Increased reactivity of the paraventricular nucleus of the hypothalamus and decreased threat responding in male rats following psilocin administration.

Psychedelics have experienced renewed interest following positive clinical effects, however the neurobiological mechanisms underlying effects remain unclear. The paraventricular nucleus of the hypothalamus (PVN) plays an integral role in stress response, autonomic function, social behavior, and other affective processes. We investigated the effect of psilocin, the psychoactive metabolite of psilocybin, on PVN reactivity in Sprague Dawley rats. Psilocin increased stimulus-independent PVN activity as measured by c-Fos expression in male and female rats. Psilocin increased PVN reactivity to an aversive air-puff stimulus in males but not females. Reactivity was restored at 2- and 7-days post-injection with no group differences. Additionally, prior psilocin injection did not affect PVN reactivity following acute restraint stress. Experimental groups sub-classified by baseline threat responding indicate that increased male PVN reactivity is driven by active threat responders. These findings identify the PVN as a significant site of psychedelic drug action with implications for threat responding behavior.

Negative modulation of AMPA receptors bound to transmembrane AMPA receptor regulatory protein γ-8 blunts the positive reinforcing properties of alcohol and sucrose in a brain region-dependent manner in male mice.

RATIONALE: The development and progression of alcohol use disorder (AUD) are widely viewed as maladaptive neuroplasticity. The transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) regulatory protein γ8 (TARP γ-8) is a molecular mechanism of neuroplasticity that has not been evaluated in AUD or other addictions. OBJECTIVE: To address this gap in knowledge, we evaluated the mechanistic role of TARP γ-8 bound AMPAR activity in the basolateral amygdala (BLA) and ventral hippocampus (vHPC) in the positive reinforcing effects of alcohol, which drive repetitive alcohol use throughout the course of AUD, in male C57BL/6 J mice. These brain regions were selected because they exhibit high levels of TARP γ-8 expression and send glutamate projections to the nucleus accumbens (NAc), which is a key nucleus in the brain reward pathway. METHODS AND RESULTS: Site-specific pharmacological inhibition of AMPARs bound to TARP γ-8 in the BLA via bilateral infusion of the selective negative modulator JNJ-55511118 (0-2 µg/µl/side) significantly decreased operant alcohol self-administration with no effect on sucrose self-administration in behavior-matched controls. Temporal analysis showed that reductions in alcohol-reinforced response rate occurred > 25 min after the onset of responding, consistent with a blunting of the positive reinforcing effects of alcohol in the absence of nonspecific behavioral effects. In contrast, inhibition of TARP γ-8 bound AMPARs in the vHPC selectively decreased sucrose self-administration with no effect on alcohol. CONCLUSIONS: This study reveals a novel brain region-specific role of TARP γ-8 bound AMPARs as a molecular mechanism of the positive reinforcing effects of alcohol and non-drug rewards.

Hepatitis C Virus Infection Preceding an Outbreak of Human Immunodeficiency Virus Among Persons Who Inject Drugs-Kanawha County, West Virginia, 2019-2021.

Of 65 cases during a human immunodeficiency virus (HIV) outbreak among persons who inject drugs (PWID) in West Virginia (2019-2021), 61 (94%) had hepatitis C diagnosed a median of 46 months prior to HIV diagnosis. Hepatitis C diagnosis among PWID should trigger improved access to prevention and treatment services.

Inhibition of AMPA receptors (AMPARs) containing transmembrane AMPAR regulatory protein γ-8 with JNJ-55511118 shows preclinical efficacy in reducing chronic repetitive alcohol self-administration.

