Search

The increased risk of alcohol use disorder (AUD) in individuals with post-traumatic stress disorder (PTSD) is well-documented. Compared to individuals with PTSD or AUD alone, those with co-existing PTSD and AUD exhibit greater symptom severity, poorer quality of life, and poorer treatment outcomes. Although the treatment of comorbid AUD is vital for the effective management of PTSD, there is a lack of evidence on how to best treat comorbid PTSD and AUD, and currently, there are no FDA-approved treatments for the PTSD-AUD comorbidity. The objective of this manuscript is to review the evidence of a promising target for treating the AUD-PTSD comorbidity. First, we summarize the epidemiological evidence and review the completed clinical studies that have tested pharmacotherapeutic approaches for co-existing AUD and PTSD. Next, we summarize the shared pathological factors between AUD and PTSD. We conclude by providing a rationale for selectively inhibiting aldehyde dehydrogenase-2 as a potential target to treat comorbid AUD in persons with PTSD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

In the present study, we tested the hypothesis that the potent and selective dopamine-β-hydroxylase (DβH) inhibitor nepicastat would have minimal effects on cardiovascular and pharmacokinetic parameters associated with cocaine administration and would reduce the positive subjective effects produced by cocaine. We conducted a double-blind, placebo-controlled, inpatient study of oral nepicastat (0, 80 and 160mg) concurrent with intravenous (IV) cocaine (0, 10, 20 and 40mg) in non-treatment seeking participants who metcriteria for cocaine use disorder. Safety analyses revealed that nepicastat was well-tolerated and there were no differences in adverse events observed after nepicastat plus cocaine vs. cocaine alone. In addition, the pharmacokinetic properties of cocaine administration were not altered by nepicastat treatment. Cocaine-induced cardiovascular and subjective effects were evaluated for completers in the cohort randomized to nepicastat (n=13) using a within-subjects statistical analysis strategy. Specifically, the cardiovascular and subjective effects of cocaine were assessed in the presence of placebo (0mg), 80mg of nepicastat or 160mg of nepicastat on study Days 4, 8 and 12, respectively. Analyses revealed a main effect of nepicastat to reduce several cocaine-induced positive subjective effects. Taken together, these data indicate that nepicastat is safe when co-administered with cocaine and may suppress its positive subjective effects, and may be viable as a pharmacotherapy for treatment of cocaine use disorder., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Unlabelled: Long-term, high-dose methamphetamine (METH) use is associated with decrements in neurocognition and, given the association between impaired neurocognition and poorer treatment outcomes in individuals dependent on alcohol and drugs, it is considered to be a neglected area of critical concern. The objective of this study was to determine whether varenicline, a partial agonist at α4β2- and a full agonist at α7-nicotinic acetylcholine receptors, enhances attention/information processing speed, episodic memory, and working memory in non-treatment seeking METH-dependent participants. Twenty-six participants were randomly assigned to receive oral placebo or oral varenicline (titrated up to 1 mg) over 5 days during three separate inpatient phases, and 17 completed each inpatient phase. Participants were predominately male (71%) and Caucasian (71%). Varenicline significantly improved reaction time on the n-back for visual stimuli (F(1,47)=5.369, p=0.025, η2=0.103), and a trend was observed for improvement in reaction time for auditory stimuli (F(1,47)=3.141, p=0.083, η2=0.063). For those study participants whose reaction time was in the lower half of the distribution at baseline, the effect was even more pronounced for auditory (F(1,22)=5.287, p=0.031, η2=0.194) and visual (F(1,22)=11.981, p=0.002, η2=0.353) stimuli relative to placebo. In contrast, varenicline did not modulate mean or maximum span of working memory or performance on tests of episodic memory or attention (p's>0.05). Given the potential importance of this finding, it should be replicated in a larger sample over a longer treatment period with a higher dose of varenicline (2 mg)., Trial Registration: clinicalTrials.gov Identifier NCT01571167., (Copyright © 2014. Published by Elsevier Ltd.)

