Cannabis remains by far the most consumed illicit drug in Europe. The availability of more potent cannabis has raised concerns regarding the enhanced health risks associated with its use, particularly among pregnant women. Growing evidence shows that cannabis use during pregnancy increases the risks of child psychopathology. We have previously shown that only male rat offspring prenatally exposed to Δ9-tetrahydrocannabinol (THC), a rat model of prenatal cannabinoid exposure (PCE), display a hyperdopaminergic phenotype associated with a differential susceptibility to acute THC- and stress-mediated effects on sensorimotor gating functions. Here, we explore the contribution of the hypothalamic-pituitary-adrenal (HPA) axis, key regulator of body adaptive stress responses, to the detrimental effects of acute stress on ventral tegmental area (VTA) dopamine neurons and sensorimotor gating function of PCE rats. We report a sex-dependent compromised balance in mRNA levels of genes encoding mineralocorticoid and glucocorticoid receptors in the VTA, alongside with stress-induced pre-pulse inhibition (PPI) impairment. Notably, VTA dopamine neuronal activity is causally linked to the manifestation of stress-dependent deterioration of PPI. Finally, pharmacological manipulations targeting glycogen-synthase-kinase-3-β signaling during postnatal development correct these stress-induced, sex-specific and dopamine-dependent disruption of PPI. Collectively, these results highlight the critical sex-dependent interplay between HPA axis and dopamine system in the regulation of sensorimotor gating functions in rats.

Autism spectrum disorders (ASDs) are characterized by core behavioral symptoms in the domains of sociability, language/communication, and repetitive or stereotyped behaviors. Deficits in the prefrontal and hippocampal excitatory/inhibitory balance due to a functional loss of GABAergic interneurons are proposed to underlie these symptoms. Increasing the postsynaptic effects of GABA with compounds that selectively modulate GABAergic receptors could be a potential target for treating ASD symptoms. In addition, deficits in GABAergic interneurons have been linked to dopamine (DA) system dysregulation, and, despite conflicting evidence, abnormalities in the DA system activity may underly some ASD symptoms. Here, we investigated whether the positive allosteric modulator of α5-containing GABAA receptors (α5-GABAARs) SH-053-2'F-R-CH3 (10 mg/kg) attenuates behavioral abnormalities in rats exposed to valproic acid (VPA) in utero, an established risk factor for autism. We also evaluated if animals exposed to VPA in utero present changes in the ventral tegmental area (VTA) DA system activity using in vivo electrophysiology and if SH-053-2'F-R-CH3 could attenuate these changes. SH-053-2'F-R-CH3 was administered intraperitoneally 30 min before each behavioral test and electrophysiology. In utero VPA exposure caused male and female rats to present increased repetitive behavior (self-grooming) in early adolescence and deficits in social interaction in adulthood. Male, but not female VPA rats, also presented deficits in recognition memory as adults. SH-053-2'F-R-CH3 attenuated the impairments in sociability and cognitive function in male VPA-exposed rats without attenuating the decreased social interaction in females. Adult male and female VPA-exposed rats also showed an increased VTA DA neuron population activity, which was not changed by SH-053-2'F-R-CH3. Despite sex differences, our findings indicate that α5-GABAARs positive allosteric modulators may effectively attenuate some core ASD symptoms.

The expression pattern of gamma aminobutyric acid (GABA) receptor subunits are commonly altered in patients with schizophrenia, which may lead to nerve excitation/inhibition problems, affecting cognition, emotion, and behavior.

To explore GABA receptor expression and its relationship with schizophrenia and to provide insights into more effective treatments.

This case-control study enrolled 126 patients with schizophrenia treated at our hospital and 126 healthy volunteers who underwent physical examinations at our hospital during the same period. The expression levels of the GABA receptor subunits were detected using 1H-magnetic resonance spectroscopy. The recognized cognitive battery tool, the MATRICS Consensus Cognitive Battery, was used to evaluate the scores for various dimensions of cognitive function. The correlation between GABA receptor subunit downregulation and schizophrenia was also analyzed.

Significant differences in GABA receptor subunit levels were found between the case and control groups (P < 0.05). A significant difference was also found between the case and control groups in terms of cognitive function measures, including attention/alertness and learning ability (P < 0.05). Specifically, as the expression levels of GABRA1 (α1 subunit gene), GABRB2 (β2 subunit gene), GABRD (δ subunit), and GABRE (ε subunit) decreased, the severity of the patients' condition increased gradually, indicating a positive correlation between the downregulation of these 4 receptor subunits and schizophrenia (P < 0.05). However, the expression levels of GABRA5 (α5 subunit gene) and GABRA6 (α6 subunit gene) showed no significant correlation with schizophrenia (P > 0.05).

Downregulation of the GABA receptor subunits is positively correlated with schizophrenia. In other words, when GABA receptor subunits are downregulated in patients, cognitive impairment becomes more severe.

