Alterations In Dopamine Levels Research Articles

Neurotransmitter Dysregulation in Sleep and Circadian Rhythms: Implications for Postpartum Depression

Postpartum depression (PPD) is a major mental health disorder that affects mothers both emotionally and physically, hindering their ability to care for the child. Other neurotransmitter imbalances during the postpartum period include serotonin, dopamine, melatonin, GABA, and orexin, which result in disturbances in sleep. The reduction in serotonin concentration is related to mood and sleep, while altered dopamine levels are related to alertness and coordinating circadian rhythms. Further, women postpartum demonstrates higher melatonin levels and a subsequent neuronal excitation due to lesser functioning GABA-A receptors, which in addition combine to cause disturbances with sleep. This paper reviews the literature to analyze the effects of neurotransmitter disorders in sleep and circadian rhythm on postpartum depression. The review provides emerging treatment options for postpartum depression including selective serotonin reuptake inhibitors (SSRIs), melatonin agonists, and benzodiazepines, which have shown promising results in relieving symptoms by modulating neurotransmitter pathways. However, more research needs to be undertaken in the field of non-pharmacological interventions, the long-term outcome of neurotransmitter dysregulation, and preventive measures during pregnancy that would go a long way toward improving overall outcomes for mothers as well as their infants.

Caffeine's Neuroprotective Effect on Memory Impairment: Suppression of Adenosine A2A Receptor and Enhancement of Tyrosine Hydroxylase in Dopaminergic Neurons Under Hypobaric Hypoxia Conditions.

Chronic hypobaric hypoxia frequently results in memory deficits, with severe cases showing marked alterations in dopamine levels and its metabolites. This research explores caffeine's modulation of the adenosine A2A receptor (A2AR) and its regulatory effects on tyrosine hydroxylase (TH), aiming to restore dopamine homeostasis and mitigate memory impairments associated with hypoxia. The goal is to identify novel preventive strategies against cognitive decline induced by hypoxia. Network pharmacological analysis was employed to predict the interactions between caffeine, cognitive function, and hypobaric hypoxia-related disorders. The novel object recognition and Y-maze tests were utilized to assess caffeine's impact on memory deficits under hypobaric hypoxia conditions in male mice. LC-MS/MS analysis was subsequently conducted to examine the variations in dopamine and its metabolites within the midbrain. Molecular docking further confirmed the binding affinities between A2AR and caffeine, as well as TH and caffeine. Additionally, immunofluorescence and protein-protein docking were employed to elucidate the interaction between A2AR and TH. The findings highlight the pivotal role of adenosine receptors and dopamine-related pathways in the interplay between caffeine, cognition, and hypobaric hypoxia-related disorders. Behavioral tests demonstrated that caffeine effectively alleviated memory impairments caused by chronic hypobaric hypoxia. LC-MS/MS results revealed significant differences in dopamine, metanephrine, and 3-hydroxyanthranilic acid levels following caffeine treatment for hypoxia-induced cognitive deficits. Molecular docking confirmed the high affinity between A2AR and caffeine, as well as TH and caffeine, while immunofluorescence and protein-protein docking provided insights into the A2AR-TH interaction and its modulation during hypobaric hypoxia. Caffeine exhibits potent neuroprotective effects against chronic high-altitude-induced cognitive impairments, potentially through its action on A2AR, leading to enhanced TH expression and subsequent release of dopamine and its related neurotransmitters.

