract the cocaine-induced adaptation and prevent these behavioral outcomes. Their findings may contribute to the development of therapeutic interventions aimed at preventing or treating addiction.