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Using data from the Louisiana Department of Public Health, we explored the spatial relationships between the Social Vulnerability Index (SVI) and COVID-19-related vaccination and mortality rates. Publicly available COVID-19 vaccination and mortality data accrued from December 2020 to October 2021 was downloaded from the Louisiana Department of Health website and merged with the SVI data; geospatial analysis was then performed to identify the spatial association between the SVI and vaccine uptake and mortality rate. Bivariate Moran’s I analysis revealed significant clustering of high SVI ranking with low COVID-19 vaccination rates (1.00, p p

Xylenes are aromatic hydrocarbons used for industrial applications such as the production of petrochemicals and plastics. Acute xylene exposures can negatively impact health through neurotoxicity and irritation of respiratory and dermal tissues. We quantified urinary biomarkers of xylene exposure [2-methylhippuric acid (2MHA) and a mixture of 3- and 4-methylhippuric acids (34MH)] in a representative sample of the U.S. population. Spot urine obtained during the National Health and Nutrition Examination Survey 2005–2006 and 2011–2016 was analyzed using ultra-high-performance liquid chromatography/tandem mass spectrometry. Exclusive smokers were distinguished from non-users using a combination of self-report and serum cotinine data. The median 2MHA and 34MH levels were higher for exclusive smokers (100 μg/g and 748 μg/g creatinine, respectively) than for non-users (27.4 μg/g and 168 μg/g creatinine, respectively). Participants who smoked cigarettes had significantly higher 2MHA and 34MH levels (p20 cigarettes per day (CPD) was significantly associated with 181%, 339% and 393% higher 2MHA levels, respectively. For 34MH, smoking 1–10, 11–20, and >20 CPD was significantly associated with 201%, 398%, and 471% higher 34MH levels, respectively. We confirm that tobacco smoke is a significant source of xylene exposure as measured by urinary 2MHA and 34MH levels.

Nonmedical use of prescription and nonprescription drugs is a worldwide epidemic, rapidly growing in magnitude with deaths because of overdose and chronic use. A vast majority of these drugs are stimulants that have various effects on the cardiovascular system including the cardiac rhythm. Drugs, like cocaine and methamphetamine, have measured effects on the conduction system and through several direct and indirect pathways, utilizing multiple second messenger systems, change the structural and electrical substrate of the heart, thereby promoting cardiac dysrhythmias. Substituted amphetamines and cocaine affect the expression and activation kinetics of multiple ion channels and calcium signaling proteins resulting in EKG changes, and atrial and ventricular brady and tachyarrhythmias. Preexisting conditions cause substrate changes in the heart, which decrease the threshold for such drug-induced cardiac arrhythmias. The treatment of cardiac arrhythmias in patients who take drugs of abuse may be specialized and will require an understanding of the unique underlying mechanisms and necessitates a multidisciplinary approach. The use of primary or secondary prevention defibrillators in drug abusers with chronic systolic heart failure is both sensitive and controversial. This review provides a broad overview of cardiac arrhythmias associated with stimulant substance abuse and their management.

The treatment of substance abuse with oxytocin is a novel approach to a challenging public health issue that continues to contribute to a growing economic cost for societies worldwide. Methamphetamine addiction is one of the leading causes of mortality worldwide, and despite advances in understanding the neurobiology of methamphetamine addiction, treatment options are limited. There are no medications that the Food and Drug Administration currently approves for stimulant use disorder. Off-label use of therapies for stimulant misuse include antidepressants, anxiolytics, and milder stimulants as replacement agents. Due to the shortcomings of these attempts to treat a complicated psychiatric disorder, recent attention to oxytocin therapy (OT) has gained momentum in clinical studies as a possible therapy in the context of social stress, social anxiety, social cognition, and psychosis. Oxytocin produces enhanced connectivity between cortical regions. The results from studies in rodents with OT suggest that central neuromodulation of oxytocin may be beneficial across transition states of stimulant dependence and may alleviate intense withdrawal symptoms. Studies of oxytocin in the context of other drugs of abuse, including cocaine, cannabis, and alcohol, also support the potential of oxytocin to treat stimulant use disorder, methamphetamine type. Methamphetamine abuse continues to be a significant cause of distress and dysfunction throughout the world. The effects of oxytocin on methamphetamine use outlined in this review should act as a catalyst for further investigation into the efficacy of treating stimulant use disorder, methamphetamine type with oxytocin in humans. More human-based research should initiate studies involving the long-term efficacy, side effects, and patient selection.