Subthalamic nucleus deep brain stimulation induces functional deficits in norepinephrinergic neurotransmission in a Parkinson’s disease model

BackgroundDeep brain stimulation of the subthalamic nucleus (STN-DBS) is a successful treatment option in Parkinson’s disease (PD) for different motor and non-motor symptoms, but has been linked to postoperative cognitive impairment. AimSince both dopaminergic and norepinephrinergic neurotransmissions play important roles in symptom development, we analysed STN-DBS effects on dopamine and norepinephrine availability in different brain regions and morphological alterations of catecholaminergic neurons in the 6-hydroxydopamine PD rat model. MethodsWe applied one week of continuous unilateral STN-DBS or sham stimulation, respectively, in groups of healthy and 6-hydroxydopamine-lesioned rats to quantify dopamine and norepinephrine contents in the striatum, olfactory bulb and dentate gyrus. In addition, we analysed dopaminergic cell counts in the substantia nigra pars compacta and area tegmentalis ventralis and norepinephrinergic neurons in the locus coeruleus after one and six weeks of STN-DBS. ResultsIn 6-hydroxydopamine-lesioned animals, one week of STN-DBS did not alter dopamine levels, while striatal norepinephrine levels were decreased. However, neither one nor six weeks of STN-DBS altered dopaminergic neuron numbers in the midbrain or norepinephrinergic neuron counts in the locus coeruleus. Dopaminergic fibre density in the dorsal and ventral striatum also remained unchanged after six weeks of STN-DBS. In healthy animals, one week of STN-DBS resulted in increased dopamine levels in the olfactory bulb and decreased contents in the dentate gyrus, but had no effects on norepinephrine availability. ConclusionsSTN-DBS modulates striatal norepinephrinergic neurotransmission in a PD rat model. Additional behavioural studies are required to investigate the functional impact of this finding.

Constraints on the subsecond modulation of striatal dynamics by physiological dopamine signaling.

Dopaminergic neurons play a crucial role in associative learning, but their capacity to regulate behavior on subsecond timescales remains debated. It is thought that dopaminergic neurons drive certain behaviors by rapidly modulating striatal spiking activity; however, a view has emerged that only artificially high (that is, supra-physiological) dopamine signals alter behavior on fast timescales. This raises the possibility that moment-to-moment striatal spiking activity is not strongly shaped by dopamine signals in the physiological range. To test this, we transiently altered dopamine levels while monitoring spiking responses in the ventral striatum of behaving mice. These manipulations led to only weak changes in striatal activity, except when dopamine release exceeded reward-matched levels. These findings suggest that dopaminergic neurons normally play a minor role in the subsecond modulation of striatal dynamics in relation to other inputs and demonstrate the importance of discerning dopaminergic neuron contributions to brain function under physiological and potentially nonphysiological conditions.

Chronic ultraviolet irradiation induces memory deficits via dysregulation of the dopamine pathway

The effects of ultraviolet (UV) radiation on brain function have previously been investigated; however, the specific neurotransmitter-mediated mechanisms responsible for UV radiation-induced neurobehavioral changes remain elusive. In this study, we aimed to explore the mechanisms underlying UV radiation-induced neurobehavioral changes. In a mouse model, we observed that UV irradiation of the skin induces deficits in hippocampal memory, synaptic plasticity, and adult neurogenesis, as well as increased dopamine levels in the skin, adrenal glands, and brain. Chronic UV exposure altered the expression of genes involved in dopaminergic neuron differentiation. Furthermore, chronic peripheral dopamine treatments resulted in memory deficits. Systemic administration of a dopamine D1/D5 receptor antagonist reversed changes in memory, synaptic plasticity, adult neurogenesis, and gene expression in UV-irradiated mice. Our findings provide converging evidence that chronic UV exposure alters dopamine levels in the central nervous system and peripheral organs, including the skin, which may underlie the observed neurobehavioral shifts, such as hippocampal memory deficits and impaired neurogenesis. This study underscores the importance of protection from UV exposure and introduces the potential of pharmacological approaches targeting dopamine receptors to counteract the adverse neurological impacts of UV exposure.

