- Differential executive functioning in young adulthood as a function of experienced child abuse. [Journal Article]
- IJInt J Psychophysiol 2018 Dec 12
- CONCLUSIONS: Individuals that have been abused as children must use significantly more mental effort to complete executive functioning tasks as compared to their non-abused counterparts. Increased neurological effort could be used to explain poor decision-making skills that are common within the population.
- Role of mu-opioid agonist efficacy on antinociceptive interactions between mu agonists and the nociceptin opioid peptide agonist Ro 64-6198 in rhesus monkeys. [Journal Article]
- EJEur J Pharmacol 2018 Dec 12
- Mu-opioid receptor agonists are clinically effective analgesics, but also produce undesirable effects that limit their clinical utility. The nociceptin opioid peptide (NOP) receptor system also modul...
Mu-opioid receptor agonists are clinically effective analgesics, but also produce undesirable effects that limit their clinical utility. The nociceptin opioid peptide (NOP) receptor system also modulates nociception, and NOP agonists might be useful adjuncts to enhance the analgesic effects or attenuate the undesirable effects of mu-opioid agonists. The present study determined behavioral interactions between the NOP agonist (-)-Ro 64-6198 and mu-opioid ligands that vary in mu-opioid receptor efficacy (17-cyclopropylmethyl-3,14β-dihyroxy-4,5α-epoxy-6α-[(3 ́-isoquinolyl)acetamindo]morphinan (NAQ) < buprenorphine < nalbuphine < morphine = oxycodone < methadone) in male rhesus monkeys. For comparison, Ro 64-6198 interactions were also examined with the kappa-opioid receptor agonist nalfurafine. Each opioid ligand was examined alone and following fixed-dose Ro 64-6198 pretreatments in assays of thermal nociception (n=3-4) and schedule-controlled responding (n=3). Ro 64-6198 alone failed to produce significant antinociception up to doses (0.32mg/kg, IM) that significantly decreased rates of responding. All opioid ligands, except NAQ and nalfurafine, produced dose- and thermal intensity-dependent antinociception. Ro 64-6198 enhanced the antinociceptive potency of buprenorphine, nalbuphine, methadone, and nalfurafine. Ro 64-6198 enhancement of nalbuphine antinociception was NOP antagonist SB-612111 reversible and occurred under a narrow range of dose and time conditions. All opioid ligands, except NAQ and buprenorphine, produced dose-dependent decreases in rates of responding. Ro 64-6198 did not significantly alter mu-opioid ligand rate-decreasing effects. Although these results suggest that NOP agonists may selectively enhance the antinociceptive vs. rate-suppressant effects of some mu-opioid agonists, this small enhancement occurred under a narrow range of conditions dampening enthusiasm for NOP agonists as candidate "opioid-sparing" adjuncts.
- A novel role for E2F3b in regulating cocaine action in the prefrontal cortex. [Journal Article]
- NNeuropsychopharmacology 2018 Dec 14
- Drug abuse is a multifaceted disorder that involves maladaptive decision making. Long-lasting changes in the addicted brain are mediated by a complex circuit of brain reward regions. The prefrontal c...
Drug abuse is a multifaceted disorder that involves maladaptive decision making. Long-lasting changes in the addicted brain are mediated by a complex circuit of brain reward regions. The prefrontal cortex (PFC) is one region in which chronic drug exposure changes expression and function of upstream transcriptional regulators to alter drug responses and aspects of the addicted phenotype. We reported recently that the transcription factor E2F3a is a critical mediator of cocaine responses in the nucleus accumbens. E2F3a is one of two splice variants of the E2f3 gene; the other is E2F3b. Another recent study predicted E2F3 as an upstream regulator of the transcriptional response to cocaine self-administration in PFC. Based on previous findings that E2F3a and E2F3b have divergent regulatory roles, we set out to study the putative transcriptional role of these transcripts in PFC in the context of repeated I.P. cocaine exposure. We implemented viral-mediated isoform-specific gene manipulation, RNA-sequencing, advanced bioinformatics analyses, and animal behavior to determine how E2F3a and E2F3b contribute to persistent cocaine-induced transcriptional changes in PFC. We show that E2F3b, but not E2F3a, in PFC is critical for cocaine locomotor and place preference behaviors. Interestingly, RNA-seq of PFC following E2f3b overexpression or I.P. cocaine exposure showed very different effects on expression levels of differentially expressed genes. However, we found that E2F3b drives a similar transcriptomic pattern to that of cocaine SA with overlapping upstream regulators and downstream pathways predicted. These findings reveal a novel transcriptional mechanism in PFC that controls behavioral and molecular responses to cocaine.
- Synthetic cannabinoid hydroxypentyl metabolites retain efficacy at human cannabinoid receptors. [Journal Article]
- JPJ Pharmacol Exp Ther 2018 Dec 14
- Synthetic cannabinoids (SCs) are novel psychoactive substances that are easily acquired, widely abused as a substitute for cannabis, and associated with cardiotoxicity and seizures. While the structu...
