Acute reorganization of postsynaptic GABAA receptors reveals the functional impact of molecular nanoarchitecture at inhibitory synapses.

Neurotransmitter receptors partition into nanometer-scale subdomains within the postsynaptic membrane that are precisely aligned with presynaptic neurotransmitter release sites. While spatial coordination between pre- and postsynaptic elements is observed at both excitatory and inhibitory synapses, the functional significance of this molecular architecture has been challenging to evaluate experimentally. Here we utilized an optogenetic clustering approach to acutely alter the nanoscale organization of the postsynaptic inhibitory scaffold gephyrin while monitoring synaptic function. Gephyrin clustering rapidly enlarged postsynaptic area, laterally displacing GABAA receptors from their normally precise apposition with presynaptic active zones. Receptor displacement was accompanied by decreased synaptic GABAA receptor currents even though presynaptic release probability and the overall abundance and function of synaptic GABAA receptors remained unperturbed. Thus, acutely repositioning neurotransmitter receptors within the postsynaptic membrane profoundly influences synaptic efficacy, establishing the functional importance of precision pre-/postsynaptic molecular coordination at inhibitory synapses.

Adolescent Stress Reduces Adult Morphine-Induced Behavioral Sensitization in C57BL/6J Mice.

Deaths related to opioid use have skyrocketed in the United States, leading to a public health epidemic. Research has shown that both biological (genes) and environmental (stress) precursors are linked to opioid use. In particular, stress during adolescence-a critical period of frontal lobe development-influences the likelihood of abusing drugs. However, little is known about the biological mechanisms through which adolescent stress leads to long-term risk of opioid use, or whether genetic background moderates this response. Male and female C57BL/6J and BALB/cJ mice were exposed to chronic variable social stress (CVSS) or control conditions throughout adolescence and then tested for morphine locomotor sensitization or morphine consumption in adulthood. To examine possible mechanisms that underlie stress-induced changes in morphine behaviors, we assessed physiological changes in response to acute stress exposure and prefrontal cortex (PFC) miRNA gene expression. Adolescent stress did not influence morphine sensitization or consumption in BALB/cJ animals, and there was limited evidence of stress effects in female C57BL/6J mice. In contrast, male C57BL/6J mice exposed to adolescent CVSS had blunted morphine sensitization compared to control animals; no differences were observed in the acute locomotor response to morphine administration or morphine consumption. Physiologically, C57BL/6J mice exposed to CVSS had an attenuated corticosterone recovery following an acute stressor and downregulation of twelve miRNA in the PFC compared to control mice. The specificity of the effects for C57BL/6J vs. BALB/cJ mice provides evidence of a gene-environment interaction influencing opioid behaviors. However, this conclusion is dampened by limited locomotor sensitization observed in BALB/cJ mice. It remains possible that results may differ to other doses of morphine or other behavioral responses. Long-term differences in stress reactivity or miRNA expression in C57BL/6J mice suggests two possible biological mechanisms to evaluate in future research.

Reduced expression of ethanol sensitization by α3ß4 nicotinic acetylcholine receptors in DBA/2J mice.

Alcohol use disorder (AUD) is a leading cause of preventable death in the United States, however existing treatments are ineffective and produce aversive side effects such as nausea and fatigue. One potential therapeutic for AUD is the α3ß4 nicotinic acetylcholine receptor (nAChR) antagonist 18-methoxycoronaridine (18-MC). Prior work has shown that 18-MC reduces ethanol consumption in rodent models. The present study sought to further examine the therapeutic potential of 18-MC by testing its effects on nonconsummatory behaviors. We examined 2 behavioral measures: ethanol-induced locomotor stimulation, which measures euphoric properties of the drug, and the expression of locomotor sensitization which models neuroadaptations in response to repeated exposure. We tested dose-dependent effects of 18-MC (0, 10, 20 and 30 mg/kg) administration on ethanol stimulation and locomotor sensitization in female and male DBA/2J mice. 18-MC had no effect on acute ethanol-induced stimulation, but the highest dose (30 mg/kg) significantly decreased the expression of locomotor sensitization. Our results support the involvement of α3ß4 nAChR in the expression of ethanol-induced locomotor sensitization and suggest that 18-MC may be a therapeutic for AUD. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Pharmacokinetic Profile of Spectrum Reduced Nicotine Cigarettes.