Intake of oligoelements with cytarabine or etoposide alters dopamine levels and oxidative damage in rat brain

Research on the relationships between oligoelements (OE) and the development of cancer or its prevention is a field that is gaining increasing relevance. The aim was to evaluate OE and their interactions with oncology treatments (cytarabine or etoposide) to determine the effects of this combination on biogenic amines and oxidative stress biomarkers in the brain regions of young Wistar rats. Dopamine (DA), 5-Hydroxyindoleacetic acid (5-Hiaa), Glutathione (Gsh), Tiobarbituric acid reactive substances (TBARS) and Ca+2, Mg+2 ATPase enzyme activity were measured in brain regions tissues using spectrophometric and fluorometric methods previously validated. The combination of oligoelements and cytarabine increased dopamine in the striatum but decreased it in cerebellum/medulla-oblongata, whereas the combination of oligoelements and etoposide reduced lipid peroxidation. These results suggest that supplementation with oligoelements modifies the effects of cytarabine and etoposide by redox pathways, and may become promising therapeutic targets in patients with cancer.

Genetic polymorphism in HTR2A rs6313 is associated with internet addiction disorder.

Internet addiction disorder (IAD) has grown into public health concern of global proportions. Previous studies have indicated that individuals with IAD may exhibit altered levels of serotonin and dopamine, which are known to play crucial roles in depression, anxiety, impulsivity, and addiction. Therefore, polymorphisms in the receptors that mediate the effects of serotonin and dopamine and affect their functional states as well as their activities are suspect. In this study, we aimed to investigate the association between IAD and rs6313 (T102C) polymorphism in the serotonin 2A receptor (5-HT2A) gene, (HTR2A). Twenty patients with IAD and twenty healthy controls (HCs) were included in this study. Young's Internet Addiction Test (IAT), Self-Rating Anxiety Scale, Self-Rating Depression Scale, Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Barratt Impulse Scale, Pittsburgh Sleep Quality Index (PSQI), and Social Support Rating Scale (SSRS) were used to assess the severity of internet addiction, mental status, impulsive traits, sleep quality, and social support. Genotyping was performed to identify rs6313 polymorphisms in the HTR2A gene of all participants. The frequencies of the C and T alleles of HTR2A T102C were 28% and 72% in the IAD group and 53% and 47% in the HCs group, respectively, indicating that the differences between these two groups were significant. No significant difference was observed in the distribution of the CC, CT, and TT genotypes of HTR2A gene T102C between the IAD and the HCs groups. Additionally, there was no difference in the distribution of the frequencies of the HTR2A gene T102C CC and CT+TT genotypes between the two groups. However, the distribution between the TT and CC+CT genotypes showed an apparent statistical difference in the HTR2A gene T102C between the two groups. Correlation analysis indicated that the IAT score was positively correlated with the Y-BOCS and BIS scores for the CC+CT genotype in patients with IAD. Moreover, the IAT score was positively correlated with the PSQI score in patients with IAD carrying the TT genotype. The present study demonstrates that rs6313 in HTR2A is associated with IAD, and that the T allele of rs6313 in HTR2A may be a risk factor for IAD.

Unraveling the role of Slc10a4 in auditory processing and sensory motor gating: Implications for neuropsychiatric disorders?

BackgroundPsychiatric disorders, such as schizophrenia, are complex and challenging to study, partly due to the lack of suitable animal models. However, the absence of the Slc10a4 gene, which codes for a monoaminergic and cholinergic associated vesicular transporter protein, in knockout mice (Slc10a4−/−), leads to the accumulation of extracellular dopamine. A major challenge for studying schizophrenia is the lack of suitable animal models that accurately represent the disorder. We sought to overcome this challenge by using Slc10a4−/− mice as a potential model, considering their altered dopamine levels. This makes them a potential animal model for schizophrenia, a disorder known to be associated with altered dopamine signaling in the brain. MethodsThe locomotion, auditory sensory filtering and prepulse inhibition (PPI) of Slc10a4−/− mice were quantified and compared to wildtype (WT) littermates. Intrahippocampal electrodes were used to record auditory event-related potentials (aERPs) for quantifying sensory filtering in response to paired-clicks. The channel above aERPs phase reversal was chosen for reliably comparing results between animals, and aERPs amplitude and latency of click responses were quantified. WT and Slc10a4−/− mice were also administered subanesthetic doses of ketamine to provoke psychomimetic behavior. ResultsBaseline locomotion during auditory stimulation was similar between Slc10a4−/− mice and WT littermates. In WT animals, normal auditory processing was observed after i.p saline injections, and it was maintained under the influence of 5 mg/kg ketamine, but disrupted by 20 mg/kg ketamine. On the other hand, Slc10a4−/− mice did not show significant differences between N40 S1 and S2 amplitude responses in saline or low dose ketamine treatment. Auditory gating was considered preserved since the second N40 peak was consistently suppressed, but with increased latency. The P80 component showed higher amplitude, with shorter S2 latency under saline and 5 mg/kg ketamine treatment in Slc10a4−/− mice, which was not observed in WT littermates. Prepulse inhibition was also decreased in Slc10a4−/− mice when the longer interstimulus interval of 100 ms was applied, compared to WT littermates. ConclusionThe Slc10a4−/− mice responses indicate that cholinergic and monoaminergic systems participate in the PPI magnitude, in the temporal coding (response latency) of the auditory sensory gating component N40, and in the amplitude of aERPs P80 component. These results suggest that Slc10a4−/− mice can be considered as potential models for neuropsychiatric conditions.

