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Persistence is the propensity to maintain goal-directed actions despite adversities. While this temperamental trait is crucial to mitigate depression risk, its neurobiological foundations remain elusive. Developing behavioral tasks to capture persistence in animal models is crucial for understanding its molecular underpinnings. Here, we introduce the Sinking Platform Test (SPT), a novel high-throughput paradigm to measure persistence. Mice were trained to exit a water-filled tank by ascending onto a platform above water level. Throughout the training, mice were also occasionally exposed to “failure trials,” during which an operator would submerge a platform right after the mouse climbed onto it, requiring the mouse to reach and ascend a newly introduced platform. Following training, mice were subjected to a 5-min test exclusively consisting of failure trials. Male and female mice exhibited comparable persistence, measured by the number of climbed platforms during the test. Furthermore, this index was increased by chronic administration of fluoxetine or imipramine; conversely, it was reduced by acute and chronic haloperidol. Notably, six weeks of social isolation reduced SPT performance, and this effect was rescued by imipramine treatment over the last two weeks. A 4-week regimen of voluntary wheel running also improved persistence in socially isolated mice. Finally, comparing transcriptomic profiles of the prefrontal cortex of mice with high and low SPT performance revealed significant enrichment of immediate-early genes known to shape susceptibility for chronic stress. These findings highlight the potential of SPT as a promising method to uncover the biological mechanisms of persistence and evaluate novel interventions to enhance this response.

Ample evidence suggests that acute stress can worsen symptom severity in Tourette syndrome (TS); however, the neurobiological underpinnings of this phenomenon remain poorly understood. We previously showed that acute stress exacerbates tic-like and other TS-associated responses via the neurosteroid allopregnanolone (AP) in an animal model of repetitive behavioral pathology. To verify the relevance of this mechanism to tic pathophysiology, here we tested the effects of AP in a mouse model recapitulating the partial depletion of dorsolateral cholinergic interneurons (CINs) seen in post-mortemstudies of TS. Mice underwent targeted depletion of striatal CINs during adolescence and were tested in young adulthood. Compared with controls, partially CIN-depleted male mice exhibited several TS-relevant abnormalities, including deficient prepulse inhibition (PPI) and increased grooming stereotypies after a 30-min session of spatial confinement - a mild acute stressor that increases AP levels in the prefrontal cortex (PFC). These effects were not seen in females. Systemic and intra-PFC AP administration dose-dependently worsened grooming stereotypies and PPI deficits in partially CIN-depleted males. Conversely, both AP synthesis inhibition and pharmacological antagonism reduced the effects of stress. These results further suggest that AP in the PFC mediates the adverse effects of stress on the severity of tics and other TS-related manifestations. Future studies will be necessary to confirm these mechanisms in patients and define the circuitry responsible for the effects of AP on tics.

In a program to identify pain treatments with low addiction potential, we isolated five steroids, conosteroids A–E (1–5), from the hypobranchial gland of the mollusk Conus geographus. Compounds 1–5were active in a mouse dorsal root ganglion (DRG) assay that suggested that they might be analgesic. A synthetic analogue 6was used for a detailed pharmacological study. Compound 6significantly increased the pain threshold in mice in the hot-plate test at 2 and 50 mg/kg. Compound 6at 500 nM antagonizes type-A γ-aminobutyric acid receptors (GABAARs). In a patch-clamp experiment, out of the six subunit combinations tested, 6exhibited subtype selectivity, most strongly antagonizing α1β1γ2and α4β3γ2receptors (IC501.5 and 1.0 μM, respectively). Although the structures of 1–6differ from those of known neuroactive steroids, they are cell-type-selective modulators of GABAARs, expanding the known chemical space of neuroactive steroids.

Acute sleep deprivation (SD) can trigger or exacerbate psychosis- and mania-related symptoms; the neurobiological basis of these complications, however, remains elusive. Given the extensive involvement of neuroactive steroids in psychopathology, we hypothesized that the behavioral complications of SD may be contributed by 5α-reductase (5αR), the rate-limiting enzyme in the conversion of progesterone into the neurosteroid allopregnanolone. We first tested whether rats exposed to SD may exhibit brain-regional alterations in 5αR isoenzymes and neuroactive steroid levels; then, we assessed whether the behavioral and neuroendocrine alterations induced by SD may be differentially modulated by the administration of the 5αR inhibitor finasteride, as well as progesterone and allopregnanolone. SD selectively enhanced 5αR expression and activity, as well as AP levels, in the prefrontal cortex; furthermore, finasteride (10–100 mg/kg, IP) dose-dependently ameliorated PPI deficits, hyperactivity, and risk-taking behaviors, in a fashion akin to the antipsychotic haloperidol and the mood stabilizer lithium carbonate. Finally, PPI deficits were exacerbated by allopregnanolone (10 mg/kg, IP) and attenuated by progesterone (30 mg/kg, IP) in SD-subjected, but not control rats. Collectively, these results provide the first-ever evidence that 5αR mediates a number of psychosis- and mania-like complications of SD through imbalances in cortical levels of neuroactive steroids.

