Neutralizing bFGF (FGF2) in the infralimbic medial prefrontal cortex facilitates extinction of cocaine self-administration.
Mentor 1
Devin Mueller
Location
Union Wisconsin Room
Start Date
24-4-2015 2:30 PM
End Date
24-4-2015 3:45 PM
Description
Neutralizing bFGF (FGF2) in the infralimbic medial prefrontal cortex facilitates extinction of cocaine self-administration. Chad Smies, Madalyn Hafenbreidel, Robert C. Twining, Carolynn Rafa Todd, and Devin Mueller Department of Psychology, University of Wisconsin – Milwaukee, Milwaukee, WI 532113 Prolonged exposure to drugs, such as cocaine, results in numerous structural and functional changes in brain regions found to regulate reward. These changes may underlie specific characteristics of drug addiction such as compulsive drug seeking and chronic relapse. Expression of the neurotrophic factor basic fibroblast growth factor (bFGF or FGF2) has been shown to increase after acute and chronic cocaine exposure in brain regions implicated in addiction, such as the prefrontal cortex (Fumagalli et al., 2006). Our lab has shown that cocaine seeking in the conditioned place preference paradigm upregulates bFGF expression in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), an effect which was normalized by extinction training. The infralimbic medial prefrontal cortex (IL-mPFC) has been shown to be responsible for inhibiting drug seeking after extinction (Peters et al., 2008). Therefore, we first infused a neutralizing bFGF antibody into IL-mPFC to determine if reduced bFGF levels would alter extinction of cocaine self-administration. Rats self-administered cocaine in 90-minute daily sessions before undergoing four daily shortened extinction sessions of 30 minutes. Prior to these sessions, rats received microinfusions of a neutralizing bFGF antibody or vehicle into the IL-mPFC. Short extinction trials of 30 minutes were used to ensure the antibody remained active throughout the entirety of the extinction trial (LaLumiere et al., 2010). Rats then underwent 90-minute drug-free extinction sessions to assess extinction retention from the previous shortened sessions. During the shortened 30-minute sessions, there were no differences in lever pressing between groups. When given the 90-minute drug-free session, however, vehicle-infused rats significantly increased lever pressing while neutralizing bFGF antibody-infused rats did not. These results indicate that neutralizing bFGF in IL-mPFC can facilitate extinction learning. We next wanted to determine if neutralizing bFGF alone was sufficient to facilitate extinction learning. Rats acquired self-administration as stated above, followed by four days of IL-mPFC microinfusions of the neutralizing bFGF antibody or vehicle without extinction training. Rats then underwent 90-minute drug-free extinction sessions. Both groups demonstrated normal extinction learning, indicating that neutralizing bFGF alone was not sufficient to facilitate extinction. Finally, we sought to determine the effects of extinction training on bFGF expression in the ventral medial PFC (vmPFC) and NAc following cocaine self-administration. Using Western Blot analysis, animals that underwent extinction training showed decreased expression of bFGF in the vmPFC and NAc compared to rats that did not undergo extinction. Taken together, our results indicate that extinction learning can reduce bFGF expression, and neutralizing bFGF in the IL-mPFC, in combination with extinction training, can facilitate extinction of cocaine self-administration. Thus, targeting bFGF could enhance therapeutic interventions for addictive disorders. Supported by DA027870 and a grant from the University of Wisconsin-Milwaukee Research Growth Initiative.
Neutralizing bFGF (FGF2) in the infralimbic medial prefrontal cortex facilitates extinction of cocaine self-administration.
Union Wisconsin Room
Neutralizing bFGF (FGF2) in the infralimbic medial prefrontal cortex facilitates extinction of cocaine self-administration. Chad Smies, Madalyn Hafenbreidel, Robert C. Twining, Carolynn Rafa Todd, and Devin Mueller Department of Psychology, University of Wisconsin – Milwaukee, Milwaukee, WI 532113 Prolonged exposure to drugs, such as cocaine, results in numerous structural and functional changes in brain regions found to regulate reward. These changes may underlie specific characteristics of drug addiction such as compulsive drug seeking and chronic relapse. Expression of the neurotrophic factor basic fibroblast growth factor (bFGF or FGF2) has been shown to increase after acute and chronic cocaine exposure in brain regions implicated in addiction, such as the prefrontal cortex (Fumagalli et al., 2006). Our lab has shown that cocaine seeking in the conditioned place preference paradigm upregulates bFGF expression in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), an effect which was normalized by extinction training. The infralimbic medial prefrontal cortex (IL-mPFC) has been shown to be responsible for inhibiting drug seeking after extinction (Peters et al., 2008). Therefore, we first infused a neutralizing bFGF antibody into IL-mPFC to determine if reduced bFGF levels would alter extinction of cocaine self-administration. Rats self-administered cocaine in 90-minute daily sessions before undergoing four daily shortened extinction sessions of 30 minutes. Prior to these sessions, rats received microinfusions of a neutralizing bFGF antibody or vehicle into the IL-mPFC. Short extinction trials of 30 minutes were used to ensure the antibody remained active throughout the entirety of the extinction trial (LaLumiere et al., 2010). Rats then underwent 90-minute drug-free extinction sessions to assess extinction retention from the previous shortened sessions. During the shortened 30-minute sessions, there were no differences in lever pressing between groups. When given the 90-minute drug-free session, however, vehicle-infused rats significantly increased lever pressing while neutralizing bFGF antibody-infused rats did not. These results indicate that neutralizing bFGF in IL-mPFC can facilitate extinction learning. We next wanted to determine if neutralizing bFGF alone was sufficient to facilitate extinction learning. Rats acquired self-administration as stated above, followed by four days of IL-mPFC microinfusions of the neutralizing bFGF antibody or vehicle without extinction training. Rats then underwent 90-minute drug-free extinction sessions. Both groups demonstrated normal extinction learning, indicating that neutralizing bFGF alone was not sufficient to facilitate extinction. Finally, we sought to determine the effects of extinction training on bFGF expression in the ventral medial PFC (vmPFC) and NAc following cocaine self-administration. Using Western Blot analysis, animals that underwent extinction training showed decreased expression of bFGF in the vmPFC and NAc compared to rats that did not undergo extinction. Taken together, our results indicate that extinction learning can reduce bFGF expression, and neutralizing bFGF in the IL-mPFC, in combination with extinction training, can facilitate extinction of cocaine self-administration. Thus, targeting bFGF could enhance therapeutic interventions for addictive disorders. Supported by DA027870 and a grant from the University of Wisconsin-Milwaukee Research Growth Initiative.