PS12 A new meaning to ‘picking your nose’: the use of N-acetylcysteine to treat trigeminal trophic syndrome

Abstract Trigeminal trophic syndrome (TTS) is a rare condition in which patients induce unilateral facial ulceration by persistent physical manipulation. Peripheral or central damage to the trigeminal nerve causes anaesthesia, paraesthesia, formication or pruritus. Compulsive skin picking leads to ulceration of the ala nasi, cheek, scalp or mouth in the distribution of the trigeminal nerve. Patients with TTS are often subjected to extensive investigations and can be misdiagnosed as having a psychocutaneous disorder, such as dermatitis artefacta, skin-picking disorder or delusional parasitosis. We describe a 90-year-old woman who developed TTS following rhizotomy and radiofrequency treatment for trigeminal neuralgia. Underlying infectious, malignant and vasculitic causes for her ala nasi and cheek ulceration were ruled out through six incisional biopsies and two punch biopsies over 8 years. Previous treatment of TTS has included patient education and physical barriers (e.g. face masks and occlusive dressings). Treatment to date has been challenging, with trials of medications to address paraesthesia, including carbamazepine, gabapentin and amitriptyline. This patient re-presented to dermatology in 2022 with significantly worsened ulceration to her cheek and severe loss of nasal cartilage. In September 2022, the patient was started on N-acetylcysteine (NAC) 600 mg twice daily, and within 3 months, there was a considerable improvement. This drug is a mucolytic that has historically been used as an antidote for paracetamol overdose. It has antioxidant properties by replenishing glutathione and maintaining redox balance within cells. It also modulates neurotransmitters and can increase glutamate and alter dopamine levels. In addition, it has anti-inflammatory action by inhibiting interleukins (ILs), including IL-6 (Adil M, Amin SS. N-acetylcysteine in dermatology. Indian J Dermatol Venereol Leprol 2018; 84:652). In recent years, NAC has been reported to be successful in small case series and case reports among patients with trichotillomania, skin-picking disorders, onychotillomania, toxic epidermal necrolysis, alopecia, contact dermatitis, atopic dermatitis and wound healing (Grant JE, Chamberlain SR, Redden SA, Leppink EW. N-Acetylcysteine in the treatment of excoriation disorder. JAMA Psychiatry 2016; 73:490). It is an inexpensive drug that appears to be well tolerated and effective. To our knowledge, this is the first case report of the use of NAC in TTS. In summary, this was a case of TTS in a 90-year-old woman who successfully responded to NAC. The drug has antioxidant, anti-inflammatory and neurotransmitter modulatory effects. Reliable randomized controlled studies are needed to confirm the efficacy and optimum dose of NAC. Increased awareness of this rare syndrome and potential treatment options will ensure prompt diagnosis and prevention of permanent disfiguration.

