Acute isometric and dynamic exercise do not alter cerebral sympathetic nerve activity in healthy humans.

The impact of physiological stressors on cerebral sympathetic nervous activity (SNA) remains controversial. We hypothesized that cerebral noradrenaline (NA) spillover, an index of cerebral SNA, would not change during both submaximal isometric handgrip (HG) exercise followed by a post-exercise circulatory occlusion (PECO), and supine dynamic cycling exercise. Twelve healthy participants (5 females) underwent simultaneous blood sampling from the right radial artery and right internal jugular vein. Right internal jugular vein blood flow was measured using Duplex ultrasound, and tritiated NA was infused through the participants' right superficial forearm vein. Heart rate was recorded via electrocardiogram and blood pressure was monitored using the right radial artery. Total NA spillover increased during HG (P = 0.049), PECO (P = 0.006), and moderate cycling exercise (P = 0.03) compared to rest. Cerebral NA spillover remained unchanged during isometric HG exercise (P = 0.36), PECO after the isometric HG exercise (P = 0.45), and during moderate cycling exercise (P = 0.94) compared to rest. These results indicate that transient increases in blood pressure during acute exercise involving both small and large muscle mass do not engage cerebral SNA in healthy humans. Our findings suggest that cerebral SNA may be non-obligatory for exercise-related cerebrovascular adjustments.

Dysfunction of norepinephrine and its metabolites in Alzheimer's dementia - A review with meta-analysis.

Some studies point locus coeruleus cell loss, the central nervous system main source of norepinephrine, to be one of the earliest neuropathological events of Alzheimer's disease (AD). However, there are conflicting reports regarding the level of norepinephrine and its metabolites (3-Methoxy-4-hydroxyphenylglycol (MHPG), 3,5-dihydroxyphenylglycine (DHPG) and 3,4 -dihydroxyphenylglycolaldehyde (DOPEGAL)) in AD patients. Uncover these alterations may be a key factor for understanding cognitive deficits and AD pathology. We review the literature that compare norepinephrine and its metabolites between AD patients and non-demented controls. A meta-analysis did not reveal significant statistical differences, but there was a trend towards a lower level of norepinephrine of AD, with almost no difference in MHPG in the cerebrospinal fluid. Regarding MHPG in plasma, DHPG and DOPEGAL we only performed a qualitative analyse due to the small or absent number of studies. These findings point to a decrease in norepinephrine, what is in line with locus coeluleus cell loss in AD. The absence of statistical difference and an equal level of MHGP could indicate a compensatory mechanism.

Getting Inside the Mind of Gay and Bisexual Men Who Have Sex with Men with Sexualized Drug Use - A Systematic Review.

Objectives: Sexualized Drug Use (SDU) consists of using any drug purposely before or during sex with the intent of modifying sex experiences. SDU is especially practiced among Gay and Bisexual Men who have Sex with Men (GBMSM). This study aims to review the relevant literature to identify and summarize the reasons reported by GBMSM to engage in SDU. Methods: A systematic review of the literature using PubMed/Medline, Scopus, Google Scholar, and PsycINFO, comprising qualitative and quantitative papers published between 2010 and 2022, was conducted with a narrative synthesis of the findings. PRISMA guidelines were followed. Results: Our search identified 1400 publications, of which 23 were included. Reasons to engage in SDU were aggregated as follows: (1) Enhancing sexual sensations and performance, (2) Achieving hedonic mental and emotional states, (3) Tackling negative thoughts and feelings, and (4) Social motivations. Different sample methods and ways of asking for motivations may limit the internal validity of these conclusions. Conclusion: Both individual and social factors are involved in the decision to engage in SDU. SDU practices should not be medicalized, however therapeutic support if needed should provide multidisciplinary, pleasure-centered, harm-reducing care interventions, specifically designed for these minorities of GBMSM.

Voltage-clamp evidence of GABAA receptor subunit-specific effects: pharmacodynamic fingerprint of chlornordiazepam, the major active metabolite of mexazolam, as compared to alprazolam, bromazepam, and zolpidem.