There are no Food and Drug Administration approved pharmacotherapies for methamphetamine (METH) overdose, thus identifying novel drug targets to prevent this devastating adverse event is a public-health imperative. Previous research suggests that serotonin and sigma receptors may contribute to the adverse effects of METH. The present study assessed whether pretreatment with the 5-HT2A receptor antagonist M100907 or the sigma 1 (σ1) receptor antagonist BD 1047 attenuated METH-induced lethality, hyperthermia, convulsions, and seizures. Male, Swiss-Webster mice received intraperitoneal injections of M100907 (1 and 10 mg/kg), BD 1047 (10 mg/kg), or a combination of M100907 (1 mg/kg) and BD 1047 (10 mg/kg) prior to treatment with METH (78 mg/kg). Convulsions and lethality were assessed by observation, core body temperature was assessed by surgically implanted telemetric probes, and seizures were assessed by electroencephalography. M100907 reduced METH-elicited lethality from 67% to 33%, BD1047 reduced METH-elicited lethality from 67% to 50%, and combined administration of both agents eliminated lethality in all mice tested. Similarly, both agents and their combination reduced METH-elicited seizures and convulsions. None of the treatments decreased METH-induced hyperthermia. This research suggests that reducing METH-induced seizures is an important factor in reducing lethality associated with METH overdose. However, future studies should examine whether M100907 and BD 1047 modulate METH-induced hypertension and other adverse effects that may also contribute to METH overdose. Our data support the continued investigation of compounds that target 5-HT2A and σ1 receptors in METH-induced overdose, including their potential to yield emergency reversal agents.

RATIONALE: Approximately 20 million adults in the United States have an alcohol use disorder (AUD). There are clinical and preclinical data suggesting that psychedelics may have benefits for AUD. OBJECTIVE: To investigate the effects of the synthetic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) on the behavioral effects of ethanol. METHODS: The effects of DOI were examined using ethanol-induced place conditioning (1.8 g/kg ethanol) and 2-bottle choice ethanol drinking (20% v/v), using a dose of DOI (3 mg/kg) that produced the peak response in the serotonin 2A (5-HT(2A)) receptor dependent head-twitch assay. Interactions between DOI and ethanol (3 g/kg) were examined using the ethanol-induced loss of righting reflex procedure and blood-ethanol analysis. To examine additional mechanisms by which psychedelics may interact with ethanol, we determined whether DOI reverses ethanol-induced nitric oxide release in macrophages, a marker of inflammation. RESULTS: DOI significantly attenuated ethanol-induced place conditioning and ethanol drinking. DOI-induced suppression of alcohol drinking depended upon 5-HT(2A) receptors, was selective for alcohol over water, and was selective for high alcohol preferring subjects. DOI had no apparent pharmacokinetic interactions with ethanol, and DOI reduced ethanol-induced nitric oxide release. CONCLUSIONS: Our findings demonstrate that DOI blocks ethanol place conditioning and selectively reduces voluntary ethanol consumption. This may be related to modulation of the effects of ethanol in the reward circuitry of the brain, ethanol-induced neuroinflammation, or a combination of both. Additional studies to elucidate the mechanisms through which psychedelics attenuate the effects of ethanol would inform the pathophysiology of AUD and potentially provide new treatment options.