Providing or receiving alloparental care promote partner preference and alter central oxytocin and dopamine systems in adult mandarin voles

Juveniles of cooperative breeding species usually remain in the natal area and provide care to younger siblings, a behavior considered one form of alloparenting in the natural condition. Previous studies have demonstrated the effects of providing or receiving alloparental care on adult behaviors, including anxiety-like behavior, social interaction, and parental behavior, but little is known about the influences on species-typical bonding behaviors, such as pair-bond formation. In this study, we explored this concept using socially monogamous mandarin voles (Lasiopodomys mandarinus). As the oxytocin (OT) and dopamine systems are involved in alloparental and pair-bonding behaviors, we also examined the levels of central OT and tyrosine hydroxylase (TH), as well as OT receptor (OTR) and dopamine D1-type and D2-type receptors (D1R and D2R) mRNA expression in the nucleus accumbens (NAcc) and amygdala to investigate the underlying mechanisms. Our results show that mandarin voles providing alloparental care to younger siblings displayed facilitation of partner preference formation, lower levels of OT expression in the paraventricular nucleus of the hypothalamus (PVN) and lateral hypothalamus (LH), and increased OTR and D2R mRNA expression in the NAcc compared to controls. Individuals receiving alloparental care also demonstrated facilitation of partner preference formation in adult voles. Additionally, alloparental care enhanced OT expression in the PVN, anterior medial preoptic nucleus (MPOAa), medial amygdala (MeA), and TH expression in the ventral tegmental area (VTA) and zona incerta (ZI). Furthermore, males displayed decreased D1R mRNA expression in the NAcc, whereas females showed slightly increased D2R expression in the amygdala. These results demonstrate that providing or received alloparental care can promote partner preference formation in monogamous species and that these changes are associated with altered OT and dopamine levels and their receptors in specific brain regions.

Dopamine Transmission Imbalance in Neuroinflammation: Perspectives on Long-Term COVID-19.

Dopamine (DA) is a key neurotransmitter in the basal ganglia, implicated in the control of movement and motivation. Alteration of DA levels is central in Parkinson's disease (PD), a common neurodegenerative disorder characterized by motor and non-motor manifestations and deposition of alpha-synuclein (α-syn) aggregates. Previous studies have hypothesized a link between PD and viral infections. Indeed, different cases of parkinsonism have been reported following COVID-19. However, whether SARS-CoV-2 may trigger a neurodegenerative process is still a matter of debate. Interestingly, evidence of brain inflammation has been described in postmortem samples of patients infected by SARS-CoV-2, which suggests immune-mediated mechanisms triggering the neurological sequelae. In this review, we discuss the role of proinflammatory molecules such as cytokines, chemokines, and oxygen reactive species in modulating DA homeostasis. Moreover, we review the existing literature on the possible mechanistic interplay between SARS-CoV-2-mediated neuroinflammation and nigrostriatal DAergic impairment, and the cross-talk with aberrant α-syn metabolism.

Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases.

The Japanese encephalitis virus (JEV) is the most common cause of neurodegenerative disease in Southeast Asia and the Western Pacific region; approximately 1.15 billion people are at risk, and thousands suffer from permanent neurological disorders across Asian countries, with 10-15 thousand people dying each year. JEV crosses the blood-brain barrier (BBB) and forms a complex with receptors on the surface of neurons. GRP78, Src, TLR7, caveolin-1, and dopamine receptor D2 are involved in JEV binding and entry into the neurons, and these receptors also play a role in carcinogenic activity in cells. JEV binds to GRP78, a member of the HSP70 overexpressed on malignant cells to enter neurons, indicating a higher chance of JEV infection in cancer patients. However, JEV enters human brain microvascular endothelial cells via an endocytic pathway mediated by caveolae and the ezrin protein and also targets dopamine-rich areas for infection of the midbrain via altering dopamine levels. In addition, JEV complexed with CLEC5A receptor of macrophage cells is involved in the breakdown of the BBB and central nervous system (CNS) inflammation. CLEC5A-mediated infection is also responsible for the influx of cytokines into the CNS. In this review, we discuss the neuronal and macrophage surface receptors involved in neuronal death.