BACKGROUND: Anxiolytic benzodiazepines, due to their clinical effectiveness, are one of the most prescribed drugs worldwide, despite being associated with sedative effects and impaired psychomotor and cognitive performance. Not every GABAA receptor functions in the same manner. Those containing α1 subunits are associated with sleep regulation and have a greater effect on the sedative-hypnotic benzodiazepines, whereas those containing α2 and/or α3 subunits are associated with anxiety phenomena and have a greater effect on the anxiolytic benzodiazepines. Therefore, characterization of the selectivity profile of anxiolytic drugs could translate into a significant clinical impact. METHODS: The present study pharmacodynamically evaluated chlornordiazepam, the main active metabolite of mexazolam, upon GABAA receptors containing α2 and/or α3, anxiety-related, and those containing an α1 subunit, associated with sleep modulation. RESULTS: As shown by whole-cell patch-clamp data, chlornordiazepam potentiated GABA-evoked current amplitude in α2 and α3 containing receptors without changing the current amplitude in α1 containing receptors. However, current decay time increased, particularly in GABAA receptors containing α1 subunits. In contrast, other anxiolytic benzodiazepines such as alprazolam, bromazepam, and zolpidem, all increased currents associated with GABAA receptors containing the α1 subunit. CONCLUSIONS: This novel evidence demonstrates that mexazolam (through its main metabolite chlornordiazepam) has a "pharmacodynamic fingerprint" that correlates better with an anxiolytic profile and fewer sedative effects, when compared to alprazolam, bromazepam and zolpidem, explaining clinical trial outcomes with these drugs. This also highlights the relevance of the pharmacological selectivity over GABAA receptor subtypes in the selection of benzodiazepines, in addition to their clinical performance and pharmacokinetic characteristics.

Catechol-O-methyltransferase activity in individuals with substance use disorders: a case control study.

BACKGROUND: Impulsivity and substance use disorders (SUD) have been both associated with changes in dopaminergic processes. In this study, we intended to evaluate the dopaminergic function in imprisoned SUD offenders through the determination of s-COMT activity. METHODS: The study included 46 male individuals from a Portuguese penal institution. The participants were assessed through a battery of standardised instruments: Psychopathy Checklist-Revised (PCL-R), Barratt Impulsivity Scale Version 11 (BIS-11), and the European version of the Addiction Severity Index (EuropASI). In addition, s-COMT erythrocyte activity was evaluated. RESULTS: Overall, 73.9% (n = 34) of the individuals had Antisocial personality disorder (ASPD) and 58.7% (n = 27) presented SUD. We evidenced, for the first time, that, in individuals with SUD, s-COMT activity was correlated with the severity of drug dependence (EuropASI) (p = 0.009), and with BIS-11 factors self-control (p < 0.0001) and non-planning (p = 0.002). CONCLUSIONS: This study opens new perspectives regarding the pharmacological intervention on substance dependence through the interference on dopamine pathways.

The effects of trazodone on human cognition: a systematic review.

Trazodone is a widely used antidepressant that is also useful in the control of agitation and insomnia in Alzheimer's disease. This drug is now recognized as having a new mechanism of action, an effect on the unfolded protein response (UPR) pathway, restoring protein translation and slowing neurodegenerative progression in mice. This mechanism may have a role in dementia-modifying treatment. To explore the effects of trazodone on human cognition and to search for clinical evidence of its putative benefits in human neurodegenerative diseases, a systematic review was conducted for studies that evaluated the effect of a minimum dose of 25 mg of trazodone daily, for at least 1 week, on cognition in adult humans. The search was run in MEDLINE, Web of Science, and CENTRAL from the Cochrane databases, yielding a total of 16 studies after selection. Overall, seven studies showed no effect of trazodone on cognition, five showed a beneficial effect by improving or reducing cognitive decline, and four evidenced impaired cognitive function. Our analysis highlights the possibility of a dose-independent dual effect of trazodone on human cognition, with acute utilization associated with impaired cognitive function and long-term use with preventing cognitive deterioration. There was no clinical evidence that trazodone could be used as a specific treatment of neurodegenerative diseases. Future studies should explore the role of trazodone in the UPR pathway and the implications in neurodegenerative diseases in humans.

