The relevance of emotional stimuli to threat and survival confers a privileged role in their processing. In PTSD, the ability of trauma-related information to divert attention is especially pronounced. Information unrelated to the trauma may also be highly distracting when it shares perceptual features with trauma material. Our goal was to study how trauma-related environmental cues modulate * Corresponding author. Address: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box 3918, Durham, NC 27710, USA. Tel.: +1 919 286 0411x6425; fax: +1 919 416 5912. E-mail address: E-mail: rajendra.morey@duke.edu (R.A. Morey).. Contributors Rajendra Morey, M.D. wrote the manuscript, analyzed the fMRI data, supervised the research effort, and obtained research funding. Florin Dolcos worked on designing the challenge task, consulted on data analysis, provided critical review and revisions of the manuscript. Christopher M. Petty analyzed the fMRI data and helped to write Section 2. Debra A. Cooper created the stimuli and challenge task; recruited, consented and enrolled subjects; performed MRI scans, analyzed demographic and clinical data; helped with creating figures and tables, and proofread the manuscript. Jasmeet P. Hayes analyzed the behavioral data and wrote Section 3 on behavioral performance. Kevin S. LaBar consulted on data analysis and task design, and provided critical review and revisions of the manuscript. Gregory McCarthy worked on designing the challenge task, consulted on data analysis, provided critical review and revisions of the manuscript, and obtained research funding.Publisher's Disclaimer: This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright Conflict of interest statementThe authors have no actual or potential conflict of interest including financial or personal relationships that could influence or could be perceived to influence the work in this manuscript. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript working memory networks in PTSD. We examined neural activity in participants performing a visual working memory task while distracted by task-irrelevant trauma and non-trauma material. Recent post-9/11 veterans were divided into a PTSD group (n = 22) and a trauma-exposed control group (n = 20) based on the Davidson trauma scale. Using fMRI, we measured hemodynamic change in response to emoti...

The anti-alcoholism medication disulfiram (Antabuse) inhibits aldehyde dehydrogenase (ALDH), which results in the accumulation of acetaldehyde upon ethanol ingestion and produces the aversive “Antabuse reaction” that deters alcohol consumption. Disulfiram has also been shown to deter cocaine use, even in the absence of an interaction with alcohol, indicating the existence of an ALDH-independent therapeutic mechanism. We hypothesized that disulfiram’s inhibition of dopamine β-hydroxylase (DBH), the catecholamine biosynthetic enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons, underlies the drug’s ability to treat cocaine dependence. We tested the effects of disulfiram on cocaine and food self-administration behavior and drug-primed reinstatement of cocaine seeking in rats. We then compared the effects of disulfiram with those of the selective DBH inhibitor, nepicastat. Disulfiram, at a dose (100 mg/kg, i.p.) that reduced brain NE by ~40%, did not alter responding for food or cocaine on a fixed ratio 1 (FR1) schedule, whereas it completely blocked cocaine-primed (10 mg/kg, i.p.) reinstatement of drug seeking following extinction. A lower dose of disulfiram (10 mg/kg) that did not reduce NE had no effect on cocaine-primed reinstatement. Nepicastat recapitulated the behavioral effects of disulfiram (100 mg/kg) at a dose (50 mg/kg, i.p.) that produced a similar reduction in brain NE. Food-primed reinstatement of food seeking was not impaired by DBH inhibition. Our results suggest that disulfiram’s efficacy in the treatment of cocaine addiction is associated with the inhibition of DBH and interference with the ability of environmental stimuli to trigger relapse.

