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Sacks S.,National Development and Research Institutes Inc. | Chaple M.,National Development and Research Institutes Inc. | Sirikantraporn J.,Drug Abuse Sciences | Sacks J.Y.,Inc. NDRI | And 2 more authors.
Journal of Substance Abuse Treatment | Year: 2013

The paper reports on the capability of New York State (NYS) outpatient programs to provide integrated services for co-occurring disorders (COD). Assessments of 447 outpatient clinics, using two dual diagnosis capability indices (one used in addiction settings, the other in mental health settings), produced an overall score of 2.70, interpreted to position NYS clinics closer to "capable" (3.0=Dual Diagnosis Capable) than to "basic" (1.0=Alcohol [Mental Health] Only Services). "Assessment" and "Staffing" received the highest scores; i.e., clients with COD were usually identified, and staff (with some additional training and supervision) could treat both disorders effectively. While programs were generally prepared for clients with COD (e.g., welcoming such clients into the program, employing staff with competencies in both disorders, and having established routine screening and assessment to identify COD), results showed that the actual delivery of effective treatment was less satisfactory. The project demonstrated that COD capability can be assessed system-wide, using direct observation. © 2013 Elsevier Inc.

Gould H.J.,Health science Center | Gould H.J.,Drug Abuse Sciences | Paul D.,Health science Center | Paul D.,Drug Abuse Sciences
Pharmacological Research | Year: 2015

Recently, the U.S. Food and Drug Administration (FDA) approved Zohydro®, an extended release formulation of the opioid analgesic hydrocodone that contains no acetaminophen. This approval was against the recommendation of the FDA's Expert Panel. Subsequently, both chronic pain advocates and anti-drug abuse advocates have steadfastly expressed their support of, or astonishment at this decision. Here, we review the pharmacokinetics, pharmacodynamics, safety and abuse liability of this hydrocodone formulation and how it relates to the Expert Panel's opinion and the FDA decision. We discuss the important issues, risk mitigation, potential use of abuse deterrents, and how the different viewpoints of the Expert Panel and FDA decision makers resulted in the approval and subsequent controversy. © 2014 Elsevier Ltd. All rights reserved.

Winhusen T.M.,University of Cincinnati | Kropp F.,University of Cincinnati | Lindblad R.,EMMES Corporation | Douaihy A.,Addiction Medicine Services | And 11 more authors.
Journal of Clinical Psychiatry | Year: 2014

Objective: To evaluate the potential efficacy of buspirone as a relapse-prevention treatment for cocaine dependence. Method: A randomized, double-blind, placebo-controlled, 16-week pilot trial was conducted at 6 clinical sites between August 2012 and June 2013. Adult crack cocaine users meeting DSM-IV-TR criteria for current cocaine dependence who were scheduled to be in inpatient/residential substance use disorder (SUD) treatment for 12-19 days when randomized and planning to enroll in local outpatient treatment through the end of the active treatment phase were randomized to buspirone titrated to 60 mg/d (n = 35) or placebo (n = 27). All participants received psychosocial treatment as usually provided by the SUD treatment programs in which they were enrolled. Outcome measures included maximum days of continuous cocaine abstinence (primary), proportion of cocaine use days, and days to first cocaine use during the outpatient treatment phase (study weeks 4-15) as assessed by self-report and urine drug screens. Results: There were no significant treatment effects on maximum continuous days of cocaine abstinence or days to first cocaine use. In the female participants (n = 23), there was a significant treatment-by-time interaction effect (X21 = 15.26, P < .0001), reflecting an increase in cocaine use by those receiving buspirone, relative to placebo, early in the outpatient treatment phase. A similar effect was not detected in the male participants (n = 39; X21 = 0.14, P = .70). Conclusions: The results suggest that buspirone is unlikely to have a beneficial effect on preventing relapse to cocaine use and that buspirone for cocainedependent women may worsen their cocaine use outcomes. Trial Registration: identifier: NCT01641159 © Copyright 2014 Physicians Postgraduate Press, Inc.