Neuropathic Pain in Parkinson's Disease.

Pain is a well-recognized and important non-motor manifestation in Parkinson disease (PD). Painful or unpleasant sensations in PD can be classified as musculoskeletal, dystonia, akathisia, radicular, and central or primary pain; the last two are associated with neuropathic pain. Particularly, neuropathic pain in PD has not been fully clarified; therefore, it goes somewhat unnoticed, and the affected patients do not receive adequate pain treatment. The main purpose of this literature review was to identify the incidence of neuropathic pain in PD and the involvement of dopamine of this type of pain by the integration of different lines of investigation. In this review, a search was conducted using PubMed, ProQuest, EBSCO, Medline, EMBASE, and the Science Citation index for studies evaluating pain in patients with PD. The inclusion criteria were as follows: original articles that evaluated incidence and possible mechanism of neuropathic, central, and radicular pain in PD. Nine studies related to the incidence of neuropathic pain in PD suggest the activation of cerebral areas, such as the cortex, striatum, amygdala, thalamus, raphe nuclei, and locus coeruleus. Neuropathic pain is related to altered levels of dopamine, serotonin, and norepinephrine; these neurotransmitters are related to the sensitive and emotional dimensions of pain. Dopamine could cause hypersensitivity to pain, either indirectly through modulatory effects on affective pain processing and/or directly by affecting the neural activity in key areas of the brain that modulate pain. A considerable proportion of patients with PD suffer neuropathic pain; however, it has been disregarded, this has led to an inability to achieve an adequate treatment and a decrease in pain to improve the quality of life of these patients. We consider that neuropathic pain in PD is possibly induced by neurophysiological changes due to the degradation of dopaminergic neurons.

Neurotransmitter and Related Metabolic Profiling in the Nucleus Accumbens of Chronic Unpredictable Mild Stress-Induced Anhedonia-Like Rats.

Major depressive disorder (MDD) is a serious mental disorder that affects many people. The neurotransmitter deficiency hypothesis has been the crux of much research on the treatment of depression. Anhedonia, as a core symptom, was closely associated with altered levels of 5-hydroxytryptamine (5-HT), dopamine (DA), and diverse types of glutamate (Glu) receptors in the nucleus accumbens (NAc). However, there were no reports showing how Glu changed in the NAc, and there were other unreported molecules involved in modulating stress-induced anhedonia. Thus, we investigated changes in neurotransmitters and their related metabolites in GABAergic, serotonergic and catecholaminergic pathways in the NAc of a rat model of chronic unpredictable mild stress- (CUMS-) induced anhedonia-like behavior. Then, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was employed to detect target neurotransmitters and related metabolites in the NAc. Finally, the Western blot was used to assess the expression of key enzymes and receptors. Here, we found that the 5-HT level in anhedonia-susceptible (Sus) rats was increased while the Glu level decreased. DA did not show a significant change among CUMS rats. Correspondingly, we detected a reduction in monoamine oxidase-A (MAOA) and Glu receptor 1 levels in anhedonia-Sus rats while Glu receptor 2 (GluR2) and NMDA2B levels were increased in anhedonia-resilient (Res) rats. We also found that the levels of glutamine (Gln), kynurenic acid (Kya), histamine (HA), L-phenylalanine (L-Phe), and tyramine (Tyra) were changed after CUMS. These alterations in neurotransmitters may serve as a new insight into understanding the development of anhedonia-like behavior in depression.

Altered Retinal Dopamine Levels in a Melatonin-proficient Mouse Model of Form-deprivation Myopia.