INTRODUCTION: Spectrum research cigarettes have been developed with varying nicotine content for use in studies evaluating the effects of a regulatory policy reducing the permissible nicotine content in cigarettes. This study aimed to characterize the nicotine pharmacokinetic profile of Spectrum cigarettes. METHODS: Twelve daily smokers attended four sessions and had blood nicotine, exhaled carbon monoxide, and subjective effects measured before and after smoking either a single cigarette of their preferred brand or high (10.9 mg/cigarette), medium (3.2 mg/cigarette), or low (0.2 mg/cigarette) nicotine content Spectrum research cigarettes, in a double-blind design with order counterbalanced. RESULTS: The boost in blood nicotine concentration was dose-dependent, with a boost of 0.3, 3.9, and 17.3 ng/mL for low-, medium-, and high-nicotine content Spectrum cigarettes. The high dose Spectrum had a similar nicotine boost to the "preferred brand" cigarettes (19 ng/mL). Subjects took longer puffs on the low nicotine cigarettes, but smoked these cigarettes faster than other cigarette types. High nicotine Spectrum cigarettes reduced the urge to smoke more than other cigarette types. CONCLUSIONS: This study shows that Spectrum research cigarettes produce blood nicotine absorption in a dose-dependent manner, and therefore, are appropriate for use in studies of nicotine reduction in cigarettes. IMPLICATIONS: This is the first study to determine the pharmacokinetic profile of Spectrum reduced nicotine content research cigarettes following an overnight abstinence. These data could provide evidence to regulatory agencies about the effects of reduced nicotine cigarettes when considering regulations on tobacco reduction.

The α3ß4 nicotinic acetylcholine receptor antagonist 18-Methoxycoronaridine decreases binge-like ethanol consumption in adult C57BL/6J mice.

Binge alcohol drinking is a health burden in the United States, which has an alarming economic impact. Unfortunately, medications available for alcohol abuse have low efficacy or adverse side effects, creating a need to evaluate novel therapies. Growing research suggests that 18-Methoxycoronaridine (18-MC), an α3ß4 nicotinic acetylcholine receptor (nAChR) antagonist, may be effective at reducing ethanol consumption. However, its effects on binge-like ethanol consumption and other ethanol behaviors have not been examined. The present study examined the effect of α3ß4 nAChRs antagonism on basal locomotor activity in male and female C57BL/6J mice. Next we tested the effect of 18-MC on binge-like ethanol consumption, ethanol-induced sedation, and ethanol metabolism. Finally, we tested the effect of α3ß4 nAChRs on saccharin consumption to ensure effects were specific for ethanol. We observed that 18-MC decreased binge-like ethanol consumption without altering saccharin consumption, the sedative effects of ethanol, or ethanol metabolism. High doses of 18-MC caused locomotor sedation in C57BL/6J mice, but the effects were brief and likely did not contribute to differences in ethanol consumption. Our results support the involvement of the α3ß4 nAChRs in binge-like ethanol intake, and further work should explore the use of 18-MC for treatment of alcohol use disorders.

Varenicline modulates ethanol and saccharin consumption in adolescent male and female C57BL/6J mice.

Adolescence is a critical period in brain development that coincides with the initiation of alcohol use. Nicotinic acetylcholine receptors (nAChR) have been shown to modulate ethanol behaviors in adult humans and in animal models; however, the role of these receptors in adolescent ethanol behaviors has not been explored. Throughout adolescence, nAChR expression undergoes large-scale developmental changes which may alter behavioral responses to ethanol. Here we examined the effect of varenicline, a nAChR partial agonist, on ethanol consumption, ataxia, sedation, and metabolism in adolescent male and female C57BL/6J mice. The effect of varenicline on ethanol consumption was tested through the Drinking-in-the-Dark (DID) paradigm that models binge-like ethanol consumption. To ensure that results were specific for ethanol, we also tested the effect of varenicline on saccharin consumption. Additionally, varenicline was administered 30min prior to an acute injection of ethanol before being tested for ataxia on the balance beam, sedation using the loss of righting reflex, or ethanol metabolism. Varenicline dose dependently decreased ethanol consumption, but also influenced saccharin intake. Varenicline showed no significant effect on ethanol metabolism, ataxia, or sedation. Unlike its effects in adult animals, varenicline is able to reduce ethanol consumption without increasing the ataxic and sedative effects of ethanol. This work suggests that the neurobiological mechanisms of ethanol behaviors may change across the lifespan and highlights the need for more research on the role of nAChRs in ethanol behaviors throughout development.