BACKGROUND: A prominent therapeutic indication for alcohol use disorder (AUD) is reduction in chronic repetitive alcohol use. Glutamate α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs) regulate chronic alcohol self-administration in preclinical models. Recent evidence indicates that the expression and function of AMPARs require the transmembrane AMPAR regulatory protein γ-8 (TARP γ-8). This study evaluated the preclinical efficacy of JNJ-55511118, a novel, selective, high-affinity inhibitor of TARP γ-8-bound AMPARs, in reducing chronic operant alcohol self-administration. METHODS: Separate groups of male and female C57BL/6J mice (n = 8/sex/group) were trained to lever press for sweetened alcohol (9% v/v + sucrose 2% w/v) or sucrose only (2% w/v) in operant conditioning chambers using an FR-4 schedule of reinforcement. After a 40-day baseline, JNJ-55511118 (0, 1, and 10 mg/kg, p.o.) was administered in randomized order 1 h before self-administration sessions. Parameters of operant behavior including response rate, total reinforcers, and head entries in the drinking troughs were computer recorded. RESULTS: During baseline, responding to alcohol, but not sucrose, was greater in female than male mice. In male mice, both doses of JNJ-55511118 decreased multiple parameters of alcohol self-administration but did not reduce behavior-matched sucrose-only self-administration. JNJ-55511118 had no effect on sweetened alcohol or sucrose self-administration in female mice. Subsequent tests of motor function showed that the lowest effective dose of JNJ-55511118 (1 mg/kg) had no effect on open-field activity in male mice. CONCLUSIONS: This study shows for the first time that TARP γ-8-bound AMPARs regulate a behavioral pathology associated with addiction. The preclinical efficacy of JNJ-55511118 in reducing alcohol self-administration in male mice suggests that inhibition of TARP γ-8-bound AMPARs is a novel and highly significant neural target for developing medications to treat AUD and other forms of addiction.

Calcium-permeable AMPA receptor activity and GluA1 trafficking in the basolateral amygdala regulate operant alcohol self-administration.

Addiction is viewed as maladaptive glutamate-mediated neuroplasticity that is regulated, in part, by calcium-permeable AMPA receptor (CP-AMPAR) activity. However, the contribution of CP-AMPARs to alcohol-seeking behavior remains to be elucidated. We evaluated CP-AMPAR activity in the basolateral amygdala (BLA) as a potential target of alcohol that also regulates alcohol self-administration in C57BL/6J mice. Operant self-administration of sweetened alcohol increased spontaneous EPSC frequency in BLA neurons that project to the nucleus accumbens as compared with behavior-matched sucrose controls indicating an alcohol-specific upregulation of synaptic activity. Bath application of the CP-AMPAR antagonist NASPM decreased evoked EPSC amplitude only in alcohol self-administering mice indicating alcohol-induced synaptic insertion of CP-AMPARs in BLA projection neurons. Moreover, NASPM infusion in the BLA dose-dependently decreased the rate of operant alcohol self-administration providing direct evidence for CP-AMPAR regulation of alcohol reinforcement. As most CP-AMPARs are GluA1-containing, we asked if alcohol alters the activation state of GluA1-containing AMPARs. Immunocytochemistry results showed elevated GluA1-S831 phosphorylation in the BLA of alcohol as compared with sucrose mice. To investigate mechanistic regulation of alcohol self-administration by GluA1-containing AMPARs, we evaluated the necessity of GluA1 trafficking using a TET-ON AAV encoding a dominant-negative GluA1 c-terminus (GluA1ct) that blocks activity-dependent synaptic delivery of native GluA1-containing AMPARs. GluA1ct expression in the BLA reduced alcohol self-administration with no effect on sucrose controls. These results show that CP-AMPAR activity and GluA1 trafficking in the BLA mechanistically regulate the reinforcing effects of sweetened alcohol. Pharmacotherapeutic targeting these mechanisms of maladaptive neuroplasticity may aid medical management of alcohol use disorder.

Poly[[[µ-trans-1,2-bis-(pyridin-4-yl)ethene-κ2 N:N']-µ-iodido-copper(I)]-trans-1,2-bis-(pyridin-4-yl)ethene (1/0.25)].

The title compound, {[CuI(bpe)]·0.25(bpe)} n , was synthesized similarly to (CuI)2(bpe) [Neal et al. (2019 ▸). IUCrData, 4, x190122] with red crystals grown from aceto-nitrile solutions of CuI and the bpe ligand [bpe = 1,2-bis-(pyridin-4-yl)ethene, C12H10N2]. The structure of the title compound is a type 1 complex in the Graham nomenclature [Graham et al. (2000 ▸). Inorg. Chem. 39, 5121-5132], having rhombic dimers of Cu2I2 that are bridged by two bpe ligands, to form oligomeric ribbons arranged as stairsteps. The step height is 2.8072 (11) Å, which is the Cu-Ii distance of the dimer [symmetry code (i): 1 - x, 2 - y, 1 - z]. The resulting polymer displays a two-dimensional honeycomb framework along the (01) plane, and disordered free bpe mol-ecules fill the voids in the crystal.