Monoamines and cortisol as potential mediators of the relationship between exercise and depressive symptoms.

A randomized controlled trial was conducted to assess the effects of exercise plus pharmacotherapy on monoamine neurotransmitters (dopamine, noradrenaline, adrenaline, serotonin) and cortisol levels. A total of 26 women with clinical depression were randomly assigned to one of the two groups: aerobic exercise plus pharmacotherapy or only pharmacotherapy. The exercise program consisted of aerobic exercise, 45-50 min/session, three times/week, for 16 weeks. The biological parameters were measured before and after the exercise program. Adding exercise to pharmacotherapy had no additional effects on monoamines and cortisol plasma levels. These data are preliminary outcomes from a small sample and should be replicated.

Impact of physical exercise on catechol-O-methyltransferase activity in depressive patients: A preliminary communication.

BACKGROUND: Catechol-O-methyltransferase (COMT) is a catabolic enzyme involved in the degradation of bioactive molecules including the neurotransmitters epinephrine, norepinephrine, and dopamine. Higher COMT activity in depressive patients in comparison to non-depressed individuals has been reported. The effect of aerobic exercise on depressive patients has been studied and a number of researchers and clinicians believe it to be effective in the treatment of depression and to be involved in several molecular underlying mechanisms. However, the effect of physical exercise on this enzyme activity is unknown, and it remains to be elucidated if chronic exercise changes COMT activity. This randomized control trial evaluates the effects of chronic exercise on peripheral COMT (S-COMT) activity in women with depressive disorder. METHODS: Fourteen women (aged: 51.4±10.5 years) diagnosed with depression (according to International Classification of Diseases-10) were randomized to one of two groups: pharmacotherapy plus physical exercise (n=7) or only pharmacotherapy (n=7). The aerobic exercise program was supervised, lasting between 45-50min/session, three times/week for 16 weeks. Erythrocyte soluble COMT were assessed prior to and after the exercise program. RESULTS: Exercise group when compared to a control group presented a significant decrease (p=0.02, r=-0.535) in S-COMT activity between baseline and post-intervention. LIMITATIONS: These data are preliminary outcomes from a small sample and should be replicated. CONCLUSIONS: Chronic exercise therapy combined with pharmacotherapy leads to significant decrease in S-COMT activity. Our results provide evidence that exercise interferes with S-COMT activity, a molecular mechanism involved in depression.

Flavonoids as dopaminergic neuromodulators.

SCOPE: The present study aimed to characterize and evaluate flavonoids effects on organic cation uptake in neuronal cells. METHODS AND RESULTS: Uptake experiments were conducted using radiolabeled methyl-4-phenylpyridinuim ([(3) H]-MPP(+) ), in human neuronal dopaminergic cells, SH-SY5Y. Catechin did not alter [(3) H]-MPP(+) uptake, however its metabolite 4'-methyl-catechin decreased it by almost 50%. Epicatechin and its methylated metabolites also decreased [(3) H]-MPP(+) uptake. Interestingly, the quercetin flavonol and its metabolite conjugated with glucuronic acid, as well as the flavanones naringenin and hesperitin, increased [(3) H]-MPP(+) uptake. CONCLUSION: These results showed that different classes of flavonoids, as well as its metabolites, differently influence neuronal organic cation uptake. Several xeno- and endobiotics, including neurotransmitters, are organic cations. Specific food recommendations may be beneficial in pathological conditions where levels of neurotransmitters, as dopamine, are either increased or decreased.

Effects of structured exercise and pharmacotherapy vs. pharmacotherapy for adults with depressive symptoms: A randomized clinical trial.

