Dopamine Activity Research Articles

Developmental Neurotoxicity of Trichlorfon in Zebrafish Larvae.

Trichlorfon is an organophosphorus pesticide widely used in aquaculture and has potential neurotoxicity, but the underlying mechanism remains unclear. In the present study, zebrafish embryos were exposed to trichlorfon at concentrations (0, 0.1, 2 and 5 mg/L) used in aquaculture from 2 to 144 h post fertilization. Trichlorfon exposure reduced the survival rate, hatching rate, heartbeat and body length and increased the malformation rate of zebrafish larvae. The locomotor activity of larvae was significantly reduced. The results of molecular docking revealed that trichlorfon could bind to acetylcholinesterase (AChE). Furthermore, trichlorfon significantly inhibited AChE activity, accompanied by decreased acetylcholine, dopamine and serotonin content in larvae. The transcription patterns of genes related to acetylcholine (e.g., ache, chrna7, chata, hact and vacht), dopamine (e.g., drd4a and drd4b) and serotonin systems (e.g., tph1, tph2, tphr, serta, sertb, htrlaa and htrlab) were consistent with the changes in acetylcholine, dopamine, serotonin content and AChE activity. The genes related to the central nervous system (CNS) (e.g., a1-tubulin, mbp, syn2a, shha and gap-43) were downregulated. Our results indicate that the developmental neurotoxicity of trichlorfon might be attributed to disorders of cholinergic, dopaminergic and serotonergic signaling and the development of the CNS.

Antioxidant system alterations and physiological characteristics of neonatal and juvenile DAT-KO rats.

Dopamine transporter knockout (DAT-KO) rats represent a valuable rodent model for studying the molecular and phenotypical outcomes of the effects of excessive dopamine accumulation in the synaptic cleft and the prolonged action of dopamine on neurons. Animals with DAT deficiency are characterized by hyperactivity, stereotypy, cognitive deficits, and impairments in behavioral and biochemical indicators. Several key pathophysiological mechanisms are known to be common to psychiatric, neurodegenerative, metabolic, and other diseases. Among these mechanisms, oxidative stress systems play a particularly important role. One of the main antioxidant systems in the brain is glutathione: specifically, glutathione S-transferase, glutathione reductase, and catalase play a significant role in the regulation of vital oxidative processes, and their dysfunction has been shown in Parkinson's disease, Alzheimer's disease, and other neurodegenerative diseases. The current study aimed to analyze the dynamics of the activity levels of glutathione reductase and glutathione S-transferase in erythrocytes, as well as catalase in the blood plasma, of DAT-deficient, homo- and heterozygous, neonatal and juvenile rats (both male and female). Their behavioral and physiological parameters were evaluated at the age of 1.5 months. For the first time, changes in physiological and biochemical parameters were shown in DAT-KO rats at 1.5 months of postnatal life. The key role of glutathione S-transferase, glutathione reductase, and catalase in the regulation of oxidative stress in DAT-KO rats at the 5th week of life was demonstrated. A positive effect of a slightly increased dopamine level on memory function was shown in DAT-heterozygous animals.

The effects of renal dopaminergic system on the development of hypertension with high salt diet and L-NNA administration

Objective: We aimed to investigate the intrarenal dopamine synthesis efficiency, blood pressure changes and the effects of this system on hypertension developed by NOS inhibition and high salt diet. Method: Wistar Albino male rats were administered water containing 50mg/L or 100mg/L concentrations of L-NNA, standard rat feed containing 0.8%salt, or 4%high salt alone or with L-NNA for 7days. Blood pressure measurements were made with the tail-cuff method. 24-hour water intake and urine volume were also measured. Results: Administration of L-NNA or high-salt diet alone for 7days did not cause a change in blood pressure, while their combined administration resulted in a significant increase in blood pressure. Blood pressures were found to be higher in the L-NNA100+HS group compared to the other groups. While the amount of water intake in 24hours did not change, the amount of 24-hour urine was reduced. 24-hour urinary sodium excretion, sodium clearance and GFR was decreased, and 24-hour urine dopamine concentrations were increased. Conclusion: Co-administration of nitric-oxide inhibitor and high-salt diet failed to prevent renal dopaminergic system blood pressure increase. Despite the increase in dopamine synthesis, intrarenal dopamine activity could not be realized by receptor interaction and it is thought that the increase in blood pressure is caused by the development of renal oxidative stress.