Dopamine system dysfunction, observed in animal models with psychosis-like symptomatology, can be restored by targeting Gamma-Aminobutyric Acid type A receptors (GABAAR) containing the α5, but not α1, subunit in the ventral hippocampus (vHipp). The reason for this discrepancy in efficacy remains elusive; however, one key difference is that α1GABAARs are primarily located in the synapse, whereas α5GABAARs are mostly extrasynaptic. To test whether receptor location is responsible for this difference in efficacy, we injected a small interfering ribonucleic acid (siRNA) into the vHipp to knock down radixin, a scaffolding protein that holds α5GABAARs in the extrasynaptic space. We then administered GL-II-73, a positive allosteric modulator of α5GABAARs (α5-PAM) known to reverse shock-induced deficits in dopamine system function, to determine if shifting α5GABAARs from the extrasynaptic space to the synapse would prevent the effects of α5-PAM on dopamine system function. As expected, knockdown of radixin significantly decreased radixin-associated α5GABAARs and increased the proportion of synaptic α5GABAARs, without changing the overall expression of α5GABAARs. Importantly, GL-II-73 was no longer able to modulate dopamine neuron activity in radixin-knockdown rats, indicating that the extrasynaptic localization of α5GABAARs is critical for hippocampal modulation of the dopamine system. These results may have important implications for clinical use of GL-II-73, as periods of high hippocampal activity appear to favor synaptic α5GABAARs, thus efficacy may be diminished in conditions where aberrant hippocampal activity is present.Significance Statement Currently available treatments for psychosis, a debilitating symptom linked with several brain disorders, are inadequate. While they can help manage symptoms in some patients, they do so imperfectly. They are also associated with severe side effects that can cause discontinuation of medication. This study provides preclinical evidence that the drug, GL-II-73, possesses the ability to modulate dopamine activity, a key player in psychosis symptoms, and further provides some mechanistic details regarding these effects. Overall, this work contributes to the growing body of literature suggesting that GL-II-73 and similar compounds may possess antipsychotic efficacy.

In the past 20 years, our understanding of the pathophysiology of depression has evolved from a focus on an imbalance of monoaminergic neurotransmitters to a multifactorial picture including an improved understanding of the role of glutamatergic excitatory and GABAergic inhibitory neurotransmission. FDA-approved treatments targeting the glutamatergic [esketamine for major depressive disorder (MDD)] and GABAergic (brexanolone for peripartum depression) systems have become available. This review focuses on the GABAA receptor (GABAAR) system as a target for novel antidepressants and discusses the mechanisms by which modulation of δ-containing GABAARs with neuroactive steroids (NASs) or of α5-containing GABAARs results in antidepressant or antidepressant-like actions and discusses clinical data on NASs. Moreover, a potential mechanism by which α5-GABAAR-positive allosteric modulators (PAMs) may improve cognitive deficits in depression is presented.

Autism Spectrum Disorders (ASD) are characterized by core behavioral symptoms in the domains of sociability, language/communication, and repetitive or stereotyped behaviors. Deficits in the prefrontal and hippocampal excitatory/inhibitory balance due to a functional loss of GABAergic interneurons are proposed to underlie these symptoms. Increasing the postsynaptic effects of GABA with compounds that selectively modulate GABAergic receptors could be a potential target for treating ASD symptoms. In addition, deficits in GABAergic interneurons have been linked to dopamine (DA) system dysregulation, and, despite conflicting evidence, abnormalities in the DA system activity may underly some ASD symptoms. Here, we investigated whether the positive allosteric modulator of α5-containing GABA A receptors (α5-GABA A Rs) SH-053-2'F-R-CH3 (10 mg/kg) attenuates behavioral abnormalities in a rat model for autism based on in utero VPA exposure. We also evaluated if animals exposed to VPA in utero present changes in the ventral tegmental area (VTA) DA system activity using in vivo electrophysiology and if SH-053-2'F-R-CH3 could attenuate these changes. In utero VPA exposure caused male and female rats to present increased repetitive behavior (self-grooming) in early adolescence and deficits in social interaction in adulthood. Male, but not female VPA rats, also presented deficits in recognition memory as adults. SH-053-2'F-R-CH3 attenuated the impairments in sociability and cognitive function in male VPA-exposed rats without attenuating the decreased social interaction in females. Male and female adult VPA-exposed rats also showed an increased VTA DA neuron population activity, which was not changed by SH-053-2'F-R-CH3. Despite sex differences, our findings indicate α5-GABA A Rs positive allosteric modulators may effectively attenuate some core ASD symptoms.

