Psilocybin analog 4-OH-DiPT enhances fear extinction and GABAergic inhibition of principal neurons in the basolateral amygdala.

Psychedelics such as psilocybin show great promise for the treatment of depression and PTSD, but their long duration of action poses practical limitations for patient access. 4-OH-DiPT is a fast-acting and shorter-lasting derivative of psilocybin. Here we characterized the pharmacological profile of 4-OH-DiPT and examined its impact on fear extinction learning as well as a potential mechanism of action. First, we profiled 4-OH-DiPT at all 12 human 5-HT GPCRs. 4-OH-DiPT showed strongest agonist activity at all three 5-HT2A/2B/2C receptors with near full agonist activity at 5-HT2A. Notably, 4-OH-DiPT had comparable activity at mouse and human 5-HT2A/2B/2C receptors. In a fear extinction paradigm, 4-OH-DiPT significantly reduced freezing responses to conditioned cues in a dose-dependent manner with a greater potency in female mice than male mice. Female mice that received 4-OH-DiPT before extinction training had reduced avoidance behaviors several days later in the light dark box, elevated plus maze and novelty-suppressed feeding test compared to controls, while male mice did not show significant differences. 4-OH-DiPT produced robust increases in spontaneous inhibitory postsynaptic currents (sIPSCs) in basolateral amygdala (BLA) principal neurons and action potential firing in BLA interneurons in a 5-HT2A-dependent manner. RNAscope demonstrates that Htr2a mRNA is expressed predominantly in BLA GABA interneurons, Htr2c mRNA is expressed in both GABA interneurons and principal neurons, while Htr2b mRNA is absent in the BLA. Our findings suggest that 4-OH-DiPT activates BLA interneurons via the 5-HT2A receptor to enhance GABAergic inhibition of BLA principal neurons, which provides a potential mechanism for suppressing learned fear.

cAMP-mediated upregulation of HCN channels in VTA dopamine neurons promotes cocaine reinforcement.

Chronic cocaine exposure induces enduring neuroadaptations that facilitate motivated drug taking. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are known to modulate neuronal firing and pacemaker activity in ventral tegmental area (VTA) dopamine neurons. However, it remained unknown whether cocaine self-administration affects HCN channel function and whether HCN channel activity modulates motivated drug taking. We report that rat VTA dopamine neurons predominantly express Hcn3-4 mRNA, while VTA GABA neurons express Hcn1-4 mRNA. Both neuronal types display similar hyperpolarization-activated currents (Ih), which are facilitated by acute increases in cAMP. Acute cocaine application decreases voltage-dependent activation of Ih in VTA dopamine neurons, but not in GABA neurons. Unexpectedly, chronic cocaine self-administration results in enhanced Ih selectively in VTA dopamine neurons. This differential modulation of Ih currents is likely mediated by a D2 autoreceptor-induced decrease in cAMP as D2 (Drd2) mRNA is predominantly expressed in dopamine neurons, whereas D1 (Drd1) mRNA is barely detectable in the VTA. Moreover, chronically decreased cAMP via Gi-DREADD stimulation leads to an increase in Ih in VTA dopamine neurons and enhanced binding of HCN3/HCN4 with tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b), an auxiliary subunit that is known to facilitate HCN channel surface trafficking. Finally, we show that systemic injection and intra-VTA infusion of the HCN blocker ivabradine reduces cocaine self-administration under a progressive ratio schedule and produces a downward shift of the cocaine dose-response curve. Our results suggest that cocaine self-administration induces an upregulation of Ih in VTA dopamine neurons, while HCN inhibition reduces the motivation for cocaine intake.

Treadmill exercise prevents the hyperexcitability of pyramidal neurons in medial entorhinal cortex in the 3xTg-AD mouse model of Alzheimer's disease.

Neuronal hyperactivity is a key abnormality in early stage Alzheimer's disease (AD). Medial entorhinal cortex (mEC) plays a vital role in memory function and is affected early in AD. Growing evidence indicates benefits of regular exercise on memory and cognitive function in humans with AD, although, the underlying mechanisms are not clear. Therefore, this study was designed to test the effects of 16 weeks treadmill exercise on spatial learning memory and the underlying cellular mechanisms in 6-month-old 3xTg-AD mice. Whole-cell patch clamp was used to examine neuronal intrinsic excitability, spontaneous excitatory postsynaptic currents (sEPSCs) and spontaneous inhibitory postsynaptic currents (sIPSCs) of mEC layer II/III pyramidal neurons in the following groups: wild type (WT + sham), 3xTg-AD (AD+sham), WT receiving exercise (WT + Ex), and AD receiving exercise (AD+Ex). We found that at a behavioral level, treadmill exercise decreased working memory errors in radial arm maze (RAM) test in 6-month-old AD mice. At a cellular level, we found that treadmill exercise prevented the abnormal increase in mEC pyramidal neuron input resistance and action potential firing in 6-month-old 3xTg-AD mice compared with WT + sham and AD+Ex mice; further, sEPSC amplitude and frequency were normal in AD+Ex but overactive in AD+sham; additionally, GABAergic inhibition was normal in AD+Ex mice but reduced in AD+sham. In conclusion, our results indicate that treadmill exercise improves spatial learning memory and prevents network hyperexcitability in mEC by reducing pyramidal neuronal intrinsic excitability and normalizing excitatory and inhibitory synaptic transmission in 3xTg-AD mice.