Synthetic cathinones (SCs) are β‐keto analogs of amphetamines. Like amphetamines, SCs target monoamine transporters; however, unusual neuropsychiatric symptoms have been associated with abuse of some SCs, suggesting SCs might possess additional pharmacological properties. We performed radioligand competition binding assays to assess the affinities of nine SCs at human 5‐HT(2A) receptors (5‐HT(2A)R) and muscarinic M(1) receptors (M(1)R) transiently expressed in HEK293 cells. None of the SCs exhibited affinity at M(1)R (minimal displacement of [~K(d)] [3H]scopolamine up to 10 μM). However, two SCs, α‐pyrrolidinopropiophenone (α‐PPP) and 4‐methyl‐α‐PPP, had low μM K(i) values at 5‐HT(2A)R. In 5‐HT(2A)R–phosphoinositide hydrolysis assays, α‐PPP and 4‐methyl‐α‐PPP displayed inverse agonist activity. We further assessed the 5‐HT(2A)R functional activity of α‐PPP, and observed it competitively antagonized 5‐HT(2A)R signaling stimulated by the 5‐HT(2)R agonist (±)‐2,5‐ dimethoxy‐4‐iodoamphetamine (DOI; K(b) = 851 nM). To assess in vivo 5‐HT(2A)R activity, we examined the effects of α‐PPP on the DOI‐elicited head‐twitch response (HTR) in mice. α‐PPP dose‐dependently blocked the HTR with maximal suppressiont 10 mg/kg (P < 0.0001), which is a moderate dose used in studies investigating psychostimulant properties of α‐PPP. To corroborate a 5‐HT(2A)R mechanism, we also tested 3,4‐methylenedioxy‐α‐PPP (MDPPP) and 3‐bromomethcathinone (3‐BMC), SCs that we observed had 5‐HT(2A)R K(i)s > 10 μM. Neither MDPPP nor 3‐BMC, at 10 mg/kg doses, attenuated the DOI HTR. Our results suggest α‐PPP has antagonist interactions at 5‐HT(2A)R in vitro that may translate at physiologically‐relevant doses in vivo. Considering 5‐HT(2A)R antagonism has been shown to mitigate effects of psychostimulants, this property may contribute to α‐PPPs unpopularity compared to other monoamine transporter inhibitors.

Anesthesia-Induced Hypothermia (AIH) has been reported to be the cause of many postoperative adverse effects, including increased mortality, decreased immune responses, cardiac events, and a greater prevalence of postoperative surgical wound infections. AIH can in some cases be minimized with pre-warming fluids and gases and forced-air heating systems, but such techniques are not always effective and can result in patient burns or other adverse effects. Stimulation of 5-HT2 receptors has been reported to increase body temperature through a variety of mechanisms, and as such, may be a viable target for pharmacologically minimizing AIH. In the present study, we examined the effects of 5-HT2 receptor stimulation on hypothermia induced by the injectable anesthetic ketamine in Swiss-Webster mice using rectal thermometry. We report that ketamine dose-dependently induced hypothermia, and mice did not become tolerant to this effect of ketamine over the course of three injections spaced at once per week. Ketamine-induced hypothermia was significantly attenuated by pretreatment with the selective 5-HT2C receptor agonist WAY-163909 but not by pretreatment with the mixed 5-HT2A/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). Moreover, the blockade of ketamine-induced hypothermia by WAY-163909 was reversed by pretreatment with the selective 5-HT2C receptor antagonist SB-242084. These findings demonstrate that stimulation of 5-HT2C receptors can reduce AIH, at least for ketamine-induced hypothermia. They warrant further study of the pharmacological and neurobiological mechanisms underlying this interaction and its extension to other anesthetics. Furthermore, these findings suggest that the maintenance of body temperature during surgery may be a new clinical use for 5-HT2C receptor agonists.