Long-term cocaine use is a risk factor for the onset of neurocognitive impairment. This study sought to determine whether the cholinesterase inhibitor rivastigmine could improve neurocognitive performance in cocaine-dependent individuals. Cocaine-dependent individuals who were not seeking treatment at the time of enrollment in the study were randomly assigned to receive placebo (n=16), rivastigmine 3mg (n=13), or rivastigmine 6mg (n=12). The baseline neurocognitive assessment, which included measures of attention/information processing (as measured by the Continuous Performance Task-II (CPT-II)), verbal learning/episodic memory (as measured by the Hopkins Verbal Learning Test-Revised (HVLT-R)), and working memory (as measured by the Dual N-Back Task), was conducted prior to the administration of study medication (Day 0). The follow-up assessment was conducted on Day 8 after the participants had received rivastigmine or placebo for 7days (Day 2-8). Rivastigmine administration significantly improved performance on one measure of working memory span (mean n-back span). This study provides additional data showing that cocaine-associated neurocognitive impairment, specifically working memory deficits, can be remediated, at least to some degree., (Copyright © 2013. Published by Elsevier Inc.)

The primary objective of this study was to determine the safety of lofexidine, an α2 receptor agonist, alone and concurrent with cocaine in non-treatment seeking cocaine-dependent or cocaine-abusing participants. After screening, eligible participants received double-blind, randomized infusions of saline and 20mg of cocaine on Day 1, and saline and 40mg of cocaine on Day 2. Subjects were randomized and started receiving daily administration of placebo (N=4) or lofexidine on Day 3 and continued on this schedule until Day 7. Two dosing regimens for lofexedine were investigated: 0.8 QID (N=3) and 0.2mg QID (N=11). On Days 6 and 7, subjects received double-blind infusions of saline and 20mg of cocaine on Day 6, and saline and 40mg of cocaine on Day 7. The data reveal a notable incidence of hemodynamic-related AEs over the course of the study. Two of the three participants at the 0.8mg dose level discontinued, and five of 11 participants at the 0.2mg dose level were withdrawn (or voluntarily discontinued) after hemodynamic AEs. Subjective effects and cardiovascular data were derived from all participants who were eligible to receive infusions (i.e., did not meet stopping criteria) on Days 6 and 7 (6 received lofexidine 0.2mg, QID and 4 received placebo, QID). As expected, cocaine significantly increased heart rate and blood pressure, as well as several positive subjective effects. There was a trend for lofexidine to decrease cocaine-induced cardiovascular changes and cocaine-induced ratings for "any drug effect", "good effects", and "desire cocaine", but sample size issues limit the conclusions that can be drawn. Despite the trends to reduce cocaine-induced subjective effects, cardiovascular AEs may limit future utility of lofexidine as a treatment for this population., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Current cocaine treatments may be enhanced with a better understanding of the underlying mechanisms that contribute to the onset and maintenance of the disease, such as life stress and impulsivity. Life stress and impulsivity have previously been studied independently as contributors to drug use, and the current study expands upon past research by examining how these factors interact with one another. The aim of the current study was to evaluate the role of life stress in predicting impulsivity in a non-treatment seeking cocaine-dependent sample (N=112). Analyses revealed that trait impulsivity (as measured by the Barratt Impulsiveness Scale) was associated with education (r=-3.09, p<0.01), as those who had higher educational attainment also reported lower rates of trait impulsivity. In addition, those over the age of 30 demonstrated lower impulsivity in decision-making (as measured by delay discounting) than those under 30 (t=2.21, p=0.03). Overall exposure to life stress was not significantly correlated to either aspect of impulsivity. However several specific life stressors were significantly related to greater impulsivity including having been put up for adoption or in foster care (t=-2.96, p<0.01), and having a child taken away against their will (t=-2.68, p=0.01). These findings suggest that age and education relate to impulsivity; and that while an overall compilation of life stress scores was not related to impulsivity, specific types of stress related to either being taken away from a parent or having a child taken away were. Future studies should assess these constructs longitudinally to restrict response bias., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The purpose of the present study was to determine the effects of modafinil, escitalopram, and modafinil + escitalopram administration on neurocognition in a sample of long-term, high-dose cocaine users., Method: Sixty-one cocaine-dependent individuals were randomly assigned to receive placebo (n = 14), modafinil, 200 mg, once daily (n = 16), escitalopram, 20 mg, once daily (n = 16), or modafinil and escitalopram, once daily (n = 15), for five days on an inpatient basis. Urinanalysis was used to confirm abstinence from cocaine on the day of admission and the next five days. Baseline neurocognitive assessment, which included measures of attention/information processing, episodic memory, and working memory, was conducted immediately after the washout phase and prior to the administration of modafinil. The follow-up assessment was conducted after participants had received modafinil or placebo for five days., Results: Repeated-measures, mixed model analysis of variance showed that modafinil administration was associated with significantly improved performance on two measures of working memory span (mean n-back span, maximum n-back span) and a trend toward significant improvement on a measure of visual working memory (visual accuracy) and two measures of sustained attention, consistency of response time (Variability) and reduced impulsivity (Perseveration). Modafinil administration did not modulate performance on measures of information processing speed or episodic memory. Escitalopram did not modulate performance on measures of cognition, either alone or in combination with modafinil., Conclusions: This study provides initial data showing that, in a sample of long-term, high-dose cocaine users, administration of psychotropic medications, such as modafinil, can improve performance on measures of working memory. Moreover, it confirms the utility of studying the interactive effects of psychotropic medications to confirm the manner in which the candidate medications independently and interactively affect neurocognition. These effects are likely relevant in the treatment of cocaine dependence, in which the remediation of impaired working memory may be associated with improved treatment outcomes. This article is part of a Special Issue entitled 'Cognitive Enhancers'., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Much effort has been devoted to research focused on pharmacotherapies for cocaine dependence yet there are no FDA-approved medications for this brain disease. Preclinical models have been essential to defining the central and peripheral effects produced by cocaine. Recent evidence suggests that cocaine exerts its reinforcing effects by acting on multiple neurotransmitter systems within mesocorticolimibic circuitry. Imaging studies in