Synthetic cannabinoids (SCs) are novel psychoactive substances that are easily acquired, widely abused as a substitute for cannabis, and associated with cardiotoxicity and seizures. While the structures of these compounds are based upon scaffolds with known affinity and efficacy at the human cannabinoid type-1 receptor (hCB1), upon ingestion or inhalation they can be metabolized to multiple chemical entities of unknown pharmacological activity. A large proportion of these metabolites are hydroxylated on the pentyl chain, a key substituent that determines receptor affinity and selectivity. Thus, the pharmacology of SC metabolites may be an important component in understanding the in vivo effects of SCs. We examined nine SCs (AB-PINACA, 5F-AB-PINACA, ADB/MDMB-PINACA, 5F-ADB, 5F-CUMYL-PINACA, AMB-PINACA, 5F-AMB, APINACA, and 5F-APINACA) and their hydroxypentyl (either 4-OH or 5-OH) metabolites in [3H]CP55,940 receptor binding and the [35S]GTPγS functional assay to determine the extent to which these metabolites retain activity at cannabinoid receptors. All of the SCs tested exhibited high affinity (<10 nM) and efficacy for hCB1 and hCB2 The majority of the hydroxypentyl metabolites retained full efficacy at hCB1 and hCB2, albeit with reduced affinity and potency, and exhibited greater binding selectivity for hCB2 These data suggest that phase I metabolites may be contributing to the in vivo pharmacology and toxicology of abused SCs. Considering this and previous reports demonstrating that metabolites retain efficacy at the hCB1 receptor, the full pharmacokinetic profile of the parent compounds and their metabolites needs to be considered in terms of the pharmacological effects and time course associated with these drugs.
- Recent Changes in Drug Abuse Scenarios: The New/Novel Psychoactive Substances (NPS) Phenomenon. [Editorial]
- BSBrain Sci 2018 Dec 13; 8(12)
- Over the last decade, the emergence of a vast range of new/novel/emerging psychoactive substances (NPS) has progressively changed drug market scenarios, which have shifted from the 'street' to a 'vir...
Over the last decade, the emergence of a vast range of new/novel/emerging psychoactive substances (NPS) has progressively changed drug market scenarios, which have shifted from the 'street' to a 'virtual'/online environment. [...].
- Harm caused by "Vegetamin": From the viewpoint of drug abuse and dependence. [Journal Article]
- CKChudoku Kenkyu 2017; 30(1):18-23
- Erratum to "When DAWN went dark: Can the Nationwide Emergency Department Sample (NEDS) fill the surveillance gap left by the discontinued Drug Abuse Warning Network (DAWN)?" [Drug Alcohol Depend. (2018) 201-207]. [Published Erratum]
- DADrug Alcohol Depend 2018 Dec 11; 194:526
- Lacking evidence for the association between frequent urine drug screening and health outcomes of persons on opioid agonist therapy. [Journal Article]
- IJInt J Drug Policy 2018 Dec 11; 64:30-33
- CONCLUSIONS: Our review identified an urgent gap in research evidence underpinning an area of clinical importance and that is routinely reported by patients as an area of concern.
- Promoting opioid overdose prevention and recovery: An exploratory study of an innovative intervention model to address opioid abuse. [Journal Article]
- IJInt J Drug Policy 2018 Dec 11; 64:21-29
- CONCLUSIONS: Results underscore the effort needed to integrate this important model within EDs as part of a multi-level approach to address opioid misuse. The identified challenges led to statewide strategic planning and areas for further development. OORP is a promising intervention that might increase the number of individuals suffering with opioid disorders linked to peer support, treatment and recovery.
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- Distinct regulation pattern of Egr-1, BDNF and Arc during morphine-withdrawal conditioned place aversion paradigm: role of glucocorticoids. [Journal Article]
- BBBehav Brain Res 2018 Dec 11
- Negative affective aspects of opiate abstinence contribute to the persistence of substance abuse. Importantly, interconnected brain areas involved in aversive motivational processes, such as the vent...
Negative affective aspects of opiate abstinence contribute to the persistence of substance abuse. Importantly, interconnected brain areas involved in aversive motivational processes, such as the ventral tegmental area (VTA) and medial prefrontal cortex (mPFC), become activated when animals are confined to withdrawal-paired environments. In the present study, place aversion was elicited in sham and adrenalectomized (ADX) animals by conditioned naloxone-precipitated drug withdrawal following exposure to chronic morphine. qPCR was employed to detect the expression of brain derived neurotrophic factor (Bdnf) and the immediate early genes (IEG) early growth response 1 (Egr-1) and activity-regulated cytoskeletal-associated protein (Arc) mRNAs in the VTA and mPFC at different time points of the conditioned place aversion (CPA) paradigm: after the conditioning phase and after the test phase. Sham + morphine rats exhibited robust CPA, which was impaired in ADX + morphine animals. Egr-1 and Arc were induced in the VTA and mPFC after morphine-withdrawal conditioning phase. Furthermore, Bdnf expression was enhanced in the VTA during the test phase. Bdnf induction seemed to be glucocorticoid-dependent, given that was correlated with HPA axis function and was not observed in morphine-dependent ADX animals. In addition, BDNF regulation and function was opposite in the VTA and mPFC during aversive-withdrawal memory retrieval. Our results suggest that IEGs and BDNF in these brain regions may play key roles in mediating the negative motivational component of opiate withdrawal.