Although seizures are a hallmark feature of temporal lobe epilepsy (TLE), psychiatric comorbidities, including psychosis, are frequently associated with TLE and contribute to decreased quality of life. Currently, there are no defined therapeutic protocols to manage psychosis in TLE patients, as antipsychotic agents may induce epileptic seizures and are associated with severe side effects and pharmacokinetic and pharmacodynamic interactions with antiepileptic drugs. Thus, novel treatment strategies are necessary. Several lines of evidence suggest that hippocampal hyperactivity is central to the pathology of both TLE and psychosis; therefore, restoring hippocampal activity back to normal levels may be a novel therapeutic approach for treating psychosis in TLE. In rodent models, increased activity in the ventral hippocampus (vHipp) results in aberrant dopamine system function, which is thought to underlie symptoms of psychosis. Indeed, we have previously demonstrated that targeting α5-containing γ-aminobutyric acid receptors (α5GABAARs), an inhibitory receptor abundant in the hippocampus, with positive allosteric modulators (PAMs), can restore dopamine system function in rodent models displaying hippocampal hyperactivity. Thus, we posited that α5-PAMs may be beneficial in a model used to study TLE. Here, we demonstrate that pilocarpine-induced TLE is associated with increased VTA dopamine neuron activity, an effect that was completely reversed by intra-vHipp administration of GL-II-73, a selective α5-PAM. Further, pilocarpine did not alter the hippocampal α5GABAAR expression or synaptic localization that may affect the efficacy of α5-PAMs. Taken together, these results suggest augmenting α5GABAAR function as a novel therapeutic modality for the treatment of psychosis in TLE.

Dopamine system dysfunction, observed in animal models with psychosis-like symptomatology, can be restored by targeting Gamma-Aminobutyric Acid type A receptors (GABA A R) containing the α5, but not α1, subunit in the ventral hippocampus (vHipp). The reason for this discrepancy in efficacy remains elusive; however, one key difference is that α1GABA A Rs are primarily located in the synapse, whereas α5GABA A Rs are mostly extrasynaptic. To test whether receptor location is responsible for this difference in efficacy, we injected a small interfering ribonucleic acid (siRNA) into the vHipp to knock down radixin, a scaffolding protein that holds α5GABA A Rs in the extrasynaptic space. We then administered GL-II-73, a positive allosteric modulator of α5GABA A Rs (α5-PAM) known to reverse shock-induced deficits in dopamine system function, to determine if shifting α5GABA A Rs from the extrasynaptic space to the synapse would prevent the effects of α5-PAM on dopamine system function. As expected, knockdown of radixin significantly decreased radixin-associated α5GABA A Rs and increased the proportion of synaptic α5GABA A Rs, without changing the overall expression of α5GABA A Rs. Importantly, GL-II-73 was no longer able to modulate dopamine neuron activity in radixin-knockdown rats, indicating that the extrasynaptic localization of α5GABA A Rs is critical for hippocampal modulation of the dopamine system. These results may have important implications for clinical use of GL-II-73, as periods of high hippocampal activity appear to favor synaptic α5GABA A Rs, thus efficacy may be diminished in conditions where aberrant hippocampal activity is present.

Dopamine activity is known to be altered in both psychosis patients and in animal models, with promising new antipsychotics restoring normal dopamine system function. One such drug is GL-II-73, a positive allosteric modulator of α5GABA A Rs (α5-PAM). Interestingly, previous research has shown that a positive allosteric modulator of α1GABA A Rs (α1-PAM) does not share this ability, even when directly given to the ventral hippocampus, a region known to modulate dopamine activity. One potential explanation for this difference we examined in this study is that α1GABA A Rs are primarily located in the synapse, whereas α5GABA A Rs are mostly extrasynaptic. Determining the mechanism of this differential efficacy could lead to the refinement of antipsychotic treatment and improve patient outcomes overall.

Antipsychotics increase the risk of death in elderly patients with Alzheimer's disease (AD). Thus, there is an immediate need for novel therapies to treat comorbid psychosis in AD. Psychosis has been attributed to a dysregulation of the dopamine system and is associated with aberrant regulation by the hippocampus. Given that the hippocampus is a key site of pathology in AD, we posit that aberrant regulation of the dopamine system may contribute to comorbid psychosis in AD. A ferrous amyloid buthionine (FAB) rodent model was used to model a sporadic form of AD. FAB rats displayed functional hippocampal alterations, which were accompanied by decreases in spontaneous, low-frequency oscillations and increases in the firing rates of putative pyramidal neurons. Additionally, FAB rats exhibited increases in dopamine neuron population activity and augmented responses to the locomotor-inducing effects of MK-801, as is consistent with rodent models of psychosis-like symptomatology. Further, working memory deficits in the Y-maze, consistent with an AD-like phenotype, were observed in FAB rats. These data suggest that the aberrant hippocampal activity observed in AD may contribute to dopamine-dependent psychosis, and that the FAB model may be useful for the investigation of comorbid psychosis related to AD. Understanding the pathophysiology that leads to comorbid psychosis in AD will ultimately lead to the discovery of novel targets for the treatment of this disease.