Psychopharmacology
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Randomized Controlled Trial
Opioid antagonism enhances marijuana's effects in heavy marijuana smokers.
Studies in laboratory animals strongly suggest reciprocal modulation of the opioidergic and endocannabinoid systems, a relationship that has not been demonstrated in humans. This study sought to clarify this interaction by assessing how a range of naltrexone doses altered the subjective, cognitive, and cardiovascular effects of marijuana. ⋯ In heavy marijuana smokers opioid-receptor blockade enhanced the subjective and cardiovascular effects of marijuana, suggesting that endogenous opioids dampen cannabinoid effects in this population. These findings demonstrate that a broad range of clinically used doses of naltrexone potentially increases the abuse liability and cardiovascular risks of cannabinoids.
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Randomized Controlled Trial
Human abuse liability assessment of oxycodone combined with ultra-low-dose naltrexone.
Prescription opioid abuse has risen dramatically in the United States as clinicians have increased opioid prescribing for alleviation of both acute and chronic pain. Opioid analgesics with decreased risk for abuse are needed. ⋯ The addition of ultra-low-dose NTX to OXY did not decrease abuse liability of acutely administered OXY in experienced opioid abusers.
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Social stress has been linked to several neuropsychiatric diseases, including depression, which is a debilitating disease that has genetic, environmental, and epigenetic underpinnings. ⋯ These results indicate that social defeat induces several long-lasting depressive-like behaviors in rats and induces a significant, short-lived increase in H3 acetylation in the hippocampus, although the underlying mechanism behind this change warrants further investigation.
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Individual differences in impulsive decision-making may be critical determinants of vulnerability to impulse control disorders and substance abuse, yet little is known of their biological or behavioural basis. The orbitofrontal cortex (OFC) has been heavily implicated in the regulation of impulsive decision-making. However, lesions of the OFC in rats have both increased and decreased impulsivity in delay-discounting paradigms, where impulsive choice is defined as the selection of small immediate over larger delayed rewards. ⋯ Providing explicit environmental cues to signal the delay-to-reinforcement appears to change the way in which the OFC is recruited in the decision-making process in a baseline-dependent fashion. This change may reflect activation of the dopamine system, as intra-OFC infusions of dopamine receptor antagonists increased impulsive choice but only when the delay was cued.
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Selective, centrally acting kappa opioid agonists produce antinociception in a wide range of preclinical assays, but these compounds perform poorly as analgesics in humans. This discrepancy may be related to the behavioral depressant effects of kappa agonists. Kappa antagonists do not typically produce antinociception, but they produce antidepressant-like effects in some preclinical assays. ⋯ These results support the hypothesis that prodepressant effects of kappa agonists may limit their clinical utility as analgesics. These results do not support the use of kappa antagonists to treat depressant effects of pain. These findings illustrate the potential value of using complementary assays of pain-stimulated and pain-depressed behaviors for preclinical evaluation of candidate analgesics.