Effects of exercise of different intensities on withdrawal symptoms among people with substance use disorder: a systematic review and meta-analysis.

Background: Exercise can effectively attenuate withdrawal symptoms and reduce relapse, but it is unknown whether exercise of different intensities produces different results. This study aimed to systematically review the effects of different exercise intensities on withdrawal symptoms among people with substance use disorder (SUD). Methods: Systematic searches for randomized controlled trials (RCTs) on exercise, SUD, and abstinence symptoms were conducted via electronic databases, including PubMed, up to June 2022. Study quality was evaluated using the Cochrane Risk of Bias tool (RoB 2.0) for assessment of risk of bias in randomized trials. The meta-analysis was performed by calculating the standard mean difference (SMD) in outcomes of interventions involving light-, moderate-, and high-intensity exercise for each individual study using Review Manager version 5.3 (RevMan 5.3). Results: In total, 22 RCTs (n = 1,537) were included. Overall, exercise interventions had significant effects on withdrawal symptoms, but the effect size varied with exercise intensity and by outcome measure (i.e., for different negative emotions). Light-, moderate-, and high-intensity exercise reduced cravings after the intervention [SMD = -0.71, 95% CI = (-0.90, -0.52)], and there were no statistical differences between the subgroups (p > 0.05). Light-, moderate-, and high-intensity exercise reduced depression after the intervention [light, SMD = -0.33, 95% CI = (-0.57, -0.09); moderate, SMD = -0.64, 95% CI = (-0.85, -0.42); high, SMD = -0.25, 95% CI = (-0.44, -0.05)], with moderate-intensity exercise producing the best effect (p < 0.05). Only light- and moderate-intensity exercise relieved anxiety after the intervention [light, SMD = -0.48, 95% CI = (-0.71, -0.26); moderate, SMD = -0.58, 95% CI = (-0.85, -0.31)]. Only high-intensity exercise worked in alleviating stress [SMD = -1.13, 95% CI = (-2.22, -0.04)]. Both irritability and restlessness could be improved by light- and moderate-intensity exercise [irritability, SMD = -0.74, 95% CI = (-0.98, -0.50); restless, SMD = -0.72, 95% CI = (-0.98, -0.47)], and there were no statistical differences between the subgroups (p > 0.05). Moderate- and high-intensity exercise decreased withdrawal syndrome after the intervention [moderate, SMD = -0.30, 95% CI = (-0.55, -0.05); high, SMD = -1.33, 95% CI = (-1.90, -0.76)], with high-intensity exercise producing the best effects (p < 0.01). Conclusion: Overall, exercise leads to improvements in withdrawal symptoms in individuals with SUD, but these effects vary significantly between the exercise of different intensities and according to the type of withdrawal symptoms. Moderate-intensity exercise has the greatest benefits in improving depression and anxiety; high-intensity exercise has the greatest benefits in improving withdrawal syndrome. Systematic Review Registration: www.crd.york.ac.uk/PROSPERO/, identifier, CRD42022343791.

Targeted Lipidomics and Inflammation Response to Six Weeks of Sprint Interval Training in Male Adolescents.

Lipids play an important role in coordinating and regulating metabolic and inflammatory processes. Sprint interval training (SIT) is widely used to improve sports performance and health outcomes, but the current understanding of SIT-induced lipid metabolism and the corresponding systemic inflammatory status modification remains controversial and limited, especially in male adolescents. To answer these questions, twelve untrained male adolescents were recruited and underwent 6 weeks of SIT. The pre- and post-training testing included analyses of peak oxygen consumption (VO2peak), biometric data (weight and body composition), serum biochemical parameters (fasting blood glucose, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triacylglycerol, testosterone, and cortisol), inflammatory markers, and targeted lipidomics. After the 6-week SIT, the serum C-reactive protein (CRP), interleukin (IL)-1ß, IL-2, IL-4, IL-10, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-ß significantly decreased (p < 0.05), whereas IL-6 and IL-10/TNF-α significantly increased (p < 0.05). In addition, the targeted lipidomics revealed changes in 296 lipids, of which 33 changed significantly (p < 0.05, fold change > 1.2 or <1/1.2). The correlation analysis revealed that the changes in the inflammatory markers were closely correlated with the changes in some of the lipids, such as LPC, HexCer, and FFA. In conclusion, the 6-week SIT induced significant changes in the inflammatory markers and circulating lipid composition, offering health benefits to the population.