Dopamine Turnover Research Articles

Neurotransmitter changes in rat brain regions following glyphosate exposure

The effects of glyphosate oral exposure (35, 75, 150 and 800mg/kg bw, 6 days) on brain region monoamine levels of male Wistar rats were examined. Glyphosate-treated rats (35, 75, 150 and 800mg/kg bw, 6 days), had no visible injury, i.e., no clinical signs of dysfunction were observed. After last dose of glyphosate, serotonin (5-HT), dopamine (DA) and norepinephrine (NE) and its metabolites levels were determined in the brain regions striatum, hippocampus, prefrontal, cortex, hypothalamus and midbrain, by HPLC. Glyphosate caused statistically significant changes in the 5-HT and its metabolite 5-hydroxy-3-indolacetic acid (5-HIAA), DA and its metabolites 3,4-hydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and NE and its metabolite 3-metoxy-4-hydroxyphenylethyleneglycol (MHPG) levels in a brain regional- and dose-related manner. Moreover, glyphosate, dose-dependent, evoked a statistically significant increase in 5-HT turnover in striatum and hypothalamus and in DA turnover in prefrontal cortex and hippocampus, and a statistically significant decrease in NE turnover in prefrontal cortex and hypothalamus. The present findings indicate that glyphosate significantly altered central nervous system (CNS) monoaminergic neurotransmitters in a brain regional- and dose-related manner, effects that may contribute to the overall spectrum of neurotoxicity caused by this herbicide.

Optimized Method to Quantify Dopamine Turnover in the Mammalian Retina.

Measurement of dopamine (DA) release in the retina allows the interrogation of the complex neural circuits within this tissue. A number of previous methods have been used to quantify this neuromodulator, the most common of which is HPLC with electrochemical detection (HPLC-ECD). However, this technique can produce significant concentration uncertainties. In this present study, we report a sensitive and accurate UHPLC-MS/MS method for the quantification of DA and its primary metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in mouse retina. Internal standards DA-d4 and DOPAC-d5 result in standard curve linearity for DA from 0.05-100 ng/mL (LOD = 6 pg/mL) and DOPAC from 0.5-100 ng/mL (LOD = 162 pg/mL). A systematic study of tissue extraction conditions reveals that the use of formic acid (1%), in place of the more commonly used perchloric acid, combined with 0.5 mM ascorbic acid prevents significant oxidation of the analytes. When the method is applied to mouse retinae a significant increase in the DOPAC/DA ratio is observed following in vivo light stimulation. We additionally examined the effect of anesthesia on DA and DOPAC levels in the retina in vivo and find that basal dark-adapted concentrations are not affected. Light caused a similar increase in DOPAC/DA ratio but interindividual variation was significantly reduced. Together, we systematically describe the ideal conditions to accurately and reliably measure DA turnover in the mammalian retina.

Analysis of human cerebrospinal fluid monoamines and their cofactors by HPLC.

The presence of monoamines and their cofactors (the pterins and vitamin B6 (pyridoxal phosphate (PLP))) in human cerebrospinal fluid (CSF) can be used as indicators of the biosynthesis and turnover of dopamine and serotonin in the brain. In addition, abnormalities in the CSF levels of these molecules are associated with various neurological diseases, including genetic diseases leading to dopamine and serotonin deficiency. Here, we provide a set of quantitative high-performance liquid-chromatography (HPLC) approaches to determine CSF levels of monoamines and their cofactors. This protocol describes step-by-step procedures for CSF sample preparation for the analysis of different molecules, HPLC calibration and analysis, and data quantification and interpretation. Unlike plasma/tissue/blood samples, CSF requires minimal sample preparation: in this protocol, only the analysis of PLP requires mixing with trichloroacetic acid to release the protein-bound vitamin, centrifugation, and mixing of the supernatant with phosphate buffer and sodium cyanide for derivatization in alkaline conditions. Monoamines are analyzed by HPLC with coulometric electrochemical detection (ED), pterins are analyzed by HPLC with coupled coulometric electrochemical and fluorescence detection, and PLP is analyzed by HPLC with fluorescence detection. The quantification of all compounds is achieved by external calibration procedures, and internal quality control and standards are analyzed in each run. We anticipate that investigation of dopamine and serotonin disturbances will be facilitated by measurements of these compounds in human CSF and other biological samples. The estimated time for the different procedures primarily depends on the electrochemical detector stabilization. Overnight stabilization of this detector is advised, and, after that step, preanalytical equilibration rarely exceeds 3 h.

