The Effects of Contingent and Non‐Contingent Cocaine Administration on Medial Prefrontal Cortex SAPAP Levels
Authors: Steketee Jeffery D 
Published: November 2023

Previous studies have linked obsessive compulsive disorder with reduced SAPAP3 levels in corticostriatal circuits. SAPAPs (synapse associated protein 90/PSD‐95 associated protein) are scaffolding proteins that are important in the modulation of excitatory synapses. Four isoforms (1–4) have been identified. Substance abuse, including cocaine, can be be described as a compulsive need to seek and use drugs. Furthermore, altered excitatory transmission in corticostriatal circuits is a hallmark of enhanced drug seeking behavior. Thus, the present experiments examined the effects of acute and repeated cocaine administration on cortical SAPAP levels. In initial experiments the effects of experimenter administered cocaine (15 mg/kg, ip) on SAPAP levels in the medial prefrontal cortex (mPFC) were examined. Male Sprague Dawley rats (275–300 g) received one injection of saline or cocaine and were sacrificed 2–24 hrs after this injection. A second group of animals received four once daily injections of saline or cocaine and received challenge injections of saline or cocaine one day to three weeks later. Animals were then sacrificed 2 hr later, following the collection of motor activity data, as a measure of behavioral sensitization. Following sacrifice, ventral and dorsal mPFC samples were collected and tissues were prepared and analyzed for SAPAP1‐4 levels using standard western blotting procedures. Data demonstrated that in general, cocaine decreased the levels of each of the 4 isoforms of SAPAP beginning 2 hr after acute cocaine exposure that began to recover 12 hrs after exposure and with the dorsal mPFC being more sensitive than the ventral mPFC. Three weeks following repeated cocaine exposure, which induced behavioral sensitization, SAPAPs 2 and 4 were found be reduced in the dorsal mPFC and all SAPAPs were reduced in sensitized animals upon exposure to a challenge injection of cocaine. SAPAP levels were not altered in the ventral mPFC following repeated cocaine exposure. Follow‐up studies examined the impact of contingent exposure to cocaine on mPFC SAPAP levels. Animals were trained to self‐administer cocaine (0.3 mg/kg/infusion) on an FR1 schedule with a 20 sec timeout for 3 hr/day over the course of 10 days. Control animals were yoked to self‐administering animals and received infusions of saline when their yoked mates received cocaine. Animals then went through a 3 week period of abstinence after which they were sacrificed and dorsal and ventral mPFC tissue were collected for western blot analysis of SAPAP levels. Results demonstrated that unlike non‐contingent drug exposure, contingent administration of cocaine produced significant increases in dorsal mPFC SAPAP levels. Ventral mPFC levels were not altered. The results of these studies demonstrate that repeated exposure to cocaine produces long‐lasting changes in dorsal mPFC SAPAP levels and that these changes differ based on whether the drug is administered by the experimenter or self‐administered. These data may have important implications in the role of SAPAP modulation of excitatory transmission from the dorsal mPFC to the core of the nucleus accumbent that has been shown to be involved in substance abuse. Future studies will exam this role by examining the effects of manipulation of SAPAP levels on behavioral responses to cocaine.