The symptom provocation paradigms generally used in neuroimaging studies of posttraumatic stress disorder (PTSD) have placed high demands on emotion processing but lacked cognitive processing, thereby limiting the ability to assess alterations in neural systems that subserve executive functions and their interactions with emotion processing. Thirty-nine veterans from Iraq and Afghanistan underwent functional MR imaging while exposed to emotional combat-related and neutral civilian scenes interleaved with an executive processing task. Contrast activation maps were regressed against PTSD symptoms as measured by the Davidson Trauma Scale. Activation for emotional compared to neutral stimuli was highly positively correlated with level of PTSD symptoms in ventral frontolimbic regions, notably the ventromedial prefrontal cortex, inferior frontal gyrus, and ventral anterior cingulate gyrus. Conversely, activation for the executive task was negatively correlated with PTSD symptoms in the dorsal executive network, notably the middle frontal gyrus, dorsal anterior cingulate gyrus, and inferior parietal lobule. Thus, there is a strong link between the subjectivelyassessed behavioral phenomenology of PTSD and objective neurobiological markers. These findings extend the largely symptom provocation-based functional neuroanatomy to provide evidence that interrelated executive and emotional processing systems of the brain are differentially affected by PTSD symptomatology in recently deployed war veterans.

Antagonists of the serotonin (5-hydroxytryptamine; 5-HT) type 2C receptor (5-HT 2C R) are being considered as potential pharmacotherapeutics for various affective disorders, but evidence suggests that these compounds enhance the effects of cocaine and related psychostimulants in rodents. However, the effects of selective 5-HT 2C R antagonists have not been evaluated in nonhuman primates. The present studies used operant-behavioral and in vivo microdialysis techniques to assess the impact of 5-HT 2C R antagonism on the behavioral and neurochemical effects of cocaine in squirrel monkeys. In subjects trained to lever-press on a fixed-interval schedule of stimulus termination, pretreatment with the highly selective 5-HT 2C R antagonist 6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl) oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride (SB 242084) (vehicle, 0.01-0.1 mg/kg) produced behavioralstimulant effects alone and interacted with cocaine in an apparently additive manner. In monkeys trained to selfadminister intravenous cocaine according to a second-order schedule of drug delivery, SB 242084 (vehicle, 0.03-0.1 mg/kg) modulated cocaine-induced reinstatement of previously extinguished responding and maintained selfadministration behavior when substituted for cocaine availability. These studies are the first to assess the direct reinforcing effects of a 5-HT 2C R-selective antagonist in any species. Finally, in vivo microdialysis studies revealed that pretreatment with SB 242084 (0.1 mg/kg) modulated cocaine-induced dopamine increases within the nucleus accumbens, but not the caudate nucleus, of awake subjects. Taken together, the results suggest that SB 242084 exhibits a behavioral profile that is qualitatively similar to other psychostimulants, although its efficacy is modest compared with cocaine. The observed interactions with cocaine and the substitution for cocaine self-administration may be indicative of some degree of abuse potential in humans.

Disulfiram has shown promise as a pharmacotherapy for cocaine dependence in clinical settings, although it has many targets, and the behavioral and molecular mechanisms underlying its efficacy are unclear. One of many biochemical actions of disulfiram is inhibition of dopamine b-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons. Thus, disulfiram simultaneously reduces NE and elevates DA tissue levels in the brain. In rats, both disulfiram and the selective DBH inhibitor nepicastat block cocaine-primed reinstatement, a paradigm which is thought to model some aspects of drug relapse. This is consistent with some clinical results and supports the use of DBH inhibitors for the treatment of cocaine dependence. The present study was conducted to confirm and extend these results in nonhuman primates. Squirrel monkeys trained to self-administer cocaine were pretreated with disulfiram or nepicastat prior to cocaineinduced reinstatement sessions. Neither DBH inhibitor altered cocaine-induced reinstatement. Unexpectedly, nepicastat administered alone induced a modest reinstatement effect in squirrel monkeys, but not in rats. To investigate the neurochemical mechanisms underlying the behavioral results, the effects of DBH inhibition on extracellular DA were analyzed in the nucleus accumbens (NAc) using in vivo microdialysis in squirrel monkeys. Both DBH inhibitors attenuated cocaine-induced DA overflow in the NAc. Hence, the attenuation of cocaine-induced changes in accumbal DA neurochemistry was not associated with altered cocaine-seeking behavior. Overall, the reported behavioral effects of DBH inhibition in rodent models of relapse did not extend to nonhuman primates under the conditions used in the current studies.

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