Obesity is a major public health problem, which, like many forms of addiction, is associated with an elevated tendency to choose smaller immediate rather than larger delayed rewards, a response pattern often referred to as excessive delay discounting. Although some accounts of delay discounting conceptualize this process as impulsivity (placing the emphasis on overvaluing the smaller immediate reward), others have conceptualized delay discounting as an executive function (placing the emphasis on delayed rewards failing to retain their value). The present experiments used a popular animal model of obesity that has been shown to discount delayed rewards at elevated rates (i.e., obese Zucker rats) to test two predictions that conceptualize delay discounting as executive function. In the first experiment, acquisition of lever pressing with delayed rewards was compared in obese versus lean Zucker rats. Contrary to predictions based on delay discounting as executive function, obese Zucker rats learned to press the lever more quickly than controls. In the second experiment, progressive ratio breakpoints (a measure of reward efficacy) with delayed rewards were compared in obese versus lean Zucker rats. Contrary to the notion that obese rats fail to value delayed rewards, the obese Zucker rats' breakpoints were (at least) as high as those of the lean Zucker rats.

Rich evidence has shown that cannabis products exert a broad gamut of effects on emotional regulation. The main psychoactive ingredient of hemp, Δ9-tetrahydrocannabinol (THC), and its synthetic cannabinoid analogs have been reported to either attenuate or exacerbate anxiety and fear-related behaviors in humans and experimental animals. The heterogeneity of cannabis-induced psychological outcomes reflects a complex network of molecular interactions between the key neurobiological substrates of anxiety and fear and the endogenous cannabinoid system, mainly consisting of the arachidonic acid derivatives anandamide and 2-arachidonoylglycerol (2-AG) and two receptors, respectively termed CB1 and CB2. The high degree of interindividual variability in the responses to cannabis is contributed by a wide spectrum of factors, including genetic and environmental determinants, as well as differences in the relative concentrations of THC and other alkaloids (such as cannabidiol) within the plant itself. The present article reviews the currently available knowledge on the herbal, synthetic and endogenous cannabinoids with respect to the modulation of anxiety responses, and highlights the challenges that should be overcome to harness the therapeutic potential of some of these compounds, all the while limiting the side effects associated with cannabis consumption. In addition the article presents some promising patents on cannabinoid-related agents.

The enzyme steroid 5α-reductase (S5αR) catalyzes the conversion of Δ4-3-ketosteroid precursors - such as testosterone, progesterone and androstenedione - into their 5α-reduced metabolites. Although the current nomenclature assigns five enzymes to the S5αR family, only the types 1 and 2 appear to play an important role in steroidogenesis, mediating an overlapping set of reactions, albeit with distinct chemical characteristics and anatomical distribution. The discovery that the 5α-reduced metabolite of testosterone, 5α- dihydrotestosterone (DHT), is the most potent androgen and stimulates prostatic growth led to the development of S5αR inhibitors with high efficacy and tolerability. Two of these agents, finasteride and dutasteride, have received official approval for the treatment of benign prostatic hyperplasia and are being tested for prevention of prostate cancer. Finasteride is also approved for male-pattern alopecia and has been shown to induce very limited side effects. Over the last decade, converging lines of evidence have highlighted the role of 5α- reduced steroids and their precursors in brain neurotransmission and behavioral regulation. Capitalizing on these premises, we and other groups have recently investigated the role of S5αR in neuropsychiatric disorders. Our preliminary data suggest that S5αR inhibitors may elicit therapeutic effects in a number of disorders associated with dopaminergic hyperreactivity, including psychotic disorders, Tourette syndrome and impulse control disorders. In the present article, we review emerging preclinical and clinical evidence related to these effects, and discuss some of the potential mechanisms underlying the role of S5αR in the pathophysiology of mental disorders.

The enzyme steroid 5-reductase (S5R) catalyzes the conversion of 4-3-ketosteroid precursors - such as testosterone, progesterone and androstenedione - into their 5-reduced metabolites. Although the current nomenclature assigns five enzymes to the S5R family, only the types 1 and 2 appear to play an important role in steroidogenesis, mediating an overlapping set of reactions, albeit with distinct chemical characteristics and anatomical distribution. The discovery that the 5-reduced metabolite of testosterone, 5- dihydrotestosterone (DHT), is the most potent androgen and stimulates prostatic growth led to the development of S5R inhibitors with high efficacy and tolerability. Two of these agents, finasteride and dutasteride, have received official approval for the treatment of benign prostatic hyperplasia and are being tested for prevention of prostate cancer. Finasteride is also approved for male-pattern alopecia and has been shown to induce very limited side effects. Over the last decade, converging lines of evidence have highlighted the role of 5- reduced steroids and their precursors in brain neurotransmission and behavioral regulation. Capitalizing on these premises, we and other groups have recently investigated the role of S5R in neuropsychiatric disorders. Our preliminary data suggest that S5R inhibitors may elicit therapeutic effects in a number of disorders associated with dopaminergic hyperreactivity, including psychotic disorders, Tourette syndrome and impulse control disorders. In the present article, we review emerging preclinical and clinical evidence related to these effects, and discuss some of the potential mechanisms underlying the role of S5R in the pathophysiology of mental disorders.

A novel line of mutant mice monoamine oxidase A knockout (MAOAA863TKO) harboring a spontaneous point nonsense mutation in exon 8 of the MAO A gene was serendipitously identified in a 129SvEvTac colony. This mutation is analogous to the cause of a rare human disorder, Brunner syndrome, characterized by complete MAO A deficiency and impulsive aggressiveness. Concurrent with previous studies of MAO A KO mice generated by insertional mutagenesis (‘Tg8’), MAOAA863TKO lack MAO A enzyme activity and display enhanced aggression toward intruder mice. MAOAA863TKO, however, exhibited lower locomotor activity in a novel, inescapable open field and similar immobility during tail suspension compared with wild type, observations which differ from reports of Tg8. These findings consolidate evidence linking MAO A to aggression and highlight subtle yet distinctive phenotypical characteristics.