OBJECTIVE: Physical exercise has been consistently documented as a complementary therapy in the treatment of depressive disorders. However, despite a higher prevalence among women compared to men, the trials developed in women are scarce. In addition, the optimal dosage of exercise capable of producing benefits that reduce depressive symptoms remains unclear. This clinical trial is designed to measure the effect of a structured physical exercise program as a complement to antidepressant medication in the treatment of women with depression. METHODS: From July 2013 to May 2014, we implemented a randomized controlled trial (HAPPY BRAIN study). A total of 26 women (aged 50.16 ± 12.08) diagnosed with clinical depression were randomized either to a supervised aerobic exercise group (45-50 min/week three times a week for four months) plus pharmacotherapy (intervention group), or only antidepressant medication (control group). RESULTS: The exercise group presented a decrease in BDI-II and DASS-21 total score scales. Relatively to DASS-21, it showed a significant decrease in anxiety and stress. The exercise group when compared to a control group showed improvement in relation to physical functioning parameters between baseline and post-intervention. Moreover, anthropometric parameters presented only significant differences between groups in fat mass percentage. Nonetheless, no differences were found between groups in weight, body mass index, waist circumference, and self-esteem. CONCLUSION: Our results showed that supervised structured aerobic exercise training could be an effective adjuvant therapy for treating women with depression, reducing depressive symptomatology and improving physical fitness. A key factor of this improvement included strict control of exercise workload parameters and adjustment to each subject's capacity. In our study, due to the sample size there is an increase in the probability of type II errors.

Catechol-O-methyltransferase activity in psoriasis patients treated with psoralen plus ultraviolet A therapy.

BACKGROUND: Catechol-O-methyltransferase (COMT) activity is increased in patients with mild/moderate psoriasis. Narrowband ultraviolet B (nbUVB) phototherapy decreases COMT activity. However, the effect of psoralen plus ultraviolet A (PUVA) on this enzyme activity is unknown, and it remains to be clarified if the nbUVB-induced effect in COMT activity is related to clinical response. The aim of this study is to evaluate COMT activity in moderate/severe psoriasis and assess whether PUVA therapy modifies this activity. METHODS: An observational study was conducted on 18 patients with moderate/severe psoriasis and 13 matched controls. Patients were treated with PUVA twice weekly during 6 weeks, and they were evaluated for Psoriasis Area and Severity Index (PASI) and COMT activity before photochemotherapy, at the end of it and 4 weeks after stopping. RESULTS: Before PUVA therapy, S(soluble)-COMT activity was significantly (P < 0.05) higher in psoriasis patients than in controls. After photochemotherapy, no significant differences were found in S-COMT activity at all end points. Photochemotherapy significantly decreased PASI but COMT activity values remained higher than those of control population. CONCLUSION: Psoriasis patients with moderate/severe disease present higher S-COMT activity than controls. Although a good clinical response was observed, PUVA therapy does not change S-COMT activity. This differential COMT effect of PUVA and nbUVB suggests a wavelength-specific regulation.

Locus coeruleus is involved in weight loss in a rat model of Parkinson's disease: an effect reversed by deep brain stimulation.

INTRODUCTION: In Parkinson's disease (PD) weight loss is a secondary phenomenon to the progressive neurodegeneration that changes after deep brain stimulation of the subthalamic nucleus (DBS-STN) leading to increased weight gain. The mechanism responsible for this profile in weight variation may be secondary to a central metabolic control influenced by the noradrenergic system. In this study authors evaluate the effect of additional noradrenergic neuronal degeneration, namely of the locus coeruleus (LC), on weight variation in the 6-hydroxydopamine (6-OHDA) rat model of PD. MATERIAL AND METHODS: An experimental group of parkinsonian animals with additional 6-OHDA lesion of the LC was developed to analyze the effect of this lesion on the metabolic state of rats before and after DBS-STN. Rats were placed in metabolic cages for evaluation of weight, food and liquid intake and urine and fecal volume, before and after DBS-STN. The effects of 6-OHDA lesions and DBS-STN on motor behavior were also monitored. Tissue levels of monoamines in the striatum of 6-OHDA-lesioned animals and catecholamine levels in urine and plasma were evaluated. RESULTS: In the experimental group of Parkinsonian animals with 6-OHDA degeneration of the striatum alone, no effects on weight gain, food intake and other metabolic parameters were observed before or after DBS-STN. Additional lesion of the LC produced a significant decrease in weight gain with a trend toward a decrease in solid intake. Chronic DBS-STN in rats with LC and striatum degeneration abolished the weight loss without producing changes to food intake and other metabolic parameters. Additional degeneration of the LC was not accompanied by significant changes in motor behavior but produced an additional decrease in striate monoamines levels namely a decrease in the DA/l-DOPA ratio. CONCLUSIONS: In PD degeneration of noradrenergic neurons, in particular of the LC, may be required to observe side effects unrelated to motor symptoms such as body weight deregulation. Our results support the notion that the LC may be important in maintaining the activity of the nigrostriatal dopamine pathways, and thus play a crucial role in weight variation in a PD.