PubMed | Drug Abuse Sciences and Shanghai University
Type: | Journal: Scientific reports | Year: 2016

Combination therapy is a popular treatment for various diseases in the clinic. Among the successful cases, Traditional Chinese Medicinal (TCM) formulae can achieve synergistic effects in therapeutics and antagonistic effects in toxicity. However, characterizing the underlying molecular synergisms for the combination of drugs remains a challenging task due to high experimental expenses and complication of multicomponent herbal medicines. To understand the rationale of combination therapy, we investigated Sini Decoction, a well-known TCM consisting of three herbs, as a model. We applied our established diseases-specific chemogenomics databases and our systems pharmacology approach TargetHunter to explore synergistic mechanisms of Sini Decoction in the treatment of cardiovascular diseases. (1) We constructed a cardiovascular diseases-specific chemogenomics database, including drugs, target proteins, chemicals, and associated pathways. (2) Using our implemented chemoinformatics tools, we mapped out the interaction networks between active ingredients of Sini Decoction and their targets. (3) We also in silico predicted and experimentally confirmed that the side effects can be alleviated by the combination of the components. Overall, our results demonstrated that our cardiovascular disease-specific database was successfully applied for systems pharmacology analysis of a complicated herbal formula in predicting molecular synergetic mechanisms, and led to better understanding of a combinational therapy.

Ketchum M.J.,Health science Center | Weyand T.G.,Health science Center | Weed P.F.,Health science Center | Winsauer P.J.,Health science Center | Winsauer P.J.,Drug Abuse Sciences
Hippocampus | Year: 2016

Learning is believed to be reflected in the activity of the hippocampus. However, neural correlates of learning have been difficult to characterize because hippocampal activity is integrated with ongoing behavior. To address this issue, male rats (n=5) implanted with electrodes (n=14) in the CA1 subfield responded during two tasks within a single test session. In one task, subjects acquired a new 3-response sequence (acquisition), whereas in the other task, subjects completed a well-rehearsed 3-response sequence (performance). Both tasks though could be completed using an identical response topography and used the same sensory stimuli and schedule of reinforcement. More important, comparing neural patterns during sequence acquisition to those during sequence performance allows for a subtractive approach whereby activity associated with learning could potentially be dissociated from the activity associated with ongoing behavior. At sites where CA1 activity was closely associated with behavior, the patterns of activity were differentially modulated by key position and the serial position of a response within the schedule of reinforcement. Temporal shifts between peak activity and responding on particular keys also occurred during sequence acquisition, but not during sequence performance. Ethanol disrupted CA1 activity while producing rate-decreasing effects in both tasks and error-increasing effects that were more selective for sequence acquisition than sequence performance. Ethanol also produced alterations in the magnitude of modulations and temporal pattern of CA1 activity, although these effects were not selective for sequence acquisition. Similar to ethanol, hippocampal micro-stimulation decreased response rate in both tasks and selectively increased the percentage of errors during sequence acquisition, and provided a more direct demonstration of hippocampal involvement during sequence acquisition. Together, these results strongly support the notion that ethanol disrupts sequence acquisition by disrupting hippocampal activity and that the hippocampus is necessary for the conditioned associations required for sequence acquisition. © 2016 Wiley Periodicals, Inc.

Winsauer P.J.,Health science Center | Winsauer P.J.,Drug Abuse Sciences | Sutton J.L.,Health science Center
Pharmacology Biochemistry and Behavior | Year: 2014

