Serotonin 2C receptor (5-HT2CR) agonists administered systemically attenuate both cocaine-primed and cue-elicited reinstatement of extinguished cocaine-seeking behavior. To further elucidate the role of these receptors in addiction-like processes, this study examined the effects of microinfusing the 5-HT2CR agonist MK212 (0, 10, 30, 100 ng/side/0.2µl) into the medial prefrontal cortex (mPFC) on cocaine self-administration and reinstatement of extinguished cocaine-seeking behavior. Male Sprague-Dawley rats were trained to self-administer cocaine (0.75 mg/kg, i.v.) paired with light and tone cues. Once responding stabilized, rats received MK212 microinfusions prior to tests for maintenance of cocaine self-administration. Next, extinction training to reduce cocaine-seeking behavior, defined as responses performed without cocaine reinforcement available, occurred until low extinction baselines were achieved. Rats then received MK212 microinfusions prior to tests for reinstatement of extinguished cocaine-seeking behavior elicited by cocaine-priming injections (10 mg/kg, i.p.) or response-contingent presentations of the cocaine-associated cues; operant responses during cocaine-primed reinstatement tests produced no consequences. MK212 microinfusions into the prelimbic and infralimbic, but not anterior cingulate, regions of the mPFC dose-dependently attenuated both cocaine-primed and cue-elicited reinstatement of extinguished cocaineseeking behavior but did not reliably affect cocaine self-administration. A subsequent experiment demonstrated that the effects of MK212 (100 ng/side/0.2µl) on reinstatement of extinguished cocaine-seeking behavior were blocked by co-administration of the 5-HT2CR antagonist SB242084 (200 ng/side/0.2µl). MK212 administered alone into the mPFC as a drug prime produced no discernable effects on cocaine-seeking behavior. These findings suggest that stimulation of 5-HT2CRs in the mPFC attenuates the incentive motivational effects produced by sampling cocaine or exposure to drug-paired cues.

Background Substance use disorders (SUDs) and Post Traumatic Stress Disorder (PTSD) frequently co-occur among Veterans and are associated with poor treatment outcomes. Historically, treatments for SUDs and PTSD have been delivered sequentially and independently. More recently, however, integrated treatments have shown promise. This study investigated Veterans’ perceptions of the interrelationship between SUDs and PTSD, as well as treatment preferences. Methods Participants were 35 Veterans of recent military conflicts in Iraq and Afghanistan, and prior operations, who completed the Treatment Preferences Questionnaire as well as an in-depth interview. Results The majority (94.3%) perceived a relationship between their SUD and PTSD symptoms. Veterans reported that PTSD symptom exacerbation was typically (85.3%) associated with an increase in substance use, and PTSD symptom improvement was typically (61.8%) followed by a decrease in substance use (p < .01). Approximately 66% preferred an integrated treatment approach. Conclusions Although preliminary, the findings provide clinically-relevant information that can be used to enhance the development and provision of care for Veterans with SUDs and PTSD.

Stress is a significant risk factor for the development of major depressive disorder (MDD), yet the underlying mechanisms remain unclear. Preclinically, adaptive and maladaptive stress-induced changes in glutamatergic function have been observed in the medial prefrontal cortex (mPFC). Here, we examine stress-induced changes in human mPFC glutamate using magnetic resonance spectroscopy (MRS) in two healthy control samples and a third sample of unmedicated participants with MDD who completed the Maastricht acute stress task, and one sample of healthy control participants who completed a no-stress control manipulation. In healthy controls, we find that the magnitude of mPFC glutamate response to the acute stressor decreases as individual levels of perceived stress increase. This adaptative glutamate response is absent in individuals with MDD and is associated with pessimistic expectations during a 1-month follow-up period. Together, this work shows evidence for glutamatergic adaptation to stress that is significantly disrupted in MDD.

Objective Aggressive behavior is strongly associated with both posttraumatic stress disorder (PTSD) and substance use disorders (SUD) among civilians. However, little research has examined correlates of aggression among Veterans with co-occurring PTSD and SUD. Methods This exploratory study examined the prevalence and correlates of recent (i.e., past 30 days) and lifetime aggressive behavior among a sample of U.S. Veterans (N=97) enrolled in a study examining integrated psychosocial treatment of co-occurring PTSD/SUD. Results The findings revealed high rates of recent and lifetime aggressive behaviors (39.2% and 57.7%, respectively). Participants who endorsed recent aggressive behaviors were younger, had less education, more severe PTSD numbing and hyperarousal symptoms, were more likely to report recent suicidal ideation, more frequent alcohol and marijuana use, had higher rates of physical and sexual abuse, greater combat exposure, and more severe aftermath of battle experiences. Participants who endorsed lifetime aggression were younger, reported more total PTSD symptom severity, PTSD re-experiencing severity, depression severity, and fewer post-deployment stressors compared to those who did not. Logistic regression analyses indicated that education and number of drinking days were correlated with recent aggression while depression and post-deployment stressors were correlated with lifetime aggression. Conclusions The findings demonstrate high rates of aggressive behaviors among Veterans with PTSD/SUD, as well as clinically relevant correlates of aggressive behaviors. Although preliminary, the findings suggest potential targets for improving assessment and treatment of Veterans with PTSD/SUD.

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