Study of the photoperiodic dynamics of the peripheral dopamine content in comparison with the thyroid profile in various groups of men from the European North

Knowledge of the physiological mechanisms of adaptation arising in response to changes in photoperiods is especially important for residents of the European North. In the literature, there is practically no information about photoperiodic dynamics of serum dopamine level, despite its significant role in the regulation of the body's activity. The mutual modulating effect of the dopaminergic and thyroid systems is known. To show the ratio of dopamine levels and the content of hormones, protines and autoantibodies of the thyroid system, taking into account photoperiod of the year, in practically healthy populations of the European North. Healthy male population (20 men) of Arkhangelsk was examined in various photoperiods of the year (80 samples): an increase in the length of daylight hours (March), its maximum duration (June), a decrease (September), and a minimum duration (December). The inhabitants of the settlements and the nomadic aboriginal population (100 men) were examined during 2 photoperiods of the year - March and December. The serum levels of iodothyronines, TSH, TG, antibodies to TPO, antibodies to TG and plasma level of dopamine were determined using ELISA methods. Residents of Arkhangelsk in June compared to December have higher levels of dopamine (0.502 and 0.365 nmol/l, p=0.01), T3 (1.09 and 0.94 nmol/l, p=0.003), T4 (113.45 and 99.03 nmol/l, p=0.0002). In September, compared with June, a decrease in dopamine (0.235 nmol/l, p=0.0003), T3 (0.92 nmol/l, p=0.004) was recorded with an increase in T4/T3 ratio from 106.54 to 117.89 units (p=0.006). The nomadic aboriginal population in March compared with December showed a tendency to a higher content of dopamine (0.00 and 0.394 nmol/l, p=0.07) with the decrease in fT4 (15.20 and 13.90, p=0.015), fT4/fT3 ratio from 3.13 to 2.28 units (p=0.006). In December, 67% of nomadic population had undetectable dopamine values (0 nmol/l) and 22% - excess dopamine values, in March 27% - excess values. Unidirectional changes in dopamine and thyroid activity in men of the European North were shown with their decrease during periods of decrease and minimum daylight hours and an increase during periods of increase and maximum daylight hours.

The motivation to flock correlates with vocal-social behaviors and dopamine-related gene expression in male European starlings

It is proposed that songbird flocks are partly reinforced by positive social interactions, however not all flock mate interactions are positive. The combination of both positive and negative social interactions with flock mates may play a role in the motivation for birds to flock. The nucleus accumbens (NAc), medial preoptic area (POM), and ventral tegmental area (VTA) are implicated in vocal-social behaviors in flocks, including singing. Dopamine (DA) within these regions modifies motivated, reward-directed behaviors. Here, we begin to test the hypothesis that individual social interactions and DA within these regions are involved in the motivation to flock. Vocal-social behaviors were recorded in eighteen male European starlings in mixed-sex flocks in fall, when starlings are highly social and form large flocks. Males were then singly removed from their flock and the motivation to flock was quantified as the amount of time spent attempting to join a flock following separation. We used quantitative real-time polymerase chain reaction to measure expression of DA-related genes in the NAc, POM, and VTA. Birds producing high levels of vocal behaviors were more highly motivated to flock and had higher tyrosine hydroxylase (the rate-limiting enzyme in DA synthesis) expression in the NAc and VTA. Birds that received high levels of agonistic behaviors were less motivated to flock and had higher DA receptor subtype 1 expression in the POM. Overall, our findings suggest that interplay between social experience and DA activity in NAc, POM, and VTA plays a key role in social motivation in flocking songbirds.

Cocaine self-administration augments kappa opioid receptor system-mediated inhibition of dopamine activity in the mesolimbic dopamine system.

