Effects of 7-day repeated treatment with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in male rhesus monkeys

Background Preclinical drug vs. food choice is an emerging group of drug self-administration procedures that have shown predictive validity to clinical drug addiction. Emerging data suggest that serotonin (5-HT)2A receptors modulate mesolimbic dopamine function, such that 5-HT2A antagonists blunt the abuse-related neurochemical effects of monoamine transporter substrates, such as amphetamine or methamphetamine. Whether subchronic 5-HT2A antagonist treatment attenuates methamphetamine reinforcement in any preclinical drug self-administration procedure is unknown. The study aim was therefore to determine 7-day treatment effects with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in monkeys. Methods Behavior was maintained under a concurrent schedule of food delivery (1 g pellets, fixed-ratio 100 schedule) and intravenous methamphetamine injections (0–0.32 mg/kg/injection, fixed-ratio 10 schedule) in male rhesus monkeys (n = 3). Methamphetamine choice dose-effect functions were determined daily before and during 7-day repeated pimavanserin (1.0–10 mg/kg/day, intramuscular) treatment periods. Results Under control conditions, increasing methamphetamine doses resulted in a corresponding increase in methamphetamine vs. food choice. Repeated pimavanserin administration failed to attenuate methamphetamine choice and produce a reciprocal increase in food choice in any monkey up to doses (3.2–10 mg/kg) that suppressed rates of operant responding primarily during components where behavior was maintained by food pellets. Conclusions Repeated 5-HT2A receptor inverse agonist/antagonist treatment did not attenuate methamphetamine reinforcement under a concurrent schedule of intravenous methamphetamine and food presentation in nonhuman primates. Overall, these results do not support the therapeutic potential of 5-HT2A inverse agonists/antagonists as candidate medications for methamphetamine addiction

Regulating Eternal Inflation II: The Great Divide

In a previous paper, two of the authors presented a "regulated" picture of eternal inflation. This picture both suggested and drew support from a conjectured discontinuity in the amplitude for tunneling from positive to negative vacuum energy, as the positive vacuum energy was sent to zero; analytic and numerical arguments supporting this conjecture were given. Here we show that this conjecture is false, but in an interesting way. There are no cases where tunneling amplitudes are discontinuous at vanishing cosmological constant; rather, the space of potentials separates into two regions. In one region decay is strongly suppressed, and the proposed picture of eternal inflation remains viable; sending the (false) vacuum energy to zero in this region results in an absolutely stable asymptotically flat space. In the other region, we argue that the space-time at vanishing cosmological constant is unstable, but not asymptotically Minkowski. The consequences of our results for theories of supersymmetry breaking are unchanged.Comment: JHEP3, 19 Pages, 7 Figure

Family and Peer Influences on Substance Attitudes and Use among Juvenile Justice-Involved Youth

Juvenile justice-involved youth experience high rates of substance use, which is concerning given associated negative consequences, including health and functional deficits. Family and peer factors are associated with a high risk of substance use among justice-involved youth. It is hypothesized that this risk process operates through pro-drug attitudes. However, limited research has been conducted on the mechanisms through which family and peer factors increase risk for substance use among juvenile justice involved youth. The current study examined both the direct and indirect effects of family and peer substance use on youth's substance use (alcohol and illicit drug use). We also examined whether this relationship differs by race. 226 detained youth (81.9% male; 74.3% Black) were recruited from an urban county in the Midwest and completed a clinical interview and substance use assessment battery. A direct effect of family/peer risk on illicit drug use was found for all youth, though the effect was stronger among White youth. Results also supported the indirect effect pathway from family/peer risk to both illicit drug use and alcohol use through pro-drug attitudes. This pathway did not vary by race. These findings suggest that interventions should focus on targeting both family/peer risk and pro-drug attitudes to reduce substance use. Given the racial difference in the direct effect of family/peer risk on illicit drug use, there may be other factors that influence risk more strongly for White youth, which warrants further investigation

Reconnecting with Joseph and Augusta Dejerine:100 years on

Joseph Dejerine passed away on 28 February 1917 in the midst of a world at war. One hundred years later we celebrate the legacy of this pioneer in neuroscience. In 1895, Joseph Jules Dejerine published the first volume of the seminal work, Anatomie des centres nerveux; volume 2 was published in 1901. In a major section of this tome (vol. 1 pp. 749–80), Joseph Dejerine and his wife and long-term collaborator, Augusta Dejerine-Klumpke, produced a treatise on the white matter pathways of the brain, composed of anatomical descriptions of meticulous detail and beautiful illustration (drawn by H. Gillet) that reflected a combination of the most advanced methodologies of the day and a review of leading neuroscientific research. We have selected and focused this specific output (which is provided for the first time as an English translation in the Supplementary material) from the many that the Dejerines published because its ideas and findings continue to be of relevance to modern neuroscience researchers today; especially those with an interest in connectional anatomy.peer-reviewe

The Trouble with de Sitter Space

In this paper we assume the de Sitter Space version of Black Hole Complementarity which states that a single causal patch of de Sitter space is described as an isolated finite temperature cavity bounded by a horizon which allows no loss of information. We discuss the how the symmetries of de Sitter space should be implemented. Then we prove a no go theorem for implementing the symmetries if the entropy is finite. Thus we must either give up the finiteness of the de Sitter entropy or the exact symmetry of the classical space. Each has interesting implications for the very long time behavior. We argue that the lifetime of a de Sitter phase can not exceed the Poincare recurrence time. This is supported by recent results of Kachru, Kallosh, Linde and Trivedi.Comment: 15 pages, 1 figure. v2: added fifth section with comments on long time stability of de Sitter space, in which we argue that the lifetime can not exceed the Poincare recurrence time. v3: corrected a minor error in the appendi