A previous study from our laboratory has shown that the selective catecholamine reuptake inhibitor 3,4-methylenedioxypyrovalerone (MDPV) persistently alters impulsive choice as measured by delay discounting. To further understand the proimpulsive effects of MDPV, we examined its capacity to modulate a different impulsive measure - impulsive action - using a differential reinforcement of low rates of responding task with an inter-response time of 20 s. Three groups of male, Sprague-Dawley rats (n = 6) were first tested in daily sessions to understand the acute effects of cocaine (1.0-30.0 mg/kg), MDPV (0.1-3.0 mg/kg), or saline (1.0 ml/kg) on impulsive action. Both cocaine and MDPV increased impulsive action, most notably by decreasing timing error responses and response efficiency, but MDPV was more effective than cocaine. Additionally, MDPV suppressed operant responding in two of six animals at the highest dose tested. Next, the same animals received 10 postsession injections, once every other day, of either 30.0 mg/kg cocaine, 3.0 mg/kg MDPV, or 1.0 ml/kg saline based on their treatment group. An acute dose-effect redetermination was completed following the repeated administration studies, and once again MDPV and cocaine demonstrated proimpulsive effects. Interestingly, timing error responses were decreased in both MDPV and cocaine groups after an acute saline injection, potentially indicating persistent impulsive changes following the repeated administration phase of the experiment. These studies indicate that MDPV increases impulsive action acutely and that this increase may be potentiated following a series of repeated administrations.

RATIONALE: Synthetic cathinones (“bath salts”) are β-ketone analogs of amphetamines, yet few studies have examined their potential neurotoxic effects. OBJECTIVE: In the current study, we assessed the persistent behavioral and neurochemical effects of exposure to the second-generation synthetic cathinone α-pyrrolidinopropiophenone (α-PPP). METHODS: Male, Swiss-Webster mice were exposed to α-PPP (80mg/kg) using a binge-like dosing regimen (QID, q2h). Behavior was assessed 4–5 days after the dosing regimen, and neurochemistry was assessed the following day. Behavior was studied using the elevated plus maze, Y-maze, and novel object recognition tests. Regional levels of dopamine, serotonin, norepinephrine, and the major dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were determined in the prefrontal cortex and striatum using high-pressure liquid chromatography. Additional experiments assessed the time courses of the effects of α-PPP on locomotor activity and core temperature using telemetry. RESULTS: Exposure to α-PPP significantly impaired performance in the Y-maze, decreased overall exploratory activity in the novel object recognition test, and resulted in regionally specific depletions in monoamine neurochemistry. In contrast, it had no significant effect on elevated plus maze performance or object discrimination in the novel object recognition test. The locomotor-stimulant effects of α-PPP were comparable to cocaine (30mg/kg), and α-PPP (80mg/kg) did not induce hyperthermia. CONCLUSIONS: α-PPP exposure results in persistent changes in exploratory behavior, spatial working memory, and monoamine neurochemistry. This research highlights potential dangers of α-PPP, including potential neurotoxicity, and suggests that the mechanisms underlying the persistent untoward effects of the cathinones may be distinct from those of the amphetamines.

The objective of our study was to develop a transdermal patch of 4-benzylpiperidine and to evaluate its in vitro transdermal permeation profile. Appropriate pressure sensitive adhesives and additives were selected based on solubility and slide crystallization studies. Release liners and backing membranes were selected based on their ability to peel without leaving a residue and their affinity to formulation respectively. Drug-in-adhesive patches developed were investigate for their in vitro drug permeation over 48 h across dermatomed human skin using Franz diffusion cells. Silicone based pressure sensitive adhesive along with colloidal silicon dioxide as viscosity builder, fluoropolymer coated membranes as the release liner and polyester based membranes as backing were chosen to develop a drug in silicone adhesive patch. Polyisobutylene adhesive based patch was developed with drug in polyisobutylene adhesive, along with oleic acid and oleyl alcohol as permeation enhancers, polyester for the release liner and polyethylene as backing. Among the patches developed, polyisobutylene adhesive based patch with higher drug concentration exhibited superior transdermal permeation (1608.5 ± 53.4 µg/cm2 over 48 h). The final patch was further tested for uniformity in coat weight, shear strength, tack and peel adhesion.