Maternal undernutrition during lactation alters nicotine reward and DOPAC/dopamine ratio in cerebral cortex in adolescent mice, but does not affect nicotine-induced nAChRs upregulation

Early undernutrition causes long lasting alterations that affect the response to psychoactive drugs. Particularly, undernutrition during lactation affects the acute locomotor response to nicotine during adolescence, but the reward effect of continued exposure to nicotine remains unknown. The goal of this study was to investigate the effects of undernutrition during lactation on the nicotine susceptibility indexed via conditioned place preference (CPP), on dopamine content and turnover and on nicotine-induced nicotinic cholinergic receptor (nAChR) upregulation in the cerebral cortex, midbrain and hippocampus of adolescent mice. The impact of undernutrition and nicotine exposure on stress-related hormones and leptin was also investigated. From postnatal day 2 (PN2) to weaning (PN21), dams were randomly assigned to one of the following groups: Control (C) – free access to standard laboratory diet (23% protein); Protein Restricted (PR) – free access to isoenergenetic diet (8% protein); Calorie Restricted (CR) – access to standard laboratory diet in restricted quantities (mean ingestion of PR). PR and CR groups showed less mass gain and less visceral fat mass. While C and CR were equally susceptible to nicotine-induced place preference conditioning, PR failed to show a conditioning pattern. In contrast, all groups presented a nicotine-evoked nAChR upregulation in the cerebral cortex. While dopamine and DOPAC levels did not differ between groups, the DOPAC/dopamine ratio was increased in CR animals. No differences in endocrine parameters were observed. Taken together, our results indicate that undernutrition during lactation programs for brain alterations later in life. Our data also suggest that early undernutrition does not affect the rewarding associative properties of nicotine at adolescence.

Type 2 Diabetes Mellitus Is Associated with Social Recognition Memory Deficit and Altered Dopaminergic Neurotransmission in the Amygdala

Objective: Diabetic neuropathy is a chronic and often disabling condition that affects a significant number of individuals with diabetes mellitus (DM). It is now established that DM causes various CNS complications like Alzheimer's, dementia, anxiety, depression, neurodegeneration, mood disorders, cognitive dysfunctioning, and so on. Since amygdala and dopaminergic circuitry are critical in controlling several aspects of social behavior, even social recognition memory (SRM), we aimed to study the expression analysis of dopaminergic circuitry in amygdala using real-time polymerase chain reaction. Material and Methods: Animals were divided into 2 age- and weight-matched groups: group I-control group and group II-diabetic group. Diabetes was induced by injecting 50 mg/kg streptozotocin (STZ; in 0.1 mL ice cold citrate buffer, pH 4.5) i.p. for 5 consecutive days. Behavioral tests were performed 8 weeks after diabetes was introduced. On day 60, animals were sacrificed, amygdala was dissected, and the total RNA was isolated. Expression analysis was carried out using real time PCR. Results: No significant changes were observed in social interaction and social isolation aspects of diabetic mice, but SRM was significantly dysregulated. Additionally, we found that dopaminergic neurotransmission (dopaminergic receptor expression and expression of enzymes controlling dopamine turnover) was significantly downregulated in the amygdala of STZ mice as compared to controls. Conclusion: We hypothesize that the altered SRM could be due to the dysregulated dopaminergic circuitry in amygdala, although a detailed investigation is required to establish a causal relationship.

Initial elevations in glutamate and dopamine neurotransmission decline with age, as does exploratory behavior, in LRRK2 G2019S knock-in mice.

