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Nicotine produces robust stimulus effects that can be conditioned to form associations with reinforcing nondrug stimuli. We examine how established associations to the nicotine stimulus may be weakened via the overexpectation effect. In two experiments, we separately conditioned sucrose associations to the interoceptive nicotine stimulus (0.4 mg/kg, SC) and to a “noisy” exteroceptive contextual stimulus (oscillating houselight and white noise) via the discriminated goal-tracking task. Thereafter, we presented additional sucrose pairings with the nicotine and noisy stimuli, now in compound. Testing of the conditioned goal-tracking evoked by the nicotine and noisy stimuli in isolation—before versus after compound conditioning (Experiment 1 ) or between treatment and control groups (Experiment 2 )—demonstrated an attenuation of conditioned responding via the overexpectation effect. We suggest that applications of the overexpectation effect may provide some promise for treatments seeking to attenuate drug-evoked conditioned responses in situations where extinction-based interventions are not suitable.

Rationale There is an emerging body of evidence that implicates a crucial role of γ-aminobutyric acid subtype A (GABA A ) receptors in modulating the rewarding effects of a number of abused drugs. Modulation of GABA A receptors may therefore represent a novel drug-class independent mechanism for the development of abuse treatment pharmacotherapeutics. Objectives We tested the hypothesis that the GABA A receptor benzodiazepine-site (BDZ) negative modulator Ro15-4513 would reduce the reward-related effects of three pharmacologically dissimilar drugs; toluene vapor, d-methamphetamine, and diazepam using intracranial self-stimulation (ICSS) in mice. We also examined whether Ro15-4513 attenuated dopamine release produced by d-methamphetamine in an in vivo microdialysis procedure. Results Ro15-4513 abolished ICSS reward facilitation produced by all three abused drugs at Ro15-4513 doses which had no effect on ICSS when administered alone. In contrast, the BDZ antagonist flumazenil only attenuated the ICSS-facilitating effects of diazepam. Administration of the same dose of Ro15-4513 which abolished drug-facilitated ICSS produced a 58 % decrease in d-methamphetamine-stimulated dopamine in the nucleus accumbens of mice relative to d-methamphetamine alone. Conclusions These results demonstrate that negative modulation of GABA A receptors can produce profound reductions in reward-related effects of a diverse group of drugs that activate the mesolimbic reward pathway through different mechanisms. These data suggest that pharmacological modulation of GABA A receptors may represent a viable pathway for the development of drug abuse pharmacotherapies.

There is an emerging body of evidence that implicates a crucial role of [gamma]-aminobutyric acid subtype A (GABA.sub.A) receptors in modulating the rewarding effects of a number of abused drugs. Modulation of GABA.sub.A receptors may therefore represent a novel drug-class independent mechanism for the development of abuse treatment pharmacotherapeutics. We tested the hypothesis that the GABA.sub.A receptor benzodiazepine-site (BDZ) negative modulator Ro15-4513 would reduce the reward-related effects of three pharmacologically dissimilar drugs; toluene vapor, d-methamphetamine, and diazepam using intracranial self-stimulation (ICSS) in mice. We also examined whether Ro15-4513 attenuated dopamine release produced by d-methamphetamine in an in vivo microdialysis procedure. Ro15-4513 abolished ICSS reward facilitation produced by all three abused drugs at Ro15-4513 doses which had no effect on ICSS when administered alone. In contrast, the BDZ antagonist flumazenil only attenuated the ICSS-facilitating effects of diazepam. Administration of the same dose of Ro15-4513 which abolished drug-facilitated ICSS produced a 58 % decrease in d-methamphetamine-stimulated dopamine in the nucleus accumbens of mice relative to d-methamphetamine alone. These results demonstrate that negative modulation of GABA.sub.A receptors can produce profound reductions in reward-related effects of a diverse group of drugs that activate the mesolimbic reward pathway through different mechanisms. These data suggest that pharmacological modulation of GABA.sub.A receptors may represent a viable pathway for the development of drug abuse pharmacotherapies.