Prior studies examining the effects of cocaine on the dynorphin/kappa opioid receptor (Dyn/KOR) system primarily focus on non-contingent cocaine exposure, but the effects of self-administration, which more closely reflects human drug-taking behaviors, are not well studied. In this study we characterized the effects of escalated intravenous cocaine self-administration on the functional state of the Dyn/KOR system and its interaction with mesolimbic dopamine signaling. Rats self-administered cocaine in an extended access, limited intake cocaine procedure, in which animals obtained 40 infusions per day (1.5mg/kg/inf) for 5 consecutive days to ensure comparable consumption levels. Following single day tests of cue reactivity and progressive ratio responding, quantitative real-time polymerase chain reaction was used to measure levels of Oprk and Pdyn transcripts in the ventral tegmental area and nucleus accumbens. Additionally, after self-administration, ex vivo fast-scan cyclic voltammetry in the NAc was used to examine the ability of the KOR agonist U50,488 to inhibit dopamine release. We found that KOR-induced inhibition of dopamine release was enhanced in animals that self-administered cocaine compared to controls, suggesting upregulated Dyn/KOR activity after cocaine self-administration. Furthermore, expression levels of Pdyn in the nucleus accumbens and ventral tegmental area, and Oprk in the nucleus accumbens, were elevated in cocaine animals compared to controls. Additionally, Pdyn expression in the nucleus accumbens was negatively correlated with progressive ratio breakpoints, a measure of motivation to self-administer cocaine. Overall, these data suggest that cocaine self-administration elevates KOR/Dyn system activity in the mesolimbic dopamine pathway.

Keluwih (Artocarpus camansi) extract effects in zebrafish models of Parkinson’s disease

Parkinson’s disease is a condition that affects the central nervous system in the brain and is brought on by a lack of dopamine. Uncontrollable tremors, uncoordinated movement, and stiffness characterize Parkinson’s disease. Until now, the medication for Parkinson’s disease is limited to relieve the symptoms and maintain the quality of life; thus, the progression of the disease can be delayed. In order to search for alternative therapy from herbs, Kluwih (Artocarpus camansi) has been used traditionally to relieve convulsants. This research aims to observe 96% ethanol extract of A. camansi leaves in dopamine and locomotor activity in adult male and female zebrafish (Dario rerio). The A. camansi extract concentration was 2.5; 5; 7.5; and 10 mg/ml for 28 days. Zebrafish locomotion was observed for 5 minutes on days 0; 7; 14; 21; and 28. ELISA measured the observations of dopamine after 28 days. The 96% ethanol extract of A. camansi leaves at 5 mg/ml can increase dopamine levels after induced with rotenone, but the dopamine level decreased at 7,5 and 10 mg/ml. The maximal concentration to increase locomotor activity is also at 5 mg/ml, along with dopamine concentration. Our findings revealed that 5 mg/ml of 96% ethanol extract of A. camansi leaves was the optimal dosage to stimulate dopamine release and enhance locomotor activity.

Medial Prefrontal Cortex to Medial Septum Pathway Activation Improves Cognitive Flexibility in Rats.

The medial prefrontal cortex (mPFC) is necessary for cognitive flexibility and projects to medial septum (MS). MS activation improves strategy switching, a common measure of cognitive flexibility, likely via its ability to regulate midbrain dopamine (DA) neuron population activity. We hypothesized that the mPFC to MS pathway (mPFC-MS) may be the mechanism by which the MS regulates strategy switching and DA neuron population activity. Male and female rats learned a complex discrimination strategy across 2 different training time points: a constant length (10 days) and a variable length that coincided with each rat meeting an acquisition-level performance threshold (males: 5.3 ± 0.3 days, females: 3.8 ± 0.3 days). We then chemogenetically activated or inhibited the mPFC-MS pathway and measured each rat's ability to inhibit the prior learned discrimination strategy and switch to a prior ignored discrimination strategy (strategy switching). Activation of the mPFC-MS pathway improved strategy switching after 10 days of training in both sexes. Inhibition of the pathway produced a modest improvement in strategy switching that was quantitatively and qualitatively different from pathway activation. Neither activation nor inhibition of the mPFC-MS pathway affected strategy switching following the acquisition-level performance threshold training regimen. Activation, but not inhibition, of the mPFC-MS pathway bidirectionally regulated DA neuron activity in the ventral tegmental area and substantia nigra pars compacta, similar to general MS activation. This study presents a potential top-down circuit from the prefrontal cortex to the midbrain by which DA activity can be manipulated to promote cognitive flexibility.