Objective. To implement and assess the impact of a hybrid flipped-classroom activity designed to increase the motivation and confidence of Doctor of Pharmacy (PharmD) students in addressing the opioid crisis. Methods. Third-professional year student pharmacists were provided with reading material developed by federal agencies and professional pharmacy organizations, as well as Georgia-specific information covering medical amnesty and local resources for opioid-overdose prevention prior to class. They then attended a four-hour classroom session that included hearing a lecture on opioid pharmacology and opioid overdose, viewing training videos, and engaging in extensive discussion. The students voluntarily completed pre- and post-intervention assessments regarding opioid abuse and opioid overdose prevention. Results. Seventy of the 107 third-year students enrolled in the course completed the pre-intervention assessment (65% response rate), and 33 of the 70 completed the post-intervention assessment (47% retention rate). The students exhibited a high baseline motivation to assist in combating the opioid crises, but less confidence in their ability to intervene. Significant increases were seen in areas related to student confidence on the post-intervention assessment. Fewer changes were seen in areas related to student motivation. Conclusion. A "hybrid" flipped classroom activity increased the confidence of student pharmacists in their understanding of the physical and adverse effects of opioids and the application of reversal agents. Increased confidence may support increased intervention.

3-fluoroamphetamine (also called PAL-353) is a synthetic amphetamine analog that has been investigated for cocaine-use disorder (CUD), yet no studies have characterized its pharmacokinetics (PK). In the present study, we determined the PK of PAL-353 in male Sprague Dawley rats following intravenous bolus injection (5 mg/kg). Plasma samples were analyzed using a novel bioanalytical method that coupled liquid-liquid extraction and LC-MS/MS. The primary PK parameters determined by WinNonlin were a C(0) (ng/mL) of 1412.09 ± 196.12 and a plasma half-life of 2.27 ± 0.67 hours. As transdermal delivery may be an optimal approach to delivering PAL-353 for CUD, we assessed its PK profile following application of 50 mg of transdermal gel (10% w/w drug over 5 cm(2)). The 10% w/w gel resulted in a short lag time, sustained delivery, and a rapid clearance in plasma immediately after removal. The rodent PK data were verified by examining in vitro permeation through human epidermis mounted on Franz diffusion cells. An in vitro-in vivo correlation (IVIVC) analysis was performed using the Phoenix IVIVC toolkit to assess the predictive relationship between rodent and human skin absorption/permeation. The in vitro permeation study revealed a dose-proportional cumulative and steady-state flux with ~70% of drug permeated. The fraction absorbed in vivo and fraction permeated in vitro showed a linear relationship. In conclusion, we have characterized the PK profile of PAL-353, demonstrated that it has favorable PK properties for transdermal administration for CUD, and provided preliminary evidence of the capacity of rodent data to predict human skin flux.

3,4-Methylenedioxypyrovalerone (MDPV) is a selective catecholamine reuptake inhibitor abused for its psychostimulant properties. This study examined if MDPV administration alters impulsive choice measured by delay discounting in rats. Three groups of rats were tested in daily delay discounting sessions to determine the effects of acute cocaine (1.0-30.0 mg/kg), MDPV (0.1-3.0 mg/kg), or saline on mean adjusted delay (MAD). Dose-dependent decreases in MAD were elicited only by acute MDPV, which also suppressed operant responding at the highest dose. Next, rats received post-session injections (30.0 mg/kg cocaine, 3.0 mg/kg MDPV, or saline) every other day for a total of 10 injections. MAD increased during saline treatment, did not change during cocaine treatment, and was reduced during MDPV treatment. In dose-effect re-determinations, no acute drug effects on MAD were observed, but compared to the initial dose-effect determination, MDPV suppressed operant responding in more animals, with zero animals completing trials at the highest dose. All saline and MDPV-treated subjects were sacrificed, and striatal and cortical dopamine levels were quantified by HPLC. These studies indicate that administration of MDPV may increase impulsive choice acutely and persistently. These proimpulsive effects are possibly mediated by increases in striatal dopamine turnover.