This study examined whether chronic Δ9-THC during early adulthood would produce the same hormonally-dependent deficits in learning that are produced by chronic Δ9-THC during adolescence. To do this, either sham-operated (intact) or ovariectomized (OVX) female rats received daily saline or 5.6 mg/kg of Δ9-THC i.p. for 40 days during early adulthood. Following chronic administration, and a drug-free period to train both a learning and performance task, acute dose-effect curves for Δ9-THC (0.56-10 mg/kg) were established in each of the four groups (intact/saline, intact/THC, OVX/saline and OVX/THC). The dependent measures of responding under the learning and performance tasks were the overall response rate and the percentage of errors. Although the history of OVX and chronic Δ9-THC in early adulthood did not significantly affect non-drug or baseline behavior under the tasks, acute administration of Δ9-THC produced both rate-decreasing and error-increasing effects on learning and performance behavior, and these effects were dependent on their hormone condition. More specifically, both intact groups were more sensitive to the rate-decreasing and error-increasing effects of Δ9-THC than the OVX groups irrespective of chronic Δ9-THC administration, as there was no significant main effect of chronic treatment and no significant interaction between chronic treatment (saline or Δ9-THC) and the dose of Δ9-THC administered as an adult. Post mortem examination of 10 brain regions also indicated there were significant differences in agonist-stimulated GTPγS binding across brain regions, but no significant effects of chronic treatment and no significant interaction between the chronic treatment and cannabinoid signaling. Thus, acute Δ9-THC produced hormonally-dependent effects on learning and performance behavior, but a period of chronic administration during early adulthood did not alter these effects significantly, which is contrary to what we and others have shown for chronic administration during adolescence. © 2013 Elsevier Inc.

Kim A.,Scripps Research Institute | Zamora-Martinez E.R.,Scripps Research Institute | Edwards S.,Drug Abuse Sciences | Mandyam C.D.,Scripps Research Institute | Mandyam C.D.,University of California at San Diego
Brain Structure and Function | Year: 2014

In rodents, chronic intermittent ethanol vapor exposure (CIE) produces alcohol dependence, alters the activity of pyramidal neurons and decreases the number of glial progenitors in the medial prefrontal cortex (mPFC). Adult male Wistar rats were exposed to CIE and were injected with mitotic markers to label and phenotype proliferating cells to test the hypothesis that CIE produces concurrent alterations in the structure of pyramidal neurons and the cell cycle kinetics and developmental stages of glial progenitors in the mPFC. Medial prefrontal cortical tissue was processed for Golgi-Cox staining, immunohistochemistry and Western blotting analysis. CIE increased dendritic arborization and spine densities within basal and apical dendrites of pyramidal neurons via aberrant reorganization of actin cytoskeleton-associated molecules. CIE concomitantly increased the expression of total NR2B subunits without affecting phosphorylation of NR2B at Tyr-1472 or levels of PSD-95. CIE reduced the length of S-phase of the cell cycle of glial progenitors and reduced proliferation and differentiation of progenitors into bHLH transcription factor Olig2-expressing premyelinating oligodendrocyte progenitor cells (OPCs). CIE also produced a corresponding hyperphosphorylation of Olig2, and reduced expression of myelin basic protein. Our findings demonstrate that CIE-induced alterations in OPCs and myelin-related proteins are associated with profound alterations in the structure of pyramidal neurons. In sum, our results not only provide evidence that alcohol dependence leads to pathological changes in the mPFC, which may in part define a cellular basis for cognitive impairments associated with alcoholism, but also show dependence-associated morphological changes in the PFC at the single neuron level. © 2014 Springer-Verlag Berlin Heidelberg.

PubMed | Drug Abuse Sciences
Type: | Journal: The international journal of neuropsychopharmacology | Year: 2016

Studies have shown the involvement of cannabinoid (CB) receptors in the behavioral and neurobiological effects of psychostimulants. Most of these studies have focused on the role of CB1 receptors in the psychostimulant effects of cocaine, while very few have investigated the respective role of CB2 receptors. Further studies are warranted to elucidate the extent of CB receptor involvement in the expression of cocaine-induced effects.The role of CB1 and CB2 receptors in the rewarding and motor properties of cocaine was assessed in conditioned place preference, conditioned motor activity, and open field activity in rats.The CB1 receptor antagonist rimonabant (3 mg/kg) decreased the acquisition and the expression of conditioned place preference induced by cocaine (20 mg/kg). Rimonabant inhibited cocaine-elicited conditioned motor activity when administered during the expression of cocaine-induced conditioned place preference. Rimonabant decreased ambulatory and vertical activity induced by cocaine. The CB2 receptor agonist JWH-133 (10 mg/kg) decreased the acquisition and the expression of cocaine-induced conditioned place preference. JWH-133 inhibited cocaine-elicited conditioned motor activity when administered during the acquisition and the expression of cocaine-induced conditioned place preference. JWH-133 decreased ambulatory activity and abolished vertical activity induced by cocaine. The effects of JWH-133 on cocaine conditioned and stimulated responses were abolished when the CB2 receptor antagonist/inverse agonist AM630 (5 mg/kg) was preadministered.Cannabinoid CB1 and CB2 receptors modulate cocaine-induced rewarding behavior and appear to have opposite roles in the regulation of cocaines reinforcing and psychomotor effects.