Catechol-O-methyltransferase activity is higher in psoriasis patients and is down-regulated by narrowband ultraviolet B treatment.

BACKGROUND: Narrowband ultraviolet B (nbUVB) phototherapy is widely used in psoriasis treatment. UVB irradiation decreases catechol-O-methyltransferase (COMT) activity in human keratinocytes and melanoma cells. COMT activity is higher in psoriatic lesions than in normal skin but the effect of nbUVB on COMT activity in psoriasis patients is unknown. OBJECTIVES: To evaluate COMT activity in patients with psoriasis and determine whether nbUVB modifies this activity. METHODS: An open observational study was conducted with 20 psoriasis patients and 15 healthy volunteers. Patients were treated with nbUVB thrice weekly during six weeks and evaluated at baseline, three and six weeks after phototherapy and four weeks after stopping. In each evaluation body mass index (BMI), Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) were calculated and blood samples for erythrocytes soluble (S-) COMT activity assessment were taken. RESULTS: Before phototherapy (baseline), using a single concentration of substrate adreneline (1,000 µM), S-COMT activity levels (pmol/mg protein/h) were significantly higher in psoriasis patients than in controls. After nbUVB treatment, S-COMT activity significantly decreased. This decrease correlated positively with baseline activity. Four weeks after stopping phototherapy, S-COMT activity returned to baseline levels. After phototherapy, PASI score improved significantly but no correlation to baseline S-COMT values or decrease in S-COMT activity was found. CONCLUSIONS: This study shows that baseline S-COMT activity is higher in psoriasis patients than in controls and that this activity is significantly decreased by nbUVB treatment for psoriasis. This decrease is more evident in patients with higher baseline S-COMT activity.

α2C-Adrenoceptors modulate L-DOPA uptake in opossum kidney cells and in the mouse kidney.

Targeted deletion or selective pharmacological inhibition of α(2C)-adrenoceptors in mice results in increased brain tissue levels of dopamine and its precursor l-3,4-dihydroxyphenylalanine (l-DOPA), without significant changes in l-DOPA synthesis. l-DOPA uptake is considered the rate-limiting step in dopamine synthesis in the kidney. Since α(2C)-adrenoceptors may influence the transport of l-DOPA, we investigated the effect of α(2C)-adrenoceptor activation on l-DOPA uptake in a kidney cell line (opossum kidney cells). l-DOPA and dopamine kidney tissue levels in α(2C)-adrenoceptor knockout (α(2C)KO) mice and in mice treated with the selective α(2C)-adrenoceptor antagonist JP-1302 were also evaluated. The α(2)-adrenoceptor agonist medetomidine (0.1-1,000 nM) produced a concentration-dependent decrease in l-DOPA uptake in opossum kidney cells (IC(50): 2.5 ± 0.5 nM and maximal effect: 28 ± 5% of inhibition). This effect was abolished by a preincubation with JP-1302 (300 nM). Furthermore, the effect of medetomidine (100 nM) was abolished by a preincubation with U-0126 (10 µM), a MEK1/2 inhibitor. Kidney tissue levels of l-DOPA were significantly higher in α(2C)KO mice compared with wild-type mice (wild-type mice: 58 ± 2 pmol/g tissue and α(2C)KO mice: 81 ± 15 pmol/g tissue, P < 0.05) and in mice treated with JP-1302 (3 µmol/kg body wt) compared with control mice (control mice: 62 ± 2 pmol/g tissue and JP-1302-treated mice: 75 ± 1 pmol/g tissue, P < 0.05), both without significant changes in dopamine kidney tissue levels. However, mice treated with JP-1302 on a high-salt diet presented significantly higher dopamine levels in the kidney and urine compared with control animals on a high-salt diet. In conclusion, in a kidney cell line, α(2C)-adrenoceptor activation inhibits l-DOPA uptake, and in mice, deletion or blockade of α(2C)-adrenoceptors increases l-DOPA kidney tissue levels.