Alcohol drinking exacerbates neural and behavioral pathology in the 3xTg-AD mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that represents the most common cause of dementia in the United States. Although the link between alcohol use and AD has been studied, preclinical research has potential to elucidate neurobiological mechanisms that underlie this interaction. This study was designed to test the hypothesis that nondependent alcohol drinking exacerbates the onset and magnitude of AD-like neural and behavioral pathology. We first evaluated the impact of voluntary 24-h, two-bottle choice home-cage alcohol drinking on the prefrontal cortex and amygdala neuroproteome in C57BL/6J mice and found a striking association between alcohol drinking and AD-like pathology. Bioinformatics identified the AD-associated proteins MAPT (Tau), amyloid beta precursor protein (APP), and presenilin-1 (PSEN-1) as the main modulators of alcohol-sensitive protein networks that included AD-related proteins that regulate energy metabolism (ATP5D, HK1, AK1, PGAM1, CKB), cytoskeletal development (BASP1, CAP1, DPYSL2 [CRMP2], ALDOA, TUBA1A, CFL2, ACTG1), cellular/oxidative stress (HSPA5, HSPA8, ENO1, ENO2), and DNA regulation (PURA, YWHAZ). To address the impact of alcohol drinking on AD, studies were conducted using 3xTg-AD mice that express human MAPT, APP, and PSEN-1 transgenes and develop AD-like brain and behavioral pathology. 3xTg-AD and wild-type mice consumed alcohol or saccharin for 4 months. Behavioral tests were administered during a 1-month alcohol-free period. Alcohol intake induced AD-like behavioral pathologies in 3xTg-AD mice including impaired spatial memory in the Morris Water Maze, diminished sensorimotor gating as measured by prepulse inhibition, and exacerbated conditioned fear. Multiplex immunoassay conducted on brain lysates showed that alcohol drinking upregulated primary markers of AD pathology in 3xTg-AD mice: Aß 42/40 ratio in the lateral entorhinal and prefrontal cortex and total Tau expression in the lateral entorhinal cortex, medial prefrontal cortex, and amygdala at 1-month post alcohol exposure. Immunocytochemistry showed that alcohol use upregulated expression of pTau (Ser199/Ser202) in the hippocampus, which is consistent with late-stage AD. According to the NIA-AA Research Framework, these results suggest that alcohol use is associated with Alzheimer's pathology. Results also showed that alcohol use was associated with a general reduction in Akt/mTOR signaling via several phosphoproteins (IR, IRS1, IGF1R, PTEN, ERK, mTOR, p70S6K, RPS6) in multiple brain regions including hippocampus and entorhinal cortex. Dysregulation of Akt/mTOR phosphoproteins suggests alcohol may target this pathway in AD progression. These results suggest that nondependent alcohol drinking increases the onset and magnitude of AD-like neural and behavioral pathology in 3xTg-AD mice.

MGluR5 activity is required for the induction of ethanol behavioral sensitization and associated changes in ERK MAP kinase phosphorylation in the nucleus accumbens shell and lateral habenula.