3,4-methylenedioxymethamphetamine (MDMA) recently achieved breakthrough status from the Food and Drug Administration (FDA) for post-traumatic stress disorder (PTSD). However, evidence indicates that exposure to toxic doses of 3,4-methylenedioxymethamphetamine (MDMA) can lead to long-lasting dysregulation of brain monoaminergic neurotransmitters, primarily from studies conducted in young adult rodents. To date, there is a paucity of data on whether toxic doses of MDMA can differentially affect neurotransmitter systems in adolescents and mature adults, which is an important question as adolescents and adults may be differentially vulnerable to MDMA abuse. In the current study, adolescent (6–7 weeks of age) and adult (16–18 weeks of age) male, Swiss-Webster mice were exposed to MDMA (20 mg/kg) using a binge-like dosing regimen (4 administrations spaced every 2 hours). Acute lethality, acute hyperthermia, and acute decreases in body weight effects following MDMA administration were more pronounced in adolescent than adult mice. Likewise, acute loss of striatal dopamine neurochemistry was also exacerbated in adolescents, as determined by high-pressure liquid chromatography (HPLC) coupled to electrochemical detection. Exposure to MDMA induced greater turnover of dopamine into its major metabolite dihydroxyphenylacetic acid (DOPAC) in adolescents, but not in adults, suggesting a novel mechanism through which adolescents may show increased vulnerability to the acute toxic and neurotoxic effects of MDMA, or conversely that mature adults show greater protection. These data caution that MDMA exposure in adolescence may be particularly dangerous and that the therapeutic window for MDMA may differ between adolescents and mature adults.

Neurodegenerative disorders are commonly associated with a complex pattern of pathophysiological hallmarks, including increased oxidative stress and neuroinflammation, which makes their treatment challenging. Omega-3 Fatty Acids (O3FA) are natural products with reported neuroprotective, anti-inflammatory, and antioxidant effects. These effects have been attributed to their incorporation into neuronal membranes or through the activation of intracellular or recently discovered cell-surface receptors (i.e., Free-Fatty Acid Receptors; FFAR). Molecular docking studies have investigated the roles of O3FA as agonists of FFAR and have led to the development of receptor-specific targeted agonists for therapeutic purposes. Moreover, novel formulation strategies for targeted delivery of O3FA to the brain have supported their development as therapeutics for neurodegenerative disorders. Despite the compelling evidence of the beneficial effects of O3FA for several neuroprotective functions, they are currently only available as unregulated dietary supplements, with only a single FDA-approved prescription product, indicated for triglyceride reduction. This review highlights the relative safety and efficacy of O3FA, their drug-like properties, and their capacity to be formulated in clinically viable drug delivery systems. Interestingly, the presence of cardiac conditions such as hypertriglyceridemia is associated with brain pathophysiological hallmarks of neurodegeneration, such as neuroinflammation, thereby further suggesting potential therapeutic roles of O3FA for neurodegenerative disorders. Taken together, this review article summarizes and integrates the compelling evidence regarding the feasibility of developing O3FA and their synthetic derivatives as potential drugs for neurodegenerative disorders.

Approximately 20 million adults in the United States have an alcohol use disorder. In recent years, modulation of the behavioral effects of ethanol by phytochemicals has been explored. In this study, we used the ethanol-induced loss of righting reflex (LORR) assay to assess potency differences between the sesquiterpene phytochemical beta-caryophyllene (BCP) and its derivative caryophyllene oxide (BCPO). We also investigated the effects of BCPO on two bottle-choice ethanol drinking and the ethanol-induced conditioned place preference (CPP). We then determined whether there are any pharmacokinetic or pharmacodynamic interactions between BCPO and ethanol, using blood ethanol analysis and pretreatments with the selective cannabinoid receptor 2 (CB2) antagonist AM630, respectively. BCPO augmented the ethanol-induced LORR at a dose (30 mg/kg) tenfold lower than BCP (300 mg/kg). Swiss-Webster mice were found to split into stable high and low drinking groups. This same dose (30 mg/kg) of BCPO significantly decreased ethanol intake and preference for ethanol over water in mice that consumed high amounts of ethanol, without any effect on total fluid intake. BCPO had limited effects in mice that consumed low amounts of ethanol. BCPO also significantly attenuated the ethanol-induced CPP. Blood ethanol analysis showed no significant effect of ethanol on the pharmacokinetics of ethanol. Furthermore, the enhancement of the ethanol-induced LORR by BCPO was reversed by AM630. These findings demonstrate that BCPO more potently modulates the behavioral effects of ethanol than the parent compound BCP. Moreover, they suggest that BCPO modulates the behavioral effects of ethanol through pharmacodynamic rather than pharmacokinetic mechanisms.