LRRK2 mutations produce end-stage Parkinson's disease (PD) with reduced nigrostriatal dopamine, whereas, asymptomatic carriers have increased dopamine turnover and altered brain connectivity. LRRK2 pathophysiology remains unclear, but reduced dopamine and mitochondrial abnormalities occur in aged G2019S mutant knock-in (GKI) mice. Conversely, cultured GKI neurons exhibit increased synaptic transmission. We assessed behavior and synaptic glutamate and dopamine function across a range of ages. Young GKI mice exhibit more vertical exploration, elevated glutamate and dopamine transmission, and aberrant D2-receptor responses. These phenomena decline with age, but are stable in littermates. In young GKI mice, dopamine transients are slower, independent of dopamine transporter (DAT), increasing the lifetime of extracellular dopamine. Slowing of dopamine transients is observed with age in littermates, suggesting premature ageing of dopamine synapses in GKI mice. Thus, GKI mice exhibit early, but declining, synaptic and behavioral phenotypes, making them amenable to investigation of early pathophysiological, and later parkinsonian-like, alterations. This model will prove valuable in efforts to develop neuroprotection for PD.

The impact of murine LRRK2 G2019S transgene overexpression on acute responses to inflammatory challenge

The most common Parkinson’s disease (PD) mutation is the gain-of-function LRRK2 G2019S variant, which has also been linked to inflammatory disease states. Yet, little is known of the role of G2019S in PD related complex behavioral or immune/hormonal processes in response to inflammatory/toxicant challenges. Hence, we characterized the behavioral, neuroendocrine-immune and central monoaminergic responses in G2019S overexpressing mutants following systemic interferon-gamma (IFN-γ) or lipopolysaccharide (LPS) administration. Although LPS markedly (and IFN-γ modestly in some cases) increased cytokine and corticosterone levels, while inducing pronounced sickness and home-cage activity deficits, the G2019S mutation had no effect on these parameters. No differences were observed with regards to brain microglia with the acute LPS injection, regardless of genotype. Nor did the G2019S mutation influence neurotransmitter levels within the medial prefrontal cortex or paraventricular nucleus of the hypothalamus. However, the LRRK2 G2019S transgenic mice did have altered monoamine levels within the striatum and hippocampus. Indeed, G2019S mice had altered basal levels and turnover of dopamine within the striatum, along with changes in hippocampal serotonin and norepinephrine activity in response to LPS and IFN-γ. The present findings suggest the importance of murine G2019S in hippocampal and striatal neurotransmission, but that the transgene didn’t appear to be involved in functional behavioral and stress-like hormonal and cytokine changes provoked by inflammatory insults.

Sirtuin 3 rescues neurons through the stabilisation of mitochondrial biogenetics in the virally-expressing mutant α-synuclein rat model of parkinsonism

Parkinson's disease (PD) is a neurodegenerative movement disorder, which affects approximately 1–2% of the population over 60years of age. Current treatments for PD are symptomatic, and the pathology of the disease continues to progresses over time until palliative care is required. Mitochondria are key players in the pathology of PD. Genetic and post mortem studies have shown a large number of mitochondrial abnormalities in the substantia nigra pars compacta (SNc) of the parkinsonian brain. Furthermore, physiologically, mitochondria of nigral neurons are constantly under unusually high levels of metabolic stress because of the excitatory properties and architecture of these neurons. The protein deacetylase, Sirtuin 3 (SIRT3) reduces the impact subcellular stresses on mitochondria, by stabilising the electron transport chain (ETC), and reducing oxidative stress. We hypothesised that viral overexpression of myc-tagged SIRT3 (SIRT3-myc) would slow the progression of PD pathology, by enhancing the functional capacity of mitochondria. For this study, SIRT3-myc was administered both before and after viral induction of parkinsonism with the AAV-expressing mutant (A53T) α-synuclein. SIRT3-myc corrected behavioural abnormalities, as well as changes in striatal dopamine turnover. SIRT3-myc also prevented degeneration of dopaminergic neurons in the SNc. These effects were apparent, even when SIRT3-myc was transduced after the induction of parkinsonism, at a time point when cell stress and behavioural abnormalities are already observed. Furthermore, in an isolated mitochondria nigral homogenate prepared from parkinsonian SIRT3–myc infected animals, SIRT3 targeted the mitochondria, to reduce protein acetylation levels. Our results demonstrate that transduction of SIRT3 has the potential to be an effective disease-modifying strategy for patients with PD. This study also provides potential mechanisms for the protective effects of SIRT3-myc.