Rationale Despite widespread abuse, there are few validated methods to study the rewarding effects of inhalants. One model that may have utility for this purpose is intracranial self-stimulation (ICSS). Objectives This study aims to compare and contrast the ICSS reward-facilitating effects of abused inhalants to other classes of abused drugs. Compounds were examined using two different ICSS procedures in mice to determine the generality of each drug’s effects on ICSS and the sensitivity of the procedures. Methods Male C57BL/6J mice with electrodes implanted in the medial forebrain bundle were trained under a three-component rate-frequency as well as a progressive ratio (PR) ICSS procedure. The effects of nitrous oxide, toluene vapor, cocaine, and diazepam on ICSS were then examined. Results Concentrations of 1,360–2,900 parts per million (ppm) inhaled toluene vapor significantly facilitated ICSS in the rate-frequency procedure and 1,360 ppm increased PR breakpoint. A concentration of 40 % nitrous oxide facilitated ICSS in the rate-frequency procedure but reduced PR breakpoint. Doses of 3–18 mg/kg cocaine facilitated ICSS in the rate-frequency procedure, and 10 and 18 mg/kg increased PR breakpoint. Doses of 1 and 3 mg/kg diazepam facilitated ICSS in the rate-frequency procedure, and 3 mg/kg increased PR breakpoint. Conclusions The reinforcement-facilitating effect of toluene in ICSS is at least as great as diazepam. By contrast, nitrous oxide weakly enhances ICSS in only the rate-frequency procedure. The data suggest that the rate-frequency procedure may be more sensitive than the PR schedule to the reward-facilitating effects of abused inhalants.

Nicotine has both unconditioned and conditioned stimulus properties. Conditioned stimulus properties of nicotine may contribute to the tenacity of nicotine addiction. The purpose of this experiment was to use neurohistochemical analysis of rapidly developing c-Fos protein to elucidate neurobiological loci involved in the processing of nicotine as an interoceptive conditioned stimulus (CS). Rats were injected (SC) in an intermixed fashion with saline or nicotine (16 sessions of each) and placed in conditioning chambers where they were given one of the three conditions depending on group assignment: (a) nicotine paired 100% of the time with intermittent access to sucrose (nicotine-CS condition), (b) nicotine and saline each paired 50% of the time with sucrose (chamber-CS condition), or (c) no sucrose US control (CS-alone condition). Rats in the nicotine-CS condition acquired the discrimination as evidenced by goal-tracking (ie, increased dipper entries before initial sucrose delivery) only on nicotine sessions. The chamber-CS condition showed goal-tracking on all sessions; no goal-tracking was seen in the CS-alone condition. On the test day, rats in each condition were challenged with saline or nicotine and later assessed for c-Fos immunoreactivity. In concordance with previous reports, nicotine induced c-Fos expression in the majority of areas tested; however, learning-dependent expression was specific to dorsomedial and ventromedial regions of caudate-putamen (dmCPu, vmCPu). Only rats in the nicotine-CS condition, when challenged with nicotine, had higher c-Fos expression in the dmCPu and vmCPu. These results suggest that medial areas of CPu involved in excitatory conditioning with an appetitive nicotine CS.

Background Alzheimer’s disease (AD) is the most common type of dementia which results in debilitating memory loss as the disease advances. However, among older adults with AD, some may experience rapid cognitive decline while others may maintain a stable cognitive status for years. In addition to the amyloid plaques, tau tangles, and neuronal inflammation characteristic of AD, there is strong evidence of dysregulation in the peripheral immune system, including decreased naïve T cells and increased memory T cells among older adults with AD. It is currently unknown what underlies dysfunction in the peripheral immune system or whether changes in peripheral immune cells are associated with cognitive decline. Method We have performed unbiased metabolomics and characterized stool metabolites present in 35 AD versus 35 propensity matched healthy controls. In our ongoing work, we are longitudinally characterizing resting peripheral immune cell populations by flow cytometry and gut microbiome composition by metagenomic sequencing. Result We have identified an increase in the metabolites methionine sulfone (1.46 fold, p<0.05), homocysteine (1.67 fold, p<0.05), and cysteine (1.33 fold, p<0.05) in the stool of older adults with AD compared to controls. Among the population of AD patients experiencing cognitive decline, determined by increasing ADAS‐Cog score >6 points over one year (n = 7 declining vs n = 8 stable cognition), we have identified increases in the bacterial genes responsible for methionine production at the point of cognitive decline compared to previous timepoints and between patients with decline versus stable cognition. In accordance with the role of methionine in promoting immune cell proliferation and differentiation, we have compared the composition of peripheral immune cells among adults with declining versus stable cognition and identified a decrease in CD4+/CD62L+ naïve T cells (percent of CD4+ lymphocytes, stable 0.3055 vs declining 0.0955, p = 0.0042) and increased effector memory CD4+ T cells (percent of CD4+ lymphocytes, stable = 0.2375 vs declining = 0.4164, p = 0.0225). Conclusion This longitudinal clinical study identifies changes in stool metabolites and resting peripheral T cell populations in AD patients and among AD patients with cognitive decline. We propose that gut bacterial produced methionine acts to promote peripheral immune differentiation and dysfunction, leading to cognitive decline in AD.