There is increasing support for the potential clinical use of compounds that interact with serotonin 2A (5-HT(2A)) receptors. It is therefore of interest to discover novel compounds that interact with 5-HT(2A) receptors. In the present study, we used computational chemistry to identify critical ligand structural features of 5-HT(2A) receptor binding and function. Query of compound databases using those ligand features revealed the adrenergic receptor antagonist carvedilol as a high priority match. As carvedilol is used clinically for cardiovascular diseases, we conducted experiments to assess whether it has any interactions with 5-HT(2A) receptors. In vitro experiments demonstrated that carvedilol has high nanomolar affinity for 5-HT(2A) receptors. In vivo experiments demonstrated that carvedilol increases the ethanol-induced loss of the righting reflex and suppresses operant responding in mice, and that these effects are attenuated by pretreatment with the selective 5-HT(2A) receptor antagonist M100907. Moreover, carvedilol did not induce the head-twitch response in mice, suggesting a lack of psychedelic effects. However, carvedilol did not activate canonical 5-HT(2A) receptor signaling pathways and antagonized serotonin-mediated signaling. It also reduced the head-twitch response induced by 2,5-Dimethoxy-4-iodoamphetamine, suggesting potential in vivo antagonism, allosteric modulation, or functional bias. These data suggest that carvedilol has functionally relevant interactions with 5-HT(2A) receptors, providing a novel mechanism of action for a clinically used compound. However, our findings do not clearly delineate the precise mechanism of action of carvedilol at 5-HT(2A) receptors, and additional experiments are needed to elucidate the role of 5-HT(2A) receptors in the behavioral and clinical effects of carvedilol.

Parkinson’s Disease (PD) is the second most common neurodegenerative disease throughout the United States. Dopamine (DA) Replacement Therapy is the standard treatment for the motor symptoms of PD. ...

Serotonin, one of the first neurotransmitters to be identified, is an evolutionarily old molecule that is highly conserved across the animal kingdom, and widely used throughout the brain. Despite this, ascribing a specific set of functions to brain serotonin and its receptors has been difficult and controversial. The 2A subtype of serotonin receptors (5-HT2A receptor) is the major excitatory serotonin receptor in the brain and has been linked to the effects of drugs that produce profound sensory and cognitive changes. Numerous studies have shown that this receptor is upregulated by a broad variety of stressors, and have related 5-HT2A receptor function to associative learning. This review proposes that stress, particularly stress related to danger and existential threats, increases the expression and function of 5-HT2A receptors. It is argued that this is a neurobiological adaptation to promote learning and avoidance of danger in the future. Upregulation of 5-HT2A receptors during stressful events forms associations that tune the brain to environmental cues that signal danger. It is speculated that life-threatening situations may activate this system and contribute to the symptoms associated with post-traumatic stress disorder (PTSD). 3,4-Methylenedioxymethamphetamine, which activates 5-HT2A receptors, has been successful in the treatment of PTSD and has recently achieved status as a breakthrough therapy. An argument is presented that 3,4-methylenedioxymethamphetamine may paradoxically act through these same 5-HT2A receptors to ameliorate the symptoms of PTSD. The central thematic contention is that a key role of serotonin may be to function as a stress detection and response system.