Effect of a change in housing conditions on body weight, behavior and brain neurotransmitters in male C57BL/6J mice

The development of modern housing regimes such as individually ventilated cage (IVC) systems has become very popular and attractive in order to reduce spreading of pathogenic organisms and to lower the risk to develop a laboratory animal allergy for staff members. Additionally, optimal housing of laboratory animals contributes to improve animal health status and ensures high and comparable experimental and animal welfare standards. However, it has not been clearly elucidated whether 1) a change to IVC systems have an impact on various physiological phenotypic parameters of mice when compared to conventional, standard cages and 2) if this is further affected by changing from social to single housing. Therefore, we investigated the influence of a change in housing conditions (standard cages with social housing changed to standard or IVC cages combined with social or single housing) on body weight, behavior and a neurochemical fingerprint of male C57BL/6J mice. Body weight progression was significantly reduced when changing mice to single or social IVC cages as well as in single standard cages when compared to social standard housing. Automated motor activity measurement in the open field showed that mice maintained in social husbandry with standard cages displayed the lowest exploratory behavior but the highest activity difference upon amphetamine treatment. Elevated plus maze test revealed that a change to IVC single and social housing as well as single standard housing produced anxiety-related behavior when compared to maintenance in social standard housing. Additionally, postmortem neurochemical analysis of the striatum using high-performance liquid chromatography coupled to electrochemical detection showed significant differences in striatal dopamine and serotonin turnover levels. In summary, our data indicate a crucial influence of a change in housing conditions on several mouse phenotype parameters. We propose that the maintenance of well-defined housing conditions is mandatory to ensure reproducible and comparable results and contributes to the application of the 3R refinement principle in animal studies by contributing to welfare and hygienical standards.

Zonisamide inhibits monoamine oxidase and enhances motor performance and social activity

Zonisamide (ZNS) is an effective drug for not only motor symptoms but also non-motor symptoms in Parkinson's disease. However, the actions of ZNS as an anti-Parkinsonian drug are not well understood. To clarify the actions of ZNS in vivo, we administered ZNS to mice and examined the effects on neurotransmitter metabolism and behaviors, focusing on motor and non-motor symptoms. Administration of ZNS decreased dopamine (DA) turnover in various brain regions, including the striatum. In behavioral tests, ZNS enhanced locomotor activity and novelty seeking in the open field test, light-dark transition test, and the social interaction test. Consistent with these results of DA metabolism in ZNS-treated mice, monoamine oxidase activity was significantly inhibited by ZNS in primary neurons and astrocytes. Collectively, these data suggest that ZNS inhibits monoamine oxidase activity and decreases DA turnover, which increases locomotor activity and novelty seeking in mice. ZNS is potentially useful to improve not only motor symptoms but also neuropsychiatric non-motor symptoms such as apathy in PD.

Prolonged Dysfunction of Astrocytes and Activation of Microglia Accelerate Degeneration of Dopaminergic Neurons in the Rat Substantia Nigra and Block Compensation of Early Motor Dysfunction Induced by 6-OHDA

Progressive degeneration of dopaminergic neurons in the substantia nigra (SN) is the underlying cause of Parkinson’s disease (PD). The disease in early stages is difficult to diagnose, because behavioral deficits are masked by compensatory processes. Astrocytic and microglial pathology precedes motor symptoms. Besides supportive functions of astrocytes in the brain, their role in PD is unrecognized. Prolonged dysfunction of astrocytes could increase the vulnerability of dopaminergic neurons and advance their degeneration during aging. The aim of our studies was to find out whether prolonged dysfunction of astrocytes in the SN is deleterious for neuronal functioning and if it influences their survival after toxic insult or changes the compensatory potential of the remaining neurons. In Wistar rat model, we induced activation, prolonged dysfunction, and death of astrocytes by chronic infusion of fluorocitrate (FC) into the SN, without causing dopaminergic neuron degeneration. Strongly enhanced dopamine turnover in the SN after 7 days of FC infusion was induced probably by microglia activated in response to astrocyte stress. The FC effect was reversible, and astrocyte pool was replenished 3 weeks after the end of infusion. Importantly, the prolonged astrocyte dysfunction and microglia activation accelerated degeneration of dopaminergic neurons induced by 6-hydroxydopamine and blocked the behavioral compensation normally observed after moderate neurodegeneration. Impaired astrocyte functioning, activation of microglia, diminishing compensatory capability of the dopaminergic system, and increasing neuronal vulnerability to external insults could be the underlying causes of PD. This animal model of prolonged astrocyte dysfunction can be useful for in vivo studies of glia–microglia–neuron interaction.