Effect of clonidine on renal sodium handling in spontaneously hypertensive rats.

Up-regulation of kidney α2-adrenoceptor expression has been implicated in the development of hypertension in spontaneously hypertensive rats (SHR). This study was carried out to evaluate renal sodium excretion in response to clonidine administration in SHR and control normotensive Wistar-Kyoto (WKY) rats. SHR and WKY rats (12-week-old) were placed in metabolic cages for 4 days: the first 2 days in control conditions and the following 2 days under oral clonidine treatment (100 µg/kg body weight). Clonidine produced a similar reduction in systolic blood pressure values in SHR and WKY rats, although SHR remained hypertensive. At the end of the study SHR and WKY rats presented similar noradrenaline plasma levels. However, noradrenaline kidney tissue levels were significantly higher in SHR compared to WKY rats. Under control conditions, SHR presented lower urine flow compared to WKY rats. Clonidine produced a significant decrease in urine flow in WKY rats but not in SHR. Furthermore, clonidine also produced a significant reduction in urinary sodium, potassium, and creatinine excretion in WKY rats, but had no effect in SHR. In conclusion, in SHR the reduction in systolic blood pressure and sympathetic activity produced by clonidine was not accompanied by a decrease in urine volume and sodium excretion.

Weight variation before and after surgery in Parkinson's disease: a noradrenergic modulation?

Changes in the nutritional profile of patients with Parkinson's disease have been reported before and after deep brain stimulation surgery. The major determinants of the weight variation in Parkinson's disease are not yet understood, and the mechanism seems complex. Based on the influence of the sympathetic nervous system in metabolic syndrome obesity, the intent of the present review is to consider the role of noradrenergic modulation on weight variations in Parkinson's disease. In this review the authors raise the following hypothesis: weight variation in Parkinson's disease before and after deep brain stimulation of the subthalamic nucleus could be influenced by noradrenergic interaction between the locus coeruleus, subthalamic nucleus, and hypothalamic nucleus.

Ultraviolet B radiation differentially modifies catechol-O-methyltransferase activity in keratinocytes and melanoma cells.

BACKGROUND: Catechol-O-methyltransferase (COMT) is a ubiquitous enzyme inactivating catecholic compounds. COMT is expressed also in human skin samples, and in melanoma cells it may be cytoprotective. A role of COMT in keratinocytes (HaCat) is unknown. OBJECTIVE: The objective of this study is: to investigate whether ultraviolet-B (UVB) radiation modifies COMT activity in melanocytes and HaCat and whether COMT inhibition plays a role in UVB-induced cell death. METHODS: Human cell lines of melanotic melanoma (SK-mel-1) and HaCat were used. COMT activity was evaluated under basal conditions and after UVB irradiation (311 nm) at a low (8 mJ/cm(2)) and a high dose (60 mJ/cm(2)). Tolcapone 1 µM was used to inhibit COMT. RESULTS: Both SK-mel-1 and Ha-Cat cells express COMT activity. In SK-mel-1, COMT activity is reduced nearly 50% both 24 h and 48 h after a high dose UVB. In Ha-Cat cells, COMT activity increased 24 h after a high dose UVB but decreased at 48 h. Tolcapone increases significantly the cytotoxic effect of high dose UVB irradiation only in HaCat. High concentrations of tolcapone reduced melanin levels in melanoma cells parallel to reduced cell numbers. CONCLUSIONS: Ultraviolet radiation differentially modifies COMT activity in melanoma cells and HaCat. Furthermore, tolcapone increased death of HaCat after irradiation but did not affect melanoma cells.