New Insight into the Function of Dopamine (DA) during Cd Stress in Duckweed (Lemna turionifera 5511).

Dopamine (DA), a kind of neurotransmitter in animals, has been proven to cause a positive influence on plants during abiotic stress. In the present study, the function of DA on plants under cadmium (Cd) stress was revealed. The yellowing of duckweed leaves under Cd stress could be alleviated by an exogenous DA (10/20/50/100/200 μM) supplement, and 50 μM was the optimal concentration to resist Cd stress by reducing root breakage, restoring photosynthesis and chlorophyll content. In addition, 24 h DA treatment increased Cd content by 1.3 times in duckweed under Cd stress through promoting the influx of Cd2+. Furthermore, the gene expression changes study showed that photosynthesis-related genes were up-regulated by DA addition under Cd stress. Additionally, the mechanisms of DA-induced Cd detoxification and accumulation were also investigated; some critical genes, such as vacuolar iron transporter 1 (VIT1), multidrug resistance-associated protein (MRP) and Rubisco, were significantly up-regulated with DA addition under Cd stress. An increase in intracellular Ca2+ content and a decrease in Ca2+ efflux induced by DA under Cd stress were observed, as well as synchrony with changes in the expression of cyclic nucleotide-gated ion channel 2 (CNGC2), predicting that, in plants, CNGC2 may be an upstream target for DA action and trigger the change of intracellular Ca2+ signal. Our results demonstrate that DA supplementation can improve Cd resistance by enhancing duckweed photosynthesis, changing intracellular Ca2+ signaling, and enhancing Cd detoxification and accumulation. Interestingly, we found that exposure to Cd reduced endogenous DA content, which is the result of a blocked shikimate acid pathway and decreased expression of the tyrosine aminotransferase (TAT) gene. The function of DA in Cd stress offers a new insight into the application and study of DA to Cd phytoremediation in aquatic systems.

Multifactor Dimensionality Reduction Analysis to Evaluate the Association of Dopamine Beta-Hydroxylase (DΒH) Polymorphisms with Susceptibility to Dementia (SADEM Study).

Dementia is a multifactorial disease in which environmental, lifestyle, and genetic factors intervene. Population studies have been used in looking for the susceptibility genes for this disease. Since the activity of dopamine b hydroxylase (DβH) is reduced in the hippocampus and neocortex in the brain, changes in the physiological status of dopamine have been reported in Alzheimer's disease (AD) induced by this enzyme. Therefore, DBH polymorphisms have been associated with susceptibility to some neurological diseases such as AD, but few studies have investigated the relationship between these polymorphisms with other types of dementia, especially in Mexican populations. The aim of this study was to evaluate the association between single-nucleotide polymorphism (SNP) in the dopamine b-hydroxylase (DBH gene (rs1611115) and their interactions with environmental factors and the dementia risk. We examined the genotype of the gene DBH (rs1611115) polymorphism in patients with dementia and healthy. The interaction and the impact of DBH (rs1611115) polymorphism on dementia were examined through multifactor dimensionality reduction (MDR) analysis, and the results were verified by the Chi-square test. Hardy-Weinberg equilibrium (HWE) was also checked by the Chi-square test. The relative risk was expressed by odds ratio (OR) and 95%. A total of 221 dementia patients and 534 controls met the inclusion criteria of MDR analyses. The results of the MDR analysis showed that the development of dementia was positively correlated with interaction between the TT genotype of the DBH1 locus rs1611115 TT and diabetes, hypertension, and alcohol consumption (OR = 6.5: 95% CI = 4.5-9.5), originating further cognitive damage. These findings provide insight into the positive correlation between the metabolism and cardiovascular disorders and the presence of the T allele by means of a recessive model of DBH rs1611115 polymorphism with the suspensibility of dementia.

Deep brain stimulation alleviates tics in Tourette syndrome via striatal dopamine transmission.