cocaine-dependent individuals have identified deficiencies in dopaminergic signaling primarily localized to corticolimbic areas. In addition to dysregulated striatal dopamine, norepinephrine and glutamate are also altered in cocaine dependence. In this review, we present these brain abnormalities as therapeutic targets for the treatment of cocaine dependence. We then survey promising medications that exert their therapeutic effects by presumably ameliorating these brain deficiencies. Correcting neurochemical deficits in cocaine-dependent individuals improves memory and impulse control, and reduces drug craving that may decrease cocaine use. We hypothesize that using medications aimed at reversing known neurochemical imbalances is likely to be more productive than current approaches. This view is also consistent with treatment paradigms used in neuropsychiatry and general medicine., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We previously reported that treatment with the cholinesterase inhibitor rivastigmine (3mg, PO for 5days) significantly attenuated "Desire for METH". Given that higher dosages of rivastigmine produce greater increases in synaptic ACh, we predicted that 6mg should have more pronounced effects on craving and other subjective measures. In the current study, we sought to characterize the effects of short-term exposure to rivastigmine (0, 3 or 6mg) on the subjective and reinforcing effects produced by administration of methamphetamine (METH) in non-treatment-seeking, METH-dependent volunteers. This was a double-blind, placebo-controlled, crossover study. Participants received METH on day 1, and were then randomized to placebo or rivastigmine on day 2 in the morning and treatment continued through day 8. METH dosing was repeated on day 6. The data indicate that METH (15 and 30mg), but not saline, increased several positive subjective effects, including "Any Drug Effect", "High", "Stimulated", "Desire METH", and "Likely to Use METH" (all p's<0.0001). In addition, during self-administration sessions, participants were significantly more likely to choose METH over saline (p<0.0001). Evaluating outcomes as peak effects, there was a trend for rivastigmine to reduce "Desire METH" (p=0.27), and rivastigmine significantly attenuated "Likely to Use METH" (p=0.01). These effects were most prominent for rivastigmine 6mg when participants were exposed to the low dose (15mg, IV), but not high dose (30mg, IV), of METH. The self-administration data reveal that rivastigmine did not alter total choices for METH (5mg, IV/choice). Overall, the results indicate some efficacy for rivastigmine in attenuating key subjective effects produced by METH, though additional research using higher doses and longer treatment periods is likely needed. These data extend previous findings and indicate that cholinesterase inhibitors, and other drugs that target acetylcholine systems, warrant continued consideration as treatments for METH dependence., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Compared to smokers alone, smokers with co-morbid substance use disorders are at greater risk of suffering from smoking-related death. Despite this, relatively few studies have examined smoking cessation treatments for those with stimulant dependence. In the current study, we sought to evaluate the effects produced by short-term exposure to the cholinesterase inhibitor rivastigmine (0, 3 or 6 mg) on cigarette smoking in non-treatment-seeking, methamphetamine-dependent volunteers. This was a double-blind, placebo-controlled, crossover study that took place over 9 days. The data indicate that rivastigmine treatment did not alter Fagerström Test for Nicotine Dependence scores, carbon monoxide readings, or cigarettes smoked per day, but a trend toward reduced urges to smoke (p<0.09) was detected during treatment with rivastigmine 3mg. These data, while preliminary, indicate that cholinesterase inhibitors warrant consideration as treatments for nicotine dependence, including use in stimulant-dependent individuals who exhibit significantly higher rates of smoking than the general population., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Abstinent methamphetamine (Meth) dependent individuals demonstrate poorer performance on tests sensitive to attention/information processing speed, learning and memory, and working memory when compared to non-Meth dependent individuals. The poorer performance on these tests may contribute to the morbidity associated with Meth-dependence. In light of this, we sought to determine the effects of acute, low-dose Meth administration on attention, working memory, and verbal learning and memory in 19 non-treatment seeking, Meth-dependent individuals. Participants were predominantly male (89%), Caucasian (63%), and cigarette smokers (63%). Following a four day, drug-free washout period, participants were given a single-blind intravenous infusion of saline, followed the next day by 30 mg of Meth. A battery of neurocognitive tasks was administered before and after each infusion, and performance on measures of accuracy and reaction time were compared between conditions. While acute Meth exposure did not affect test performance for the entire sample, participants who demonstrated relatively poor performance on these tests at baseline, identified using a median split on each test, showed significant improvement on measures of attention/information processing speed and working memory when administered Meth. Improved performance was seen on the following measures of working memory: choice reaction time task (p≤0.04), a 1-back task (p≤0.01), and a 2-back task (p≤0.04). In addition, those participants demonstrating high neurocognitive performance at baseline experienced similar or decreased performance following Meth exposure. These findings suggest that acute administration of Meth may temporarily improve Meth-associated neurocognitive performance in those individuals experiencing lower cognitive performance at baseline. As a result, stimulants may serve as a successful treatment for improving cognitive functioning in those Meth-dependent individuals experiencing neurocognitive impairment., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Unlabelled: Drug-induced craving is thought to play an important role in relapse occasioned by a "slip", or an isolated use of a previously abused drug after a period of abstinence. Clinical experience suggests that acute exposure to cocaine elicits craving (hereafter referred to as "priming"); however, this has received surprisingly little attention in the clinical literature., Aims: The intentions of this review are to provide a qualitative review of the literature as well as a more stringent quantitative review of the existence and presence of cocaine-induced priming effects., Methods: In order to determine whether priming effects occur following cocaine administration, we conducted qualitative and quantitative reviews of studies in which participants received cocaine under experimentally controlled conditions in the laboratory., Results: The results of the qualitative review were equivocal, while the quantitative review revealed that cocaine administration was associated with a significant increase in craving for cocaine, and the effect size of this relationship was large., Conclusion: A review of the individual studies revealed marked variability, suggesting that priming effects did not occur consistently and that there may be factors that mediate or moderate the intensity of the priming effects induced by cocaine. The implications of these findings are discussed.