The role of system Xc− in methamphetamine-induced dopaminergic neurotoxicity in mice

The cystine/glutamate antiporter (system Xc−, Sxc) transports cystine into cell in exchange for glutamate. Since xCT is a specific subunit of Sxc, we employed xCT knockout mice and investigated whether this antiporter affected methamphetamine (MA)-induced dopaminergic neurotoxicity. MA treatment significantly increased striatal oxidative burdens in wild type mice. xCT inhibitor [i.e., S-4-carboxy-phenylglycine (CPG), sulfasalazine] or an xCT knockout significantly protected against these oxidative burdens. MA-induced increases in Iba-1 expression and Iba-1-labeled microglial immunoreactivity (Iba-1-IR) were significantly attenuated by CPG or sulfasalazine administration or xCT knockout. CPG or sulfasalazine significantly attenuated MA-induced TUNEL-positive cell populations in the striatum of Taconic ICR mice. The decrease in excitatory amino acid transporter-2 (or glutamate transporter-1) expression and increase in glutamate release were attenuated by CPG, sulfasalazine or xCT knockout. In addition, CPG, sulfasalazine or xCT knockout significantly protected against dopaminergic loss (i.e., decreases in tyrosine hydroxylase expression and immunoreactivity, and an increase in dopamine turnover rate) induced by MA. However, CPG, sulfasalazine or xCT knockout did not significantly affect the impaired glutathione system [i.e., decrease in reduced glutathione (GSH) and increase in oxidized glutathione (GSSG)] induced by MA. Our results suggest that Sxc mediates MA-induced neurotoxicity via facilitating oxidative stress, microgliosis, proapoptosis, and glutamate-related toxicity.

Short- and long-term effects of risperidone on catalepsy sensitisation and acquisition of conditioned avoidance response: Adolescent vs adult rats

The effects of antipsychotic drugs (APDs) on the adolescent brain are poorly understood despite a dramatic increase in prescription of these drugs in adolescents over the past twenty years. Neuronal systems continue to be remodeled during adolescence. Therefore, when given in adolescence, antipsychotic drugs (APDs) have the potential to affect this remodeling. In this study we investigated the effects of chronic 22-day risperidone treatment (1.3mg/kg/day) in both adolescent and adult rats. We examined short- and long-term changes in behaviour (catalepsy, locomotion and conditioned avoidance response (CAR)), and dopaminergic and serotonergic neurochemistry in the striatum and the nucleus accumbens. Here, we report that, both during chronic treatment and after a lengthy drug-free interval, risperidone induced a sensitised cataleptic response regardless of the age of exposure. Selectively in adolescents, risperidone-induced catalepsy was inversely correlated with striatal dopamine turnover immediately after chronic treatment. After a drug-free interval, a significant proportion of rats with prior adolescent risperidone treatment also failed to acquire CAR to a defined criterion. Our data provide evidence that the same chronic risperidone treatment regimen can induce contrasting short- and long-term neural outcomes in the adolescent and adult brains.

Dopamine and μ-opioid receptor dysregulation in the brains of binge-eating female rats - possible relevance in the psychopathology and treatment of binge-eating disorder.

