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Background: Type 1 (Th1) and Type 2 (Th2) immunity have both been implicated in granuloma annulare (GA). To what extent these pathways contribute to clinical/histologic heterogeneity and/or distinct disease endotypes remains unexplored., Methods: We retrospectively analyzed 30 GA biopsies with either palisaded or interstitial histology with and without eosinophils. We performed RNA in situ hybridization to assess how markers of Type 1 (interferon gamma), Type 2 (interleukin [IL]4, IL13, IL5), and Type 3 (IL17A) immunity in GA compared with canonical inflammatory disorders and whether markers correlated with histology. We analyzed another cohort of 14 patients who had multiple biopsies across anatomic space and time for individual conservation of histologic features., Results: Interferon (IFN)G staining is highest in GA relative to other cytokines. Type 2 cytokine staining is less prominent, with IL4 increased in interstitial pattern cases. Eosinophils did not correlate with Type 2 markers. Patients with multiple biopsies display intrapatient variability in histology., Conclusion: Type 1 inflammation predominates over Type 2 inflammation in GA irrespective of histologic pattern. Distinct disease endotypes were not detected., (© 2023 the International Society of Dermatology.)

Rationale: Cariprazine is an atypical antipsychotic that acts as a D3/D2 receptor partial agonist. In addition to treating positive symptoms of schizophrenia, cariprazine may have utility for treating negative symptoms. Rodent studies have focused on the effects of cariprazine on cognitive functions and behaviors thought to be related to anhedonia. Avolition, which is characterized by reduced initiation and persistence of goal-directed behavior, is another important negative symptom., Objectives: Effort-related choice tasks have been used as animal models of avolition. In these studies, cariprazine was assessed for its effects on effort-based choice in both rats and mice. Previous work has shown that D2 antagonists such as haloperidol and eticlopride produce a low-effort bias in rodents tested on effort-based choice tasks., Results: Low doses of cariprazine produced a low-effort bias in rats tested on the fixed ratio 5/chow feeding choice task, decreasing lever pressing for high carbohydrate pellets but increasing chow intake. Cariprazine did not alter preference or intake of these foods in free-feeding tests. The effort-related effects of cariprazine were reversed by co-administration of the adenosine A 2A antagonist istradefylline, and cariprazine failed to reverse the effort-related effects of the dopamine-depleting agent tetrabenazine. In mouse touchscreen choice tests, low doses of cariprazine also produced a low-effort bias, shifting behavior away from panel pressing., Conclusions: These results demonstrate that with these rodent models of avolition, cariprazine appears to act like a D2-family antagonist even at very low doses. Furthermore, the pharmacological regulation of avolition may differ from that of other negative symptoms., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Effort-based decision-making tasks allow animals to choose between preferred reinforcers that require high effort to obtain vs. low-effort/low reward options. Mesolimbic dopamine (DA) and related neural systems regulate effort-based choice. Tetrabenazine (TBZ) is a vesicular monoamine transport type-2 inhibitor that blocks DA storage and depletes DA. In humans, TBZ induces motivational dysfunction and depression. TBZ has been shown reliably to induce a low-effort bias in rats, but there are fewer mouse studies., Objectives: The present studies used touchscreen operant procedures (Bussey-Saksida chambers) to assess the effects of TBZ on effort-based choice in mice., Methods: C57BL6 mice were trained to press an elevated lit panel on the touchscreen on a fixed ratio 1 schedule reinforced by strawberry milkshake, vs. approaching and consuming a concurrently available but less preferred food pellets (Bio-serv)., Results: TBZ (2.0-8.0 mg/kg IP) shifted choice, producing a dose-related decrease in panel pressing but an increase in pellet intake. In contrast, reinforcer devaluation by pre-feeding substantially decreased both panel pressing and pellet intake. In free-feeding choice tests, mice strongly preferred the milkshake vs. the pellets, and TBZ had no effect on milkshake intake or preference, indicating that the TBZ-induced low-effort bias was not due to changes in primary food motivation or preference. TBZ significantly decreased tissue levels of nucleus accumbens DA., Conclusion: The DA depleting agent TBZ induced an effort-related motivational dysfunction in mice, which may have clinical relevance for assessing novel drug targets for their potential use as therapeutic agents in patients with motivation impairments.