Reduced levels of retinal dopamine, a key regulator of eye development, are associated with experimental myopia in various species, but are not seen in the myopic eyes of C57BL/6 mice, which are deficient in melatonin, a neurohormone having extensive interactions with dopamine. Here, we examined the relationship between form-deprivation myopia (FDM) and retinal dopamine levels in melatonin-proficient CBA/CaJ mice. We found that these mice exhibited a myopic refractive shift in form-deprived eyes, which was accompanied by altered retinal dopamine levels. When melatonin receptors were pharmacologically blocked, FDM could still be induced, but its magnitude was reduced, and retinal dopamine levels were no longer altered in FDM animals, indicating that melatonin-related changes in retinal dopamine levels contribute to FDM. Thus, FDM is mediated by both dopamine level-independent and melatonin-related dopamine level-dependent mechanisms in CBA/CaJ mice. The previously reported unaltered retinal dopamine levels in myopic C57BL/6 mice may be attributed to melatonin deficiency.

The Novel Analogue of Modafinil CE-158 Protects Social Memory against Interference and Triggers the Release of Dopamine in the Nucleus Accumbens of Mice.

Previous studies have shown that atypical dopamine-transporter-inhibitors such as modafinil and its analogues modify behavioral and cognitive functions in rodents. Here, we tested potential promnestic effects of the novel, more dopamine-transporter selective modafinil analogue CE-158 in the social discrimination memory task in male mice. Systemic administration of CE-158 1 h before the social learning event prevented the impairment of social-recognition memory following retroactive interference 3 h after the learning session of a juvenile conspecific. This effect was dose-dependent, as mice treated with 10 mg/kg, but not with 1 mg/kg CE-158, were able to discriminate between the novel and familiar conspecific despite the presentation of an interference stimulus, both 3 h and 6 h post learning. However, when 10 mg/kg of the drug was administered after learning, CE-158 failed to prevent social memory from interference. Paralleling these behavioral effects, the systemic administration of 10 mg/kg CE-158 caused a rapid and sustained elevation of extracellular dopamine in the nucleus accumbens, a brain area where dopaminergic signaling plays a key role in learning and memory function, of freely moving mice, while 1 mg/kg was not sufficient for altering dopamine levels. Taken together, our findings suggest promnestic effects of the novel dopamine-transporter-inhibitor CE-158 in a social recognition memory test that may be in part mediated via increased dopamine-neurotransmission in the nucleus accumbens. Thus, selective-dopamine-transporter-inhibitors such as CE-158 may represent interesting drug candidates for the treatment of memory complaints observed in humans with cognitive impairments and dementia.

In vivo microdialysis reveals that blockade of accumbal orexin OX2 but not OX1 receptors enhances dopamine efflux in the nucleus accumbens of freely moving rats.

The nucleus accumbens contain orexinergic neural inputs and orexin OX1 - and OX2 -receptors. Behavioural studies suggest that accumbal orexin receptors modulate accumbal dopaminergic activity-dependent locomotion in rats. We studied the effects of intra-accumbal injection of orexin receptor ligands on accumbal extracellular dopamine levels in freely moving rats, using in vivo microdialysis and analysed the roles of OX1 - and OX2 -receptors in the regulation of basal accumbal dopamine efflux. The orexin receptor ligands were applied intra-accumbally though a microinjection needle attached with a dialysis probe. Neither the nonselective OX1 - and OX2 -receptor agonist orexin-A nor the preferential OX2 -receptor agonist orexin-B (500.0pg and 5.0ng) altered accumbal dopamine levels. The nonselective OX1 - and OX2 -receptor antagonist MK-4305 (suvorexant, 500.0pg, 2.5 and 5.0ng) enhanced dopamine efflux. A 2-h tetrodotoxin infusion into nucleus accumbens through the probe or co-administration of orexin-A (500.0pg) strongly inhibited MK-4305 (5.0ng)-induced accumbal dopamine efflux. The selective OX2 -receptor antagonist EMPA (90.0 and 900.0pg, 9.0ng) increased dopamine efflux. Intra-accumbal infusion of tetrodotoxin abolished EMPA (9.0ng)-induced dopamine efflux. The selective OX1 -receptor antagonist SB-334867 (10.0 and 20.0ng) failed to alter dopamine efflux. Co-administration of orexin-B (500.0pg) inhibited both EMPA (9.0ng)- and MK-4305 (5.0ng)-induced dopamine efflux. Intraperitoneal injection of MK-4305 (10.0mg/kg) did not affect accumbal dopamine efflux. The present study provides in vivo neuropharmacological evidence that accumbal OX2 - but not OX1 -receptors exert inhibitory regulation of basal accumbal dopamine efflux and that blockade of accumbal OX2 -receptors enhances dopamine efflux in nucleus accumbens of freely moving rats.