Tourette syndrome is a childhood-onset neuropsychiatric disorder characterized by intrusive motor and vocal tics that can lead to self-injury and deleterious mental health complications. While dysfunction in striatal dopamine neurotransmission has been proposed to underlie tic behaviour, evidence is scarce and inconclusive. Deep brain stimulation (DBS) of the thalamic centromedian parafascicular complex (CMPf), an approved surgical interventive treatment for medical refractory Tourette syndrome, may reduce tics by affecting striatal dopamine release. Here, we use electrophysiology, electrochemistry, optogenetics, pharmacological treatments and behavioural measurements to mechanistically examine how thalamic DBS modulates synaptic and tonic dopamine activity in the dorsomedial striatum. Previous studies demonstrated focal disruption of GABAergic transmission in the dorsolateral striatum of rats led to repetitive motor tics recapitulating the major symptom of Tourette syndrome. We employed this model under light anaesthesia and found CMPf DBS evoked synaptic dopamine release and elevated tonic dopamine levels via striatal cholinergic interneurons while concomitantly reducing motor tic behaviour. The improvement in tic behaviour was found to be mediated by D2 receptor activation as blocking this receptor prevented the therapeutic response. Our results demonstrate that release of striatal dopamine mediates the therapeutic effects of CMPf DBS and points to striatal dopamine dysfunction as a driver for motor tics in the pathoneurophysiology of Tourette syndrome.

Modulation of dopamine's effect at dopamine 2 receptors (D2R) mediated by association with the ghrelin receptor, GHSR

The typical action of dopamine at the dopamine 2 receptor (D2R) on CNS neurons is inhibition, an effect mediated via Gαi/o through GIRK channels. However, at two sites, autonomic preganglionic neurons in the lumbosacral spinal cord, and in the lateral hypothalamus, dopamine causes neuronal excitation through D2R. At both sites, dopamine neurons that are excited by dopamine express the ghrelin receptor, GHSR. Ghrelin is absent from the lateral hypothalamus and spinal cord, and it has been proposed that GHSR may modulate D2R signaling by the formation of heterodimers.In lumbrosacral spinal cord neurons of the defecation centre, D2R and GHSR agonists applied successively were both excitatory. Antagonism of GHSR at these neurons blocked the excitatory effect of DR2 stimulation, which was also blocked by depletion of intracellular calcium (iCa2+). We further investigated this interaction in recombinant cultured cells. In CHO cells expressing D2R, dopamine agonists had almost no effect on iCa2+, whereas in the presence of GHSR, D2R coupling to iCa2+ was observed in response to nanomolar dopamine. The elevation of iCa2+ by dopamine in D2R/GHSR cells was reduced by either D2R or GHSR antagonism, but the effect of a GHSR agonist was reduced only by GHSR antagonism. D2R coupling to iCa2+ in the presence of GHSR was dependent on both Gαq and Gαi/o, whereas ghrelin agonist coupling was dependent only on Gαq. D2R mediated effects on cAMP were dependent only on Gαi/o and were not effected by GHSR antagonism. D2R and GHSR in the membranes of CHO cells, revealed by fluorescent ligands, moved independently when tracked at high resolution in real time and, using fluorescent lifetime imaging, individual labelled DR2 sites were not in close enough proximity to detect resonance energy transfer (no detectable FRET). Consistent with coupling being via downstream crosstalk, no detectable DR2 dependent iCa2+ was evident in cells expressing the GHSR – A204E mutant, which lacks constitutive activity. The DR2-dependent iCa2+ increase was restored in these cells using subthreshold pre-stimulation with ghrelin. In native neurons of the defecation center, inward currents in response to D2R agonism were blocked by U73122, an inhibitor of PLCβ. Together this data indicates that dopamine-mediated excitation was dependent on GHSR, PLCβ and iCa2+, in both native and recombinant cells. We conclude that co-expression of GHSR causes augmentation of agonist-induced, D2R-mediated PLCβ activation and store Ca2+ release in recombinant cells and in a population of autonomic preganglionic neurons. D2R mediated excitation in D2R/GHSR cells is both Gαi/o and Gαq/11 dependent, but does not require receptor dimerisation. Our findings reveal a novel interaction between GPCRs, in a physiologically relevant system, that does not require direct receptor interaction and has broad implications for recoding of metabotropic neurotransmitter responses via modulation through other GPCRs. NHMRC grant, APP2012657, to SGBF This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Morphine and dopamine: Low dose apomorphine can prevent both the induction and expression of morphine locomotor sensitization and conditioning