Recombinant human interferon-alpha (IFN-alpha) induces depression, and neuroendocrine and neuroimmune activation, in a significant number of patients undergoing treatment for viral illnesses (e.g., hepatitis C), yet these effects have not been consistently reproduced in rodents. As such, we sought to determine the effects of acute or chronic IFN-alpha treatment on basic reward and immobility in the forced swim test (FST), neuroendocrine and neuroimmune activation, and monoamine turnover in brain. In the first experiment, male Wistar rats (N = 7/group) treated with human recombinant IFN-alpha (100,000 IU/kg, i.p.), as compared to saline, did not exhibit alterations to rate of sucrose pellet self-administration or total reinforcers obtained, corticosterone release, plasma IL-6 release, IL-1beta or IL-6 mRNA expression in hippocampus, or monoamine turnover in prefrontal cortex, striatum, nucleus accumbens, or amygdala. However, acute IFN-alpha decreased body weight and produced a trend toward reduced food consumption in the home cage 2 h after injection. In the second experiment, Wistar rats (N=4/group) were subjected to a chronic treatment regimen of saline or IFN-alpha (100,000 IU/kg, i.p.) once daily for 14 consecutive days. The data reveal that animals exposed to chronic IFN-alpha exhibited similar amounts of time immobile and similar latencies to primary immobility in the FST as compared to saline-treated controls. Chronic IFN-alpha did not induce corticosterone release, plasma TNF-alpha, or IL-6 release. Tissue monoamine analysis revealed that chronic IFN-alpha reduced DA levels in prefrontal cortex, and decreased 5-HT levels and increased 5-HT turnover in amygdala. In the third experiment, Wistar rats (N = 4/group) were exposed to either acute or chronic pegylated IFN-alpha (pegIFN-alpha: 3.25, 10 or 75 mg/kg, i.p.) at one of several time points from 1 h to 23 days. The data reveal that neither acute nor chronic pegIFN-alpha induced corticosterone release. Overall, the current report demonstrates that neither acute nor chronic IFN-alpha induced depressive-like behavior and neither IFN-alpha nor peg-IFN-alpha was capable of inducing neuroendocrine or neuroimmune activation. Despite the neurochemical alterations observed in the chronic treatment regimen, the data indicate that recombinant human IFN-alpha does not produce a robust model of depressive-like behavior in rodents.

