Comparison of the function of two novel human dopamine D2 receptor variants identifies a likely mechanism for their pathogenicity.

Two recently discovered DRD2 mutations, c.634A > T, p.Ile212Phe and c.1121T > G, p.Met374Arg, cause hyperkinetic movement disorders that have overlapping features but apparently differ in severity. The two known carriers of the Met374Arg variant had early childhood disease onset and more severe motor, cognitive, and neuropsychiatric deficits than any known carriers of the Ile212Phe variant, whose symptoms were first apparent in adolescence. Here, we evaluated if differences in the function of the two variants in cultured cells could explain differing pathogenicity. Both variants were expressed less abundantly than the wild type receptor and exhibited loss of agonist-induced arrestin binding, but differences in expression and arrestin binding between the variants were minor. Basal and agonist-induced activation of heterotrimeric Gi/o/z proteins, however, showed clear differences; agonists were generally more potent at Met374Arg than at the Ile212Phe or wild type variants. Furthermore, all Gα subtypes tested were constitutively activated more by Met374Arg than by Ile212Phe. Met374Arg produced greater constitutive inhibition of cyclic AMP accumulation than Ile212Phe or the wild type D2 receptor. Met374Arg and Ile212Phe were more sensitive to thermal inactivation than the wild type D2 receptor, as reported for other constitutively active receptors, but Ile212Phe was affected more than Met374Arg. Additional pharmacological characterization suggested that the mutations differentially affect the shape of the agonist binding pocket and the potency of dopamine, norepinephrine, and tyramine. Molecular dynamics simulations provided a structural rationale for enhanced constitutive activation and agonist potency. Enhanced constitutive and agonist-induced G protein-mediated signaling likely contributes to the pathogenicity of these novel variants.

Regulation of alcohol drinking by ventral striatum and extended amygdala circuitry.

Alcohol use disorder is a complex psychiatric disorder that can be modeled in rodents using a number of drinking paradigms. Drinking-in-the-dark (DID) is widely used to model the binge/intoxication stage of addiction, and chronic intermittent ethanol vapor procedures (CIE) are used to induce dependence and model withdrawal/negative affect induced escalation of drinking. We discuss experiments showing the ventral striatum (vStr) and extended amygdala (EA) are engaged in response to ethanol in rodents through c-Fos/Fos immunoreactivity studies. We also discuss experiments in rodents that span a wide variety of techniques where the function of vStr and EA structures are changed following DID or CIE, and the role of neurotransmitter and neuropeptide systems studies in these ethanol-related outcomes. We note where signaling systems converge across regions and paradigms and where there are still gaps in the literature. Dynorphin/κ-opioid receptor (KOR) signaling, as well as corticotropin releasing factor (CRF)/CRF receptor signaling were found to be important regulators of drinking behaviors across brain regions and drinking paradigms. Future research will require that females and a variety of rodent strains are used in preclinical experiments in order to strengthen the generalizability of findings and improve the likelihood of success for testing potential therapeutics in human laboratory studies.

Exploratory study of a screening measure for polycystic ovarian syndrome, quality of life assessment, and neuropsychological evaluation.

BACKGROUND: The universally adopted 2018 PCOS medical diagnostic and treatment guidelines for Polycystic Ovarian Syndrome (PCOS) cites the need for a brief screening measure that can be easily administered in the clinical care setting. We evaluate a 12-item questionnaire emphasizing the medical symptoms of PCOS with a group of women with PCOS as well as comparison samples of college women not diagnosed with PCOS. METHOD: Of 120 undergraduate psychology women 18 to 41 years of age, 86 screened negative on a 12-item PCOS symptoms inventory. They were compared to a group of PCOS patients diagnosed medically in a manner consistent with the Teede et al. (2018) evidence-based diagnostic guidelines. The screen-positive, screen-negative, and PCOS-confirmed groups were compared on the PCOS Quality-of-Life (QoL) questionnaire, Zung Self-Rating Depression Scale (ZDS), Spielberg State-Trait Anxiety Inventory (STAI), Fatigue Symptom Inventory (FSI), Spiritual well-being and Spiritual Beliefs Inventories, the computerized Automated Neuropsychological Assessment Metric (ANAM) battery, and an experimental tachistoscopic Bilateral Perceptual Asymmetries Letter and Dots Matching Bilateral Field Advantage (BFA) test (to evaluate the effects of early brain androgenization possible from PCOS). For each questionnaire and neuropsychological performance principal outcome, the Linear Mixed Effects (LME) model was employed to evaluate the predictive significance of demographic characteristics and group membership (confirmed cases, screen negative and screen positive cases) for these outcomes. RESULTS: The PCOS-confirmed women scored more poorly than the screen-negative (reference) and screen-positive groups on all the measures of physical, emotional, social, and spiritual well-being measures. On the ANAM neuropsychological battery, PCOS-confirmed women did more poorly on Sternberg Memory and Stimulus Response throughput measures. They also had slower correct response speed for both the unilateral and bilateral dot- and letter-matching tachistoscopic stimulus presentations. However, the bilateral field advantage throughput performance ratio did not differ among groups, which is a global measure of bilateral versus unilateral brain/behavior asymmetries. CONCLUSION: PCOS screening can be a feasible and important part of women's healthcare. PCOS-confirmed women should receive not only the medical standard of care from the 2018 guidelines, but also comprehensive psychosocial and neurocognitive support to enhance their quality of life.