Ethanol-induced Sedative Behavior: An Assay to Investigate Increased Dopamine Signaling in Caenorhabditis elegans.

Dopamine (DA) signaling affects locomotion, feeding, learning, and memory in C. elegans. Various assays have been developed to study the proteins involved in these behaviors; however, these assays show behavioral output only when there is a drastic change in DA levels. We designed an assay capable of observing behavioral output even with only slight alterations in DA levels. To achieve this, we designed a behavioral paradigm where we combined C. elegans movement with ethanol (EtOH) administration. The behavioral response to alcohol/EtOH and susceptibility to alcohol-use disorders (AUDs) have been linked to DA. Our assay correlates an increase in DA levels due to EtOH and movement obstruction due to a dry surface to a circular sedative behavior, which we designated as EtOH-induced sedative (EIS) behavior. We successfully utilized this assay to assign physiological and behavioral functions to a DA autoreceptor, DOP-2.

A Basal Ganglia Computational Model to Explain the Paradoxical Sensorial Improvement in the Presence of Huntington's Disease.

The basal ganglia (BG) represent a critical center of the nervous system for sensorial discrimination. Although it is known that Huntington's disease (HD) affects this brain area, it still remains unclear how HD patients achieve paradoxical improvement in sensorial discrimination tasks. This paper presents a computational model of the BG including the main nuclei and the typical firing properties of their neurons. The BG model has been embedded within an auditory signal detection task. We have emulated the effect that the altered levels of dopamine and the degree of HD affectation have in information processing at different layers of the BG, and how these aspects shape transient and steady states differently throughout the selection task. By extracting the independent components of the BG activity at different populations, it is evidenced that early and medium stages of HD affectation may enhance transient activity in the striatum and the substantia nigra pars reticulata. These results represent a possible explanation for the paradoxical improvement that HD patients present in discrimination task performance. Thus, this paper provides a novel understanding on how the fast dynamics of the BG network at different layers interact and enable transient states to emerge throughout the successive neuron populations.

Altered monoaminergic levels, spasticity, and balance disability following repetitive blast-induced traumatic brain injury in rats

Spasticity and balance disability are major complications following traumatic brain injury (TBI). Although monoaminergic inputs provide critical adaptive neuromodulations to the motor system, data are not available regarding the levels of monoamines in the brain regions related to motor functions following repetitive blast TBI (bTBI). The objective of this study was to determine if mild, repetitive bTBI results in spasticity/balance deficits and if these are correlated with altered levels of norepinephrine, dopamine, and serotonin in the brain regions related to the motor system. Repetitive bTBI was induced by a blast overpressure wave in male rats on days 1, 4, and 7. Following bTBI, physiological/behavioral tests were conducted and tissues in the central motor system (i.e., motor cortex, locus coeruleus, vestibular nuclei, and lumbar spinal cord) were collected for electrochemical detection of norepinephrine, dopamine, and serotonin by high-performance liquid chromatography. The results showed that norepinephrine was significantly increased in the locus coeruleus and decreased in the vestibular nuclei, while dopamine was significantly decreased in the vestibular nuclei. On the other hand, serotonin was significantly increased in the motor cortex and the lumbar spinal cord. Because these monoamines play important roles in regulating the excitability of neurons, these results suggest that mild, repetitive bTBI-induced dysregulation of monoaminergic inputs in the central motor system could contribute to spasticity and balance disability. This is the first study to report altered levels of multiple monoamines in the central motor system following acute mild, repetitive bTBI.