The disinhibition of dopamine neurons in the VTA by morphine is considered an important contributor to the reward potency of morphine. In this report, three experiments were conducted in which a low dose of apomorphine (0.05 mg/kg) was used as a pretreatment to reduce dopamine activity. Locomotor hyperactivity was used as the behavioral response to morphine (10.0 mg/kg). In the first experiment, five treatments with morphine induced the development of locomotor and conditioned hyperactivity that were prevented by apomorphine given 10 min prior to morphine. Apomorphine before either vehicle or morphine induced equivalent reductions in locomotion. In the second experiment, the apomorphine pretreatment was initiated after induction of a conditioned hyperactivity and apomorphine prevented the expression of the conditioning. To assess the effects of apomorphine on VTA and the nucleus accumbens, ERK measurements were carried out after the induction of locomotor and conditioned hyperactivity. Increased ERK activation was found and these effects were prevented by the apomorphine in both experiments. A third experiment was conducted to assess the effects of acute morphine on ERK before locomotor stimulation was induced by morphine. Acute morphine did not increase locomotion, but a robust ERK response was produced indicating that the morphine-induced ERK activation was not secondary to locomotor stimulation. ERK activation was again prevented by the apomorphine pretreatment. We suggest that contiguity between the ongoing behavioral activity and the morphine activation of the dopamine reward system incentivizes and potentiates the ongoing behavior generating equivalent behavioral sensitization and conditioned effects.

Neurotensin receptor 1-biased ligand attenuates neurotensin-mediated excitation of ventral tegmental area dopamine neurons and dopamine release in the nucleus accumbens

Strong expression of the G protein-coupled receptor (GPCR) neurotensin receptor 1 (NTR1) in ventral tegmental area (VTA) dopamine (DA) neurons and terminals makes it an attractive target to modulate DA neuron activity and normalize DA-related pathologies. Recent studies have identified a novel class of NTR1 ligand that shows promising effects in preclinical models of addiction. A lead molecule, SBI-0654553 (SBI-553), can act as a positive allosteric modulator of NTR1 β-arrestin recruitment while simultaneously antagonizing NTR1 Gq protein signaling. Using cell-attached recordings from mouse VTA DA neurons we discovered that, unlike neurotensin (NT), SBI-553 did not independently increase spontaneous firing. Instead, SBI-553 blocked the NT-mediated increase in firing. SBI-553 also antagonized the effects of NT on dopamine D2 auto-receptor signaling, potentially through its inhibitory effects on G-protein signaling. We also measured DA release directly, using fast-scan cyclic voltammetry in the nucleus accumbens and observed antagonist effects of SBI-553 on an NT-induced increase in DA release. Further, in vivo administration of SBI-553 did not notably change basal or cocaine-evoked DA release measured in NAc using fiber photometry. Overall, these results indicate that SBI-553 blunts NT's effects on spontaneous DA neuron firing, D2 auto-receptor function, and DA release, without independently affecting these measures. In the presence of NT, SBI-553 has an inhibitory effect on mesolimbic DA activity, which could contribute to its efficacy in animal models of psychostimulant use.

Facile preparation of metal-free graphitic-like carbon nitride/graphene oxide composite for simultaneous determination of uric acid and dopamine

Graphitic-like carbon nitride/graphene oxide composite nanosheets (g-C3N4/GO) were synthesized for simultaneous determination of uric acid (UA) and dopamine (DA). The surface features and electrochemical properties of the g-C3N4/GO were investigated by scanning electron microscopy, X-ray diffraction, cyclic voltammetry and electrochemical impedance spectra. The voltammetric responses of UA and DA were determinated by cyclic voltammetry and differential pulse voltammetry. g-C3N4/GO had significantly improved electrical conductivity, selective oxidation capacity and electrocatalytic activity. The proposed g-C3N4/GO modified glassy carbon electrode (GCE) consequently displayed excellent electrocatalytic activity for UA and DA, with a broad linear detection range (0.03–30 μM) and extremely low detection limits (UA 4.6 nM; DA 5.4 nM). The proposed g-C3N4/GO/GCE also demonstrated excellent reproducibility, selectivity and stability. The levels of UA and DA in human serum were measured by the g-C3N4/GO/GCE, and then the known concentrations of UA and DA were spiked to the samples, which proved that the recoveries were good.

