Impact of Cocaine Sensitization and Metformin on AMPK Phosphorylation in the Corticostriatal Circuit
Cocaine is an addictive stimulant, with over one million people suffering from cocaine use disorder. Cocaine sensitization, an enhanced motor response to repeated, intermittent cocaine administration, impacts regions that regulate reward-seeking behavior like the medial prefrontal cortex (mPFC), dorsal Striatum (dStr), and Nucleus Accumbens (NAc). Adenosine monophosphate-activated protein kinase (AMPK) maintains cellular energy homeostasis, and phosphorylated AMPK (pAMPK) in the dStr and PFC is impacted by acute cocaine. We aimed to determine cocaine sensitization’s impact on AMPK in the mPFC, NAc, and mPFC. Rats were given cocaine (15 mg/kg) or saline injections for six days and a challenge injection on the seventh day. They were divided into groups based on the initial and challenge injections they received: saline & saline (s-s, n=13), saline & cocaine (s-c, n=11), cocaine & saline (c-s; n=11), cocaine & cocaine (c-c; n=15). The locomotion of rats was tracked for forty-five minutes following daily injections to assess sensitization. Western blots were used to quantify pAMPK and total AMPK levels. Results showed higher pAMPK levels in the mPFC and a higher percent of pAMPK in the dStr of c-s compared to c-c. In the NAc core (NAcC), c-c had higher tAMPK than c-s. Introducing metformin to the NAcC decreases cue-induced cocaine seeking in rats, so we aimed to determine if metformin pre-treatment could prevent cocaine sensitization and associated protein changes. For 7 days, rats were given metformin (200mg/kg) or saline pretreatment followed by saline or cocaine treatment to create three groups: vehicle-cocaine (v-c, n=8), metformin-vehicle (m-v, n=8), and metformin-cocaine (m-c, n=8). Locomotion was tracked for 45 minutes post-treatment and showed that metformin prevented sensitization in females and males. Preliminary results showed that MV had a higher percentage of pAMPK than MC in the dStr. There was also a trend of MV having lower tAMPK compared to MC in NAcC. These results imply that metformin might introduce changes to regions that could combat cocaine sensitization.