Adult, female rats given irregular, limited access to chocolate develop binge-eating behaviour with normal bodyweight and compulsive/perseverative and impulsive behaviours similar to those in binge-eating disorder. We investigated whether (a) dysregulated central nervous system dopaminergic and opioidergic systems are part of the psychopathology of binge-eating and (b) these neurotransmitter systems may mediate the actions of drugs ameliorating binge-eating disorder psychopathology. Binge-eating produced a 39% reduction of striatal D1 receptors with 22% and 23% reductions in medial and lateral caudate putamen and a 22% increase of striatal μ-opioid receptors. There was no change in D1 receptor density in nucleus accumbens, medial prefrontal cortex or dorsolateral frontal cortex, striatal D2 receptors and dopamine reuptake transporter sites, or μ-opioid receptors in frontal cortex. There were no changes in ligand affinities. The concentrations of monoamines, metabolites and estimates of dopamine (dopamine/dihydroxyphenylacetic acid ratio) and serotonin/5-hydroxyindolacetic acid ratio turnover rates were unchanged in striatum and frontal cortex. However, turnover of dopamine and serotonin in the hypothalamus was increased ~20% and ~15%, respectively. Striatal transmission via D1 receptors is decreased in binge-eating rats while μ-opioid receptor signalling may be increased. These changes are consistent with the attenuation of binge-eating by lisdexamfetamine, which increases catecholaminergic neurotransmission, and nalmefene, a μ-opioid antagonist.

Can psychopathy be treated?

IntroductionPsychopaths are incapable of feeling empathy and guilt, being responsible for most violent crimes. To date, confinement has been the option of choice to minimize the harm they inflict. However, a deeper understanding of the neurobiology of psychopathy may lead to new insight on possible treatment approaches.AimsThis work aims to review the current knowledge in psychopathy treatment.MethodsA literature search of MEDLINE (2000-present) was conducted using the search terms “psychopathy” + “treatment” and “drug therapy”.ResultsDefects in the amygdala and the prefrontal cortex have been implicated in the pathological basis of psychopathy. The most affected areas are the ventromedial prefrontal cortex (VMPC) and the associated anterior cingulated cortex. Alterations in connectivity between the amygdala and the VMPC with other areas of the brain have been demonstrated and seem to be responsible for the non-empathetic, unemotional, and amoral features of psychopaths. Also, they present an increase in dopamine turnover and metabolism and a serotonin dysregulation.As not all individuals with the biological substrate for psychopathy become violent, it seems that plasticity in forebrain circuits may allow the development of more prosocial responses, especially in youth. Some authors emphasize the need to address other behaviours that can be responsible for violent actions, namely, impulsive aggression. Some drugs have shown efficacy in controlling impulsive aggression.ConclusionsPharmacological approaches to treating psychopathy have been disappointing. A more reasonable goal would be to focus on impulsive aggression, for which treatment effectiveness has been demonstrated. Additional research is needed if we hope to design rational therapeutic strategies for this disorder.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Effect of D-Ala2GIP, a stable GIP receptor agonist on MPTP-induced neuronal impairments in mice

The aim of the present study was to evaluate the ability of D-Ala2GIP, a gastric inhibitory polypeptide (GIP) receptor agonist, to attenuate the behavioral phenotype of Parkinson's disease caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in mice. In the behavioral studies, MPTP administration led to spontaneous locomotor activity deficits, impaired rotarod performance, akinesia, muscular rigidity and increased tremor amplitude, which was attenuated by pretreatment with D-Ala2GIP (50–100 nmol/kg, i.p.). This acute neuroprotective response by D-Ala2GIP was found to be blocked by a selective GIP receptor antagonist, (Pro3)GIP (50 nmol/kg, i.p.), indicating that the observed effects are mediated through GIP receptor mediated signaling pathway. Biochemical studies revealed that D-Ala2GIP reduced the brain malondialdehyde levels and enhanced the brain glutathione levels, thereby mitigating the MPTP-induced oxidative stress. MPTP administration resulted in reduction of the striatal concentration of dopamine and its metabolites, homovanillic acid (HVA) and 3, 4-Dihydroxyphenylacetic acid (DOPAC). Pretreatment with D-Ala2GIP attenuated the loss of striatal dopamine levels without affecting the normal dopamine catabolism. Thus, the observed effects in the MPTP-induced Parkinsonism model could be in part attributable to the antioxidant properties of D-Ala2GIP and enhanced turnover of dopamine in the nigrostriatal pathways in mouse brain. These findings together suggest that GIP receptor could be a therapeutic target in the management of symptoms of Parkinson's disease.

Selective post-training time window for memory consolidation interference of cannabidiol into the prefrontal cortex: Reduced dopaminergic modulation and immediate gene expression in limbic circuits

The prefrontal cortex