Oxytocin (OT) has broad effects in the brain and plays an important role in cognitive, social, and neuroendocrine function. OT has also been identified as potentially therapeutic in neuropsychiatric disorders such as autism and depression, which are often comorbid with epilepsy, raising the possibility that it might confer protection against the behavioral and seizure phenotypes in epilepsy. Dravet syndrome (DS) is an early-life encephalopathy associated with prolonged and recurrent early-life febrile seizures (FSs), treatment-resistant afebrile epilepsy, and cognitive and behavioral deficits. De novo loss-of-function mutations in the voltage-gated sodium channel SCN1A are the main cause of DS, while genetic epilepsy with febrile seizures plus (GEFS+), also characterized by early-life FSs and afebrile epilepsy, is typically caused by inherited mutations that alter the biophysical properties of SCN1A. Despite the wide range of available antiepileptic drugs, many patients with SCN1A mutations do not achieve adequate seizure control or the amelioration of associated behavioral comorbidities. In the current study, we demonstrate that nanoparticle encapsulation of OT conferred robust and sustained protection against induced seizures and restored more normal social behavior in a mouse model of Scn1a-derived epilepsy. These results demonstrate the ability of a nanotechnology formulation to significantly enhance the efficacy of OT. This approach will provide a general strategy to enhance the therapeutic potential of additional neuropeptides in epilepsy and other neurological disorders.

Classic hallucinogens share pharmacology as serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptor agonists. Unique among most other Schedule 1 drugs, they are generally non-addictive and can be effective tools in the treatment of addiction. Mechanisms underlying these attributes are largely unknown. However, many preclinical studies show that 5-HT2C agonists counteract the addictive effects of drugs from several classes, suggesting this pharmacological property of classic hallucinogens may be significant. Drawing from a comprehensive analysis of preclinical behavior, neuroanatomy, and neurochemistry studies, this review builds rationale for this hypothesis, and also proposes a testable, neurobiological framework. 5-HT2C agonists work, in part, by modulating dopamine neuron activity in the ventral tegmental area—nucleus accumbens (NAc) reward pathway. We argue that activation of 5-HT2C receptors on NAc shell, GABAergic, medium spiny neurons inhibits potassium Kv1.x channels, thereby enhancing inhibitory activity via intrinsic mechanisms. Together with experiments that show that addictive drugs, such as cocaine, potentiate Kv1.x channels, thereby suppressing NAc shell GABAergic activity, this hypothesis provides a mechanism by which classic hallucinogen-mediated stimulation of 5-HT2C receptors could thwart addiction. It also provides a potential reason for the non-addictive nature of classic hallucinogens.

Parkinson's disease (PD) is a devastating neurodegenerative disease that leads to motor deficits and selective destruction of nigrostriatal dopaminergic neurons. PD is typically treated by dopamine replacement agents; however, dopamine replacement loses effectiveness in the later stages of the disease. Here, we describe the neuroprotective effects of the omega-3 fatty acid docosahexaenoic acid (DHA) in the medial forebrain bundle 6-hydroxydopamine (6-OHDA) model of advanced-stage PD in rats. We show that daily administration of DHA protects against core symptoms of PD, including deficits in postural stability, gait integrity, and dopamine neurochemistry in motor areas of the striatum. Our results also demonstrate that DHA increases striatal dopamine synthesis via phosphorylation of the rate-limiting catecholamine synthesizing enzyme tyrosine hydroxylase, in a manner dependent on the second messenger-linked protein kinases PKA and PKC. We also show that DHA specifically reverses dopamine loss in the nigrostriatal pathway, with no effect in the mesolimbic or mesocortical pathways. This suggests that DHA is unlikely to produce pharmacotherapeutic or adverse effects that depend on dopamine pathways other than the nigrostriatal pathway. To our knowledge, previous reports have not examined the effects of DHA in such an advanced-stage model, documented that the dopamine synthesizing effects of DHA in vivo are mediated through the activation of protein kinases and regulation of TH activity, or demonstrated specificity to the nigrostriatal pathway. These novel findings corroborate the beneficial effects of omega-3 fatty acids seen in PD patients and suggest that DHA provides a novel means of protecting patients for dopamine neurodegeneration.