PubMed | Drug Abuse Sciences
Type: | Journal: Forensic science international | Year: 2016

This paper presents an overview of a set of amphetamines and cannabinoids tests performed on head hair samples from the Medico-Legal sector at the Madrid Department of the Spanish National Institute of Toxicology and Forensic Sciences during the years 2013 and 2014. The hair samples were tested for five stimulant phenylalkylamine derivatives -amphetamine (AP), methamphetamine (MA), 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxy-amphetamine (MDA), and 3,4-methylenedioxy-N-ethylamphetamine (MDEA)- and/or two cannabinoids-(9)-tetrahydrocannabinol (THC) and cannabinol (CBN)- by gas chromatography equipped with mass spectrometry detection in selected-ion monitoring mode, applying a method accredited to ISO/IEC 17025 standards. The test results were interpreted according to the confirmation cut-offs proposed by the Society of Hair Testing (SoHT) to identify chronic drug use. The ratios of positive results were studied in relation to gender, age, hair colour, dyeing and length of the tested samples to assess the independence from these variables or the association with them. Low, medium and high ranges of concentration were also estimated for each drug. 21.94% of the 2954 hair samples tested for phenylalkylamine derivatives were positive for one or more substances. 16.38% of the samples were positive for AP, 12.09% for MDMA and only 0.44% for MA. 6.60% of the tested samples were positive for AP/MDMA combination. A total of 3178 samples were tested for cannabinoids, resulting in 53.40% positive for THC and CBN. Simultaneous tests for phenylalkylamine derivatives and cannabinoids were performed in 2931 of the samples; 14.94% of them were positive for THC, CBN, and one or more amphetamines. According to the results from the statistical analysis, the use of THC and MDMA vary with age and gender among the Medico-Legal sector in an extended area of Spain, while the use of AP appears to be independent of these variables. On the other hand, the results of THC in hair could be influenced by the length of the tested segment; therefore, a consensus regarding the hair length between 3.0 and 5.5cm for THC testing should be reached.

PubMed | Drug Abuse Sciences
Type: Journal Article | Journal: The Journal of pharmacology and experimental therapeutics | Year: 2016

The identification of sigma receptor (R) subtypes has been based on radioligand binding and, despite progress with 1R cellular function, less is known about R subtype functions in vivo. Recent findings that cocaine self administration experience will trigger R agonist self administration was used in this study to assess the in vivo receptor subtype specificity of the agonists (+)-pentazocine, PRE-084 [2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate hydrochloride], and 1,3-di-o-tolylguanidine (DTG) and several novel putative R antagonists. Radioligand binding studies determined in vitro R selectivity of the novel compounds, which were subsequently studied for self administration and antagonism of cocaine, (+)-pentazocine, PRE-084, or DTG self administration. Across the dose ranges studied, none of the novel compounds were self administered, nor did they alter cocaine self administration. All compounds blocked DTG self administration, with a subset also blocking (+)-pentazocine and PRE-084 self administration. The most selective of the compounds in binding 1Rs blocked cocaine self administration when combined with a dopamine transport inhibitor, either methylphenidate or nomifensine. These drug combinations did not decrease rates of responding maintained by food reinforcement. In contrast, the most selective of the compounds in binding 2Rs had no effect on cocaine self administration in combination with either dopamine transport inhibitor. Thus, these results identify subtype-specific in vivo antagonists, and the utility of R agonist substitution for cocaine self administration as an assay capable of distinguishing R subtype selectivity in vivo. These results further suggest that effectiveness of dual R antagonism and dopamine transport inhibition in blocking cocaine self administration is specific for 1Rs and further support this dual targeting approach to development of cocaine antagonists.

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