Increased Synaptic Strength and mGlu_2/3 Receptor Plasticity on Mouse Prefrontal Cortex Intratelencephalic Pyramidal Cells Following Intermittent Access to Ethanol

Abstract

Background The medial prefrontal cortex (PFC) is crucial for regulating craving and alcohol seeking in alcohol use disorder (AUD) patients and alcohol seeking in animal models. Maladaptive changes in volitional ethanol (EtOH) intake have been associated with PFC function, yet synaptic adaptations within PFC have not been consistently detected in voluntary drinking rodent models. At least 80% of the neurons in PFC are glutamatergic pyramidal cells. Pyramidal cells provide the predominant cortical output to several brain regions relevant to AUD, including structures within the telencephalon (IT: e.g., basal ganglia, amygdala, other neocortical regions) and outside the telencephalon (ET: e.g., lateral hypothalamus, midbrain monoaminergic structures, thalamus). Methods In addition to their anatomical distinctions, studies from several laboratories have revealed that prefrontal cortical IT and ET pyramidal cells may be differentiated by specific electrophysiological parameters. These distinguishable parameters make it possible to readily classify pyramidal cells into separable subtypes. Here, we employed and validated the hyperpolarization sag ratio as a diagnostic proxy for separating ET (type A) and IT (type B) neurons. We recorded from deep‐layer prelimbic PFC pyramidal cells of mice 1 day after 4 to 5 weeks of intermittent access (IA) EtOH exposure. Results Membrane properties were not altered by IA EtOH, but excitatory postsynaptic strength onto IT type B neurons was selectively enhanced in slices from IA EtOH mice. The increased excitatory drive was accompanied by enhanced mGlu2/3 receptor plasticity on IT type B neurons, providing a potential translational approach to mitigate cognitive and motivational changes to PFC function related to binge drinking. Conclusions Together, these studies provide insight into the specific PFC neurocircuits altered by voluntary drinking. In addition, the findings provide an additional rationale for developing compounds that potentiate mGlu2 and/or mGlu3 receptor function as potential treatments for AUD.

Effects of acute lysergic acid diethylamide on intermittent ethanol and sucrose drinking and intracranial self-stimulation in C57BL/6 mice

“…For example, metabotropic glutamate (mGlu) receptors offer an interesting target to further clarify the mechanisms of action of psychedelics. Changes in mGlu receptor system have been implicated in intermittent ethanol intake in mice, including increased mGlu 2/3 receptor-mediated long-term depression in the subset of pyramidal cells of the medial prefrontal cortex (Joffe et al, 2021), increased mGlu 5 receptor expression in the nucleus accumbens (Cozzoli et al, 2012), and, furthermore, mGlu2/3 agonist reduces alcohol seeking in mice (Windisch and Czachowski, 2018). Beyond the previously suggested interplay between the mGlu 2/3 receptors and 5-HT 2A receptor (González-Maeso et al, 2008; Toneatti et al, 2020), it was recently shown that psilocybin can recover the alcohol dependence-induced downregulation of mGlu 2 expression in the infralimbic cortex in rats, and that this recovery was correlated with significant reductions in craving-like alcohol-seeking behaviours (Meinhardt et al, 2021).…”

Recovery of superior frontal gyrus cortical thickness and resting‐state functional connectivity in abstinent heroin users after 8 months of follow‐up

“…Consistently, we found that after protracted abstinence, reduced craving was correlated with improved RSFC between the bilateral SFG and the left OFC (Figure 6). Our results highlight the possible roles of SFG-OFC circuits in craving Joffe, Winder, and Conn (2021). The OFC is a crucial region for controlling goal-oriented behavior in SUD and is thought to be related to the incubation of heroin craving (Altshuler et al, 2021) induced by salient stimuli, which then leads to drug-seeking and drug-taking behaviors.…”

Targeting prefrontal cortex GABAergic microcircuits for the treatment of alcohol use disorder

“…Moreover, an important consideration for future experiments is that neocortical pyramidal cells can be differentiated into several subclasses based on projection target as well as the expression of GPCRs and other proteins. Thus, it is likely that disease-related experiences differentially alter the IN regulation of pyramidal cell subpopulations, as we have observed with respect to excitatory transmission (Joffe et al, 2021). Future studies will need to use a priori means to distinguish cell types to parse subtle or bidirectional changes to specific subpopulations.…”