Interferon (IFN) is a pro-inflammatory cytokine that is widely used for the treatment of a number of disorders including viral infections, hematological proliferative disorders, and skin malignancies. Unfortunately, IFN frequently induced depression and has led to compromised tolerability with lowering of the dose of IFN and even discontinuation of treatment. Thus, it is imperative to diagnose IFN-induced depression early, evaluate whether this depression is associated with IFN-induced anemia or thyroid dysfunction, which can be corrected, and if necessary treat with antidepressants. IFN-induced depression is highly responsive to antidepressants with benefits occurring frequently at relatively low doses and after only a few weeks. Although SSRIs have mainly been studied, non-SSRIs appear to be effective also. Antidepressants have a number of risks and side effects that must be considered and may enter into the decision as to which antidepressant to choose. If IFN induces a depression in a patient with a bipolar disorder history, antidepressant treatment must include a mood stabilizer. In the case of vulnerable patients (e.g., those who have significant depressive symptoms prior to IFN or who have had an IFN-induced depression in the past) prophylactic antidepressant treatment appears to decrease the likelihood of having an IFN-induced depression. On the basis of known and effective treatment strategies, IFN-induced depression should not be an obstacle for continued treatment in most patient populations.

In humans, exposure to endotoxins or pro-inflammatory cytokines induces a number of neuropsychological symptoms collectively referred to as 'flu-like syndrome'. The degree of overlap between flu-like syndrome and major depressive disorder is considerable and a close linkage between these has been predicted to arise due to hypersecretion of endogenous pro-inflammatory cytokines and activation of the hypothalamic pituitary adrenal axis. In animals, exposure to pro-inflammatory cytokines or endotoxins induces a 'sickness behavior' syndrome that is analogous to flu-like symptoms observed in human patients. The goal of the current paper is to review evidence implicating endotoxin- or cytokine-induced sickness behavior as an animal model of depression, with an emphasis on reduced consumption of highly palatable substances as a defining feature.

The specificity and pharmacological characteristics of the effects of local administration of nicotine on cerebellar Purkinje cells in the rat were examined electrophysiologically. Local application of nicotine, whether by pressure-ejection or by iontophoresis, depressed the spontaneous discharge of Purkinje neurons in a reversible and dose-dependent manner. This action could not be mimicked by local application of vehicle alone. The inhibitory effects of (-)-nicotine were several-fold more potent than that of the (+)-enantiomer. Systemic administration of the ganglion blocker mecamylamine reliably and reproducibly antagonized the nicotine-induced inhibitions of Purkinje cells whereas nicotine-induced excitation of interneurons was not altered. Local pressure-ejection of mecamylamine also antagonized the inhibitory actions of nicotine, administered by iontophoresis. Since the central effects of nicotine on behavior are stereospecific and sensitive to mecamylamine, the data in this study further support the hypothesis that the actions of nicotine on Purkinje neurons are mediated by ganglionic-like receptors. These findings also suggest that the Purkinje cell may serve as a good cellular model for studies on central pharmacology of nicotine.

Spontaneous discharge rates of cerebellar Purkinje neurons were decreased in rats withdrawn from chronic treatment with alprazolam, diazepam, and lorazepam relative to discharge rates recorded from control rats. Prior treatment with 6-hydroxydopamine to deplete cerebellar levels of norepinephrine significantly reduced this effect of diazepam upon Purkinje cell firing rates. The data suggest that increased noradrenergic activity may be occurring during withdrawal from benzodiazepines.