Out of equilibrium: understanding cosmological evolution to lower-entropy states

Despite the importance of the Second Law of Thermodynamics, it is not absolute. Statistical mechanics implies that, given sufficient time, systems near equilibrium will spontaneously fluctuate into lower-entropy states, locally reversing the thermodynamic arrow of time. We study the time development of such fluctuations, especially the very large fluctuations relevant to cosmology. Under fairly general assumptions, the most likely history of a fluctuation out of equilibrium is simply the CPT conjugate of the most likely way a system relaxes back to equilibrium. We use this idea to elucidate the spacetime structure of various fluctuations in (stable and metastable) de Sitter space and thermal anti-de Sitter space.Comment: 27 pages, 11 figure

Stress as a Risk Factor for Substance Use Disorders: A Mini-Review of Molecular Mediators

The extant literature supports the role of stress in enhancing the susceptibility of drug abuse progressing to a substance use disorder diagnosis. However, the molecular mediators by which stress enhances the progression from cocaine abuse to cocaine use disorder via the mesolimbic pathway remain elusive. In this mini-review article, we highlight three mechanisms by which glucocorticoids (GCs) and the dopaminergic system interact. First, GCs upregulate tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine (DA) synthesis. Second, GCs downregulate monoamine-oxidase (MAO), an enzyme responsible for DA removal. Lastly, GCs are hypothesized to decrease DA reuptake, subsequently increasing synaptic DA. Based on these interactions, we review preclinical literature highlighting how stress modulates the mesolimbic pathway, including the ventral tegmental area (VTA) and nucleus accumbens (NAcs), to alter cocaine abuse-related effects. Taken together, stress enhances cocaine’s abuse-related effects at multiple points along the VTA mesolimbic projection, and uniquely in the NAcs through a positive feedback type mechanism. Furthermore, we highlight future directions to elucidate the interaction between the prefrontal cortex (PFC) and key intermediaries including ΔFosB, cAMP response element binding protein (CREB) and cyclin-dependent kinase 5 (CDK5) to highlight possible mechanisms that underlie stress-induced acceleration of the progression to a cocaine use disorder diagnosis

Poly-use of cannabis and other substances among juvenile-justice involved youth: variations in psychological and substance-related problems by typology

Background: Adolescent cannabis use is associated with increased risk for psychological problems, with evidence for more severe problems among youth who use cannabis in combination with other substances (i.e., polysubstance use). Juvenile offenders engage in both cannabis use and polysubstance use at higher rates than the general adolescent population. Yet, limited research has examined the relationship between cannabis poly-use (e.g., cannabis and alcohol use) and functional or psychological problems among juvenile offenders. Objectives: The current study addresses this gap by examining the association of polysubstance use of cannabis compared to cannabis only use with cognitive functioning, psychological distress, and substance-related problems among juvenile detainees. Methods: Participants were 238 detained youth ages 12–18 (80.4% male, 77.3% non-White) who completed assessments of substance use, intellectual functioning, psychological symptoms, and substance-related problems. Youth were also assessed by a clinical psychologist for substance use disorder. Results: Four cannabis-use typologies were identified; cannabis and alcohol use was the largest class, followed by cannabis only use, cannabis, alcohol and other drug use, then cannabis and other drug use. Polysubstance use was associated with lower scores on measures of intellectual functioning, more externalizing and internalizing symptomology, and more substance-related problems relative to cannabis only use. However, the relationship between polysubstance use and problems varied by typology. Conclusions: Findings suggest that justice-involved youth engaged in polysubstance use may be at greater need for concurrent academic, affective, and behavioral support in their rehabilitation and transition back to the community

MDAN-21: A Bivalent Opioid Ligand Containing mu-Agonist and Delta-Antagonist Pharmacophores and Its Effects in Rhesus Monkeys

MDAN-21, , a bivalent opioid ligand containing a mu-opioid receptor agonist (derived from oxymorphone) linked to the delta-opioid receptor antagonist (related to naltrindole) by a spacer of 21 atoms, was reported to have potent analgesic properties in mice. Tolerance, physical dependence, and conditioned place preference were not evident in that species. The finding that bivalent ligands in this series, with spacers 19 atoms or greater, were devoid of tolerance and dependence led to the proposal that MDAN-21 targets heteromeric mu-delta-opioid receptors. The present study focused on its effects in nonhuman primates (Macaca mulatta), a species with a physiology and behavioral repertoire not unlike humans. With regard to opioids, this species usually better predicts clinical outcomes. MDAN-21 substituted for morphine in morphine-dependent monkeys in the remarkably low dose range 0.006–0.032 mg/kg, subcutaneously. Although MDAN-21 failed to produce reliable thermal analgesia in the dose range 0.0032–0.032 mg/kg, intramuscularly, it was active in the same dose range and by the same route of administration, in the capsaicin-induced thermal allodynia assay. The results suggest that MDAN-21 may be useful in the treatment of opioid dependence and allodynia. The data provide additional evidence that opioid withdrawal is associated with sensitized pain