Dopamine-independent development and maintenance of mouse striatal medium spiny neuron dendritic spines

Striatal medium spiny neurons (MSNs) and striatal dopamine (DA) innervation are profoundly important for brain function such as motor control and cognition. A widely accepted theory posits that striatal DA loss causes (or leads to) MSN dendritic atrophy. However, examination of the literature indicates that the data from Parkinson's disease (PD) patients and animal PD models were contradictory among studies and hard to interpret. Here we have re-examined the potential effects of DA activity on MSN morphology or lack thereof. We found that in 15-day, 4- and 12-month old Pitx3 null mutant mice that have severe DA denervation in the dorsal striatum while having substantial residual DA innervation in the ventral striatum, MSN dendrites and spine numbers were similar in dorsal and ventral striatum, and also similar to those in normal mice. In 15-day, 4- and 12-month old tyrosine hydroxylase knockout mice that cannot synthesize L-dopa and thus have no endogenous DA in the entire brain, MSN dendrites and spine numbers were also indistinguishable from age-matched wild-type (WT) mice. Furthermore, in adult WT mice, unilateral 6-OHDA lesion at 12 months of age caused an almost complete striatal DA denervation in the lesioned side, but MSN dendrites and spine numbers were similar in the lesioned and control sides. Taken together, our data indicate that in mice, the development and maintenance of MSN dendrites and spines are DA-independent such that DA depletion does not trigger MSN dendritic atrophy; our data also suggest that the reported MSN dendritic atrophy in PD may be a component of neurodegeneration in PD rather than a consequence of DA denervation.

β-carotene-loaded nanoparticles protect against neuromotor damage, oxidative stress, and dopamine deficits in a model of Parkinson's disease in Drosophila melanogaster

β-carotene-loaded nanoparticles improves absorption by increasing bioavailability. The Drosophila melanogaster model of Parkinson's disease must be helpful in investigating potential neuroprotective effects. Four groups of four-day-old flies were exposed to: (1) control; (2) diet containing rotenone (500 μM); (3) β-carotene-loaded nanoparticles (20 μM); (4) β-carotene-loaded nanoparticles and rotenone for 7 days. Then, the percentage of survival, geotaxis tests, open field, aversive phototaxis and food consumption were evaluated. At the end of the behaviors, the analyses of the levels of reactive species (ROS), thiobarbituric acid reactive substances (TBARS), catalase (CAT) and superoxide dismutase (SOD) activity was carried out, as well as an evaluation of the levels of dopamine and acetylcholinesterase (AChE) activity, in the head of flies. Nanoparticles loaded with β-carotene were able to improve motor function, memory, survival and also restored the oxidative stress indicators (CAT, SOD, ROS and TBARS), dopamine levels, AChE activity after exposure to rotenone. Overall, nanoparticles loaded with β-carotene showed significant neuroprotective effect against damage induced by the Parkinson-like disease model, emerging as a possible treatment. Overall, β-carotene-loaded nanoparticles presented significant neuroprotective effect against damage induced by model of Parkinson-like disease, emerging as a possible treatment.

Efficacy of Serotonin and Dopamine Activity Modulators in the Treatment of Negative Symptoms in Schizophrenia: A Rapid Review