Alzheimer's disease (AD) is the most common type of dementia which results in debilitating memory loss as the disease advances. However, among older adults with AD, some may experience rapid cognitive decline while others may maintain a stable cognitive status for years. In addition to the amyloid plaques, tau tangles, and neuronal inflammation characteristic of AD, there is strong evidence of dysregulation in the peripheral immune system, including decreased naïve T cells and increased memory T cells among older adults with AD. It is currently unknown what underlies dysfunction in the peripheral immune system or whether changes in peripheral immune cells are associated with cognitive decline. We have performed unbiased metabolomics and characterized stool metabolites present in 35 AD versus 35 propensity matched healthy controls. In our ongoing work, we are longitudinally characterizing resting peripheral immune cell populations by flow cytometry and gut microbiome composition by metagenomic sequencing. We have identified an increase in the metabolites methionine sulfone (1.46 fold, p<0.05), homocysteine (1.67 fold, p<0.05), and cysteine (1.33 fold, p<0.05) in the stool of older adults with AD compared to controls. Among the population of AD patients experiencing cognitive decline, determined by increasing ADAS-Cog score >6 points over one year (n = 7 declining vs n = 8 stable cognition), we have identified increases in the bacterial genes responsible for methionine production at the point of cognitive decline compared to previous timepoints and between patients with decline versus stable cognition. In accordance with the role of methionine in promoting immune cell proliferation and differentiation, we have compared the composition of peripheral immune cells among adults with declining versus stable cognition and identified a decrease in CD4 /CD62L naïve T cells (percent of CD4 lymphocytes, stable 0.3055 vs declining 0.0955, p = 0.0042) and increased effector memory CD4 T cells (percent of CD4 lymphocytes, stable = 0.2375 vs declining = 0.4164, p = 0.0225). This longitudinal clinical study identifies changes in stool metabolites and resting peripheral T cell populations in AD patients and among AD patients with cognitive decline. We propose that gut bacterial produced methionine acts to promote peripheral immune differentiation and dysfunction, leading to cognitive decline in AD.

PurposeThe prevalence of medical cannabis (MC) use in patients with cancer is growing, but questions about safety, efficacy, and dosing remain. Conducting randomized, controlled trials (RCTs) using state-sponsored MC programs is novel and could provide data needed to guide patients and providers.MethodsA pilot RCT of patients with stage IV cancer requiring opioids was conducted. Thirty patients were randomized 1:1 to early cannabis (EC, n = 15) versus delayed start cannabis (DC, n = 15). The EC group obtained 3 months (3 M) of MC through a state program at no charge, while the DC group received standard oncology care without MC for the first 3 M. Patients met with licensed pharmacists at one of two MC dispensaries to determine a suggested MC dosing, formulation, and route. Patients completed surveys on pain levels, opioid/MC use, side effects, and overall satisfaction with the study.ResultsInterest in the study was high as 36% of patients who met eligibility criteria ultimately enrolled. The estimated mean daily THC and CBD allotments at 3 M were 34 mg and 17 mg, respectively. A higher proportion of EC patients achieved a reduction in opioid use and improved pain control. No serious safety issues were reported, and patients reported high satisfaction.ConclusionConducting RCTs using a state cannabis program is feasible. The addition of MC to standard oncology care was well-tolerated and may lead to improved pain control and lower opioid requirements. Conducting larger RCTs with MC in state-sponsored programs may guide oncology providers on how to safely and effectively incorporate MC for interested patients.