Pre- and postsynaptic signatures in the prelimbic cortex associated with "alcohol use disorder" in the rat.

The transition to alcohol use disorder (AUD) involves persistent neuroadaptations in executive control functions primarily regulated by the medial prefrontal cortex. However, the neurophysiological correlates to behavioral manifestations of AUD are not fully defined. The association between cortical neuroadaptations and behavioral manifestations of addiction was studied using a multi-symptomatic operant model based on the DSM-5 diagnostic criteria for AUD. This model aimed to characterize an AUD-vulnerable and AUD-resistant subpopulation of outbred male Wistar rats and was combined with electrophysiological measurements in the prelimbic cortex (PL). Mirroring clinical observations, rats exhibited individual variability in their vulnerability to develop AUD-like behavior, including motivation to seek for alcohol (crit 1), increased effort to obtain the substance (crit 2), and continued drinking despite negative consequences (crit 3). Only a small subset of rats met all the aforementioned AUD criteria (3 crit, AUD-vulnerable), while a larger fraction was considered AUD-resilient (0 crit). The development of AUD-like behavior was characterized by disruptions in glutamatergic synaptic activity, involving decreased frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and heightened intrinsic excitability in layers 2/3 PL pyramidal neurons. These alterations were concomitant with a significant impairment in the ability of mGlu2/3 receptors to negatively regulate glutamate release in the PL but not in downstream regions like the basolateral amygdala or nucleus accumbens core. In conclusion alterations in PL synaptic activity were strongly associated with individual addiction scores, indicating their role as potential markers of the behavioral manifestations linked to AUD psychopathology.

The GlyT1-inhibitor Org 24598 facilitates the alcohol deprivation abolishing and dopamine elevating effects of bupropion + varenicline in rats.

Alcohol Use Disorder (AUD) is a relapsing brain disorder that involves perturbations of brain dopamine (DA) systems, and combined treatment with varenicline + bupropion produces additive effects on accumbal DA output and abolishes the alcohol deprivation effect (ADE) in rats. Also, direct and indirect glycine receptor (GlyR) agonists raise basal DA, attenuate alcohol-induced DA release in the nucleus Accumbens (nAc) and reduce alcohol consumption in rats. This study in rats examines whether the GlyT1-inhibitor Org 24598, an indirect GlyR agonist, enhances the ADE-reducing and DA elevating action of the combined administration of varenicline + bupropion in lower doses than previously applied. Effects on voluntary alcohol consumption, the ADE and extracellular levels of glycine and DA in nAc were examined following treatment with Org 24598 6 and 9 mg/kg i.p., bupropion 3.75 mg/kg i.p. and varenicline 1.5 mg/kg s.c., in monotherapy or combined, using a two-bottle, free-choice alcohol consumption paradigm with an ADE paradigm, and in vivo microdialysis in male Wistar rats. Notably, all treatment regimens appeared to abolish the ADE but only the effect produced by the triple combination (Org24598 + varenicline + bupropion) was significant compared to vehicle. Hence, addition of Org 24598 may enhance the ADE-reducing action of varenicline + bupropion and appears to allow for a dose reduction of bupropion. Treatment with Org 24598 raised accumbal glycine levels but did not significantly alter DA output in monotherapy. Varenicline + bupropion produced a substantial elevation in accumbal DA output that was slightly enhanced following addition of Org 24598. Conceivably, the blockade of the ADE is achieved by the triple combination enhancing accumbal DA transmission in complementary ways, thereby alleviating a hypothesized hypodopaminergia and negative reinforcement to drink. Ultimately, combining an indirect or direct GlyR agonist with varenicline + bupropion may constitute a new pharmacological treatment principle for AUD, although further refinement in dosing and evaluation of other glycinergic compounds are warranted.

Nicotine but not saline self-administering or yoked control conditions produces sustained neuroadaptations in the accumbens shell.

Introduction: Using yoked animals as the control when monitoring operant drug-self-administration is considered the golden standard. However, instrumental learning per se recruits several neurocircuits that may produce distinct or overlapping neuroadaptations with drugs of abuse. The aim of this project was to assess if contingent responding for nicotine or saline in the presence of a light stimulus as a conditioned reinforcer is associated with sustained neurophysiological adaptations in the nucleus accumbens shell (nAcS), a brain region repeatedly associated with reward related behaviors. Methods: To this end, nicotine-or saline-administrating rats and yoked-saline stimulus-unpaired training conditions were assessed in operant boxes over four consecutive weeks. After four additional weeks of home cage forced abstinence and subsequent cue reinforced responding under extinction conditions, ex vivo electrophysiology was performed in the nAcS medium spiny neurons (MSNs). Results: Whole cell recordings conducted in voltage and current-clamp mode showed that excitatory synapses in the nAcS were altered after prolonged forced abstinence from nicotine self-administration. We observed an increase in sEPSC amplitude in animals with a history of contingent nicotine SA potentially indicating higher excitability of accumbal MSNs, which was further supported by current clamp recordings. Interestingly no sustained neuroadaptations were elicited in saline exposed rats from nicotine associated visual cues compared to the yoked controls. Conclusion: The data presented here indicate that nicotine self-administration produces sustained neuroadaptations in the nAcS while operant responding driven by nicotine visual stimuli has no long-term effects on MSNs in nAcS.

Resonant driving of a single photon emitter embedded in a mechanical oscillator.

Coupling a microscopic mechanical resonator to a nanoscale quantum system enables control of the mechanical resonator via the quantum system and vice-versa. The coupling is usually achieved through functionalization of the mechanical resonator, but this results in additional mass and dissipation channels. An alternative is an intrinsic coupling based on strain. Here we employ a monolithic semiconductor system: the nanoscale quantum system is a semiconductor quantum dot (QD) located inside a nanowire. We demonstrate the resonant optical driving of the QD transition in such a structure. The noise spectrum of the resonance fluorescence signal, recorded in the single-photon counting regime, reveals a coupling to mechanical modes of different types. We measure a sensitivity to displacement of 65 fm/[Formula: see text] limited by charge noise in the device. Finally, we use thermal excitation of the different modes to determine the location of the QD within the trumpet, and calculate the contribution of the Brownian motion to the dephasing of the emitter.Resonant driving of a nanoscale quantum system coupled to a microscopic mechanical resonator may have uses in precision sensing and quantum information. The authors realize this by tailoring the geometry of a semiconductor nanowire embedding a quantum dot, detecting sub-picometre displacements.

Vectorial scanning force microscopy using a nanowire sensor.

Self-assembled nanowire (NW) crystals can be grown into nearly defect-free nanomechanical resonators with exceptional properties, including small motional mass, high resonant frequency and low dissipation. Furthermore, by virtue of slight asymmetries in geometry, a NW's flexural modes are split into doublets oscillating along orthogonal axes. These characteristics make bottom-up grown NWs extremely sensitive vectorial force sensors. Here, taking advantage of its adaptability as a scanning probe, we use a single NW to image a sample surface. By monitoring the frequency shift and direction of oscillation of both modes as we scan above the surface, we construct a map of all spatial tip-sample force derivatives in the plane. Finally, we use the NW to image electric force fields distinguishing between forces arising from the NW charge and polarizability. This universally applicable technique enables a form of atomic force microscopy particularly suited to mapping the size and direction of weak tip-sample forces.