Schizophrenia is among the fifteen most disabling diseases worldwide. Negative symptoms (NS) are highly prevalent in schizophrenia, negatively affect the functional outcome of the disorder, and their treatment is difficult and rarely specifically investigated. Serotonin-dopamine activity modulators (SDAMs), of which aripiprazole, cariprazine, brexpiprazole, and lumateperone were approved for schizophrenia treatment, represent a possible therapy to reduce NS. The aim of this rapid review is to summarize the evidence on this topic to make it readily available for psychiatrists treating NS and for further research. We searched the PubMed database for original studies using SDAM, aripiprazole, cariprazine, brexpiprazole, lumateperone, schizophrenia, and NS as keywords. We included four mega-analyses, eight meta-analyses, two post hoc analyses, and 20 clinical trials. Aripiprazole, cariprazine, and brexpiprazole were more effective than placebo in reducing NS. Only six studies compared SDAMs with other classes of antipsychotics, demonstrating a superiority in the treatment of NS mainly for cariprazine. The lack of specific research and various methodological issues, related to the study population and the assessment of NS, may have led to these partial results. Here, we highlight the need to conduct new methodologically robust investigations with head-to-head treatment comparisons and long-term observational studies on homogeneous groups of patients evaluating persistent NS with first- and second-generation scales, namely the Brief Negative Symptom Scale and the Clinical Assessment Interview for Negative Symptoms. This rapid review can expand research on NS therapeutic strategies in schizophrenia, which is fundamental for the long-term improvement of patients' quality of life.

The Mechanisms of GPR55 Receptor Functional Selectivity during Apoptosis and Proliferation Regulation in Cancer Cells

GPR55 is a non-canonical cannabinoid receptor, important for cancer proliferation. Depending on the ligand, it induces either cell proliferation or death. The objective of the study was to establish the mechanisms of this multidirectional signaling. Using the CRISPR-Cas9 system, the GPR55, CB1, CB2, and GPR18 receptor knockouts of the MDA-MB-231 line were obtained. After the CB2 receptor knockout, the pro-apoptotic activity of the pro-apoptotic ligand docosahexaenoyl dopamine (DHA-DA) slightly increased, while the pro-proliferative activity of the most active synthetic ligand of the GPR55 receptor (ML-184) completely disappeared. On the original cell line, the stimulatory effect of ML-184 was removed by the CB2 receptor blocker and by GPR55 receptor knockout. Thus, it can be confidently assumed that when proliferation is stimulated with the participation of the GPR55 receptor, a signal is transmitted from the CB2 receptor to the GPR55 receptor due to the formation of a heterodimer. GPR18 was additionally involved in the implementation of the pro-apoptotic effect of DHA-DA, while the CB1 receptor is not involved. In the implementation of the pro-apoptotic action of DHA-DA, the elimination of Gα13 led to a decrease in cytotoxicity. The obtained data provide novel details to the mechanism of the pro-proliferative action of GPR55.

Dopamine receptor agonists mechanism of actions on glucose lowering and their connections with prolactin actions.

Robust experiment evidence suggests that prolactin can enhance beta-cell proliferation and increase insulin secretion and sensitivity. Apart from acting as an endocrine hormone, it also function as an adipokine and act on adipocytes to modulate adipogenesis, lipid metabolism and inflammation. Several cross-sectional epidemiologic studies consistently showed that circulating prolactin levels positive correlated with increased insulin sensitivity, lower glucose and lipid levels, and lower prevalence of T2D and metabolic syndrome. Bromocriptine, a dopamine receptor agonist used to treat prolactinoma, is approved by Food and Drug Administration for treatment in type 2 diabetes mellitus since 2009. Prolactin lowering suppress insulin secretion and decrease insulin sensitivity, therefore dopamine receptor agonists which act at the pituitary to lower serum prolactin levels are expected to impair glucose tolerance. Making it more complicating, studies exploring the glucose-lowering mechanism of bromocriptine and cabergoline have resulted in contradictory results; while some demonstrated actions independently on prolactin status, others showed glucose lowering partly explained by prolactin level. Previous studies showed that a moderate increase in central intraventricular prolactin levels stimulates hypothalamic dopamine with a decreased serum prolactin level and improved glucose metabolism. Additionally, sharp wave-ripples from the hippocampus modulates peripheral glucose level within 10 minutes, providing evidence for a mechanistic link between hypothalamus and blood glucose control. Central insulin in the mesolimbic system have been shown to suppress dopamine levels thus comprising a feedback control loop. Central dopamine and prolactin levels plays a key role in the glucose homeostasis control, and their dysregulation could lead to the pathognomonic central insulin resistance depicted in the "ominous octet". This review aims to provide an in-depth discussion on the glucose-lowering mechanism of dopamine receptor agonists and on the diverse prolactin and dopamine actions on metabolism targets.