Metabotropic glutamate receptor subtype-5 (mGluR5) activity regulates a variety of behavioral pathologies associated with alcohol addiction. The main goal of this study was to determine if mGluR5 regulates the induction of ethanol-induced locomotor sensitization, which is a model of experience-dependent plasticity following initial exposure to drugs of abuse. The extracellular signal-regulated kinase (ERK1/2) pathway is downstream of mGluR5 and implicated in alcohol addiction; however, its role in sensitization remains unexplored. We sought to determine if mGluR5-mediated changes in ethanol-induced sensitization are associated with changes in ERK1/2 phosphorylation (pERK1/2) in specific brain regions. Adult male DBA/2 J mice were tested for acute locomotor response to ethanol (0 or 2 g/kg, IP) followed by a 9-day induction period in which the mGluR5 antagonist MPEP (0 or 30 mg/kg, IP) was administered prior to ethanol (0 or 2.5 g/kg, IP). One day later, ethanol (2 g/kg) produced a robust within- and between-group increase in locomotor activity, indicating sensitization in mice that received MPEP (0 mg/kg) during induction. MPEP (30 mg/kg) treatment during induction resulted in locomotor response to ethanol (2 g/kg) challenge that was equivalent to an acute response, indicating full blockade of sensitization. Sensitization was associated with increased pERK1/2 immunoreactivity (IR) in nucleus accumbens shell (AcbSh) and a reduction in lateral habenula (LHb), both of which were blocked by MPEP treatment during induction. Sensitization was also associated with mGluR5-independent increases in pERK1/2 IR in the nucleus accumbens core and decreases in the dentate gyrus and lateral septum. These data indicate that mGluR5 activity is required for the induction of ethanol locomotor sensitization and associated changes in ERK1/2 phosphorylation in the AcbSh and LHb, which raises the hypothesis that mGluR5-mediated cell signaling in these brain regions may mediate the induction of sensitization. Elucidating mechanisms of sensitization may increase understanding of how ethanol hijacks behavioral functions during the development of addiction.

Reversal learning and experimenter-administered chronic intermittent ethanol exposure in male rats.

RATIONALE: Chronic alcohol exposure is associated with impaired decision making skills, cognitive deficits, and poor performance on tasks requiring behavioral flexibility. Although oral routes of alcohol administration are commonly used to examine effects of alcohol on various behaviors in rodents, only a few investigations have used intragastric exposures to evaluate ethanol's effects on behavioral flexibility in the adult rat. OBJECTIVES: The aim of the current series of experiments was to determine if behavioral flexibility impairments would be demonstrated across a variety of procedural factors, including route of administration [intraperitoneal injection (i.p.), intragastric gavage (i.g.)], ethanol dose (3-5 g/kg), number of daily exposures (once/day, twice/day), duration of exposure (2-6 weeks), or length of abstinence (5-7 days). METHODS: Adult male Sprague-Dawley rats were exposed to chronic intermittent ethanol (CIE) or vehicle and evaluated for behavioral intoxication, blood ethanol concentrations (BEC), and performance on a reversal learning odor discrimination task. RESULTS: While all rats displayed behavioral intoxication and elevated BECs, CIE i.p. rats had prolonged elevation in BECs and made the most errors during the reversal learning task. Unexpectedly, CIE i.g. exposures failed to produce deficits during reversal learning tasks regardless of ethanol dose, frequency/duration of exposure, or length of abstinence. CONCLUSIONS: Behavioral flexibility deficits resulting from CIE i.p. exposures may be due to the severity and chronicity of alcohol intoxication. Elucidating the impact of ethanol on behavioral flexibility is critical for developing a better understanding of the behavioral consequences of chronic alcohol exposure.

Stability Design and Response to Waves by Batoids.

Unsteady flows in the marine environment can affect the stability and locomotor costs of animals. For fish swimming at shallow depths, waves represent a form of unsteady flow. Waves consist of cyclic oscillations, during which the water moves in circular or elliptical orbits. Large gravity waves have the potential to displace fish both cyclically and in the direction of wave celerity for animals floating in the water column or holding station on the bottom. Displacement of a fish can exceed its stability control capability when the size of the wave orbit is equivalent to the size of the fish. Previous research into compensatory behaviors of fishes to waves has focused on pelagic osteichthyan fishes with laterally compressed bodies. However, dorsoventrally compressed batoid rays must also contend with waves. Examination of rays subjected to waves showed differing strategies for stability between pelagic and demersal species. Pelagic cownose rays (Rhinoptera bonasus) would glide through or be transported by waves, maintaining a positive dihedral of the wing-like pectoral fins. Demersal Atlantic stingrays (Dasyatis sabina) and freshwater rays (Potamotrygon motoro) maintained contact with the bottom and performed compensatory fin motions and body postures. The ability to limit displacement due to wave action by the demersal rays was also a function of the bottom texture. The ability of rays to maintain stability due to wave action suggests mechanisms to compensate for the velocity flux of the water impinging on the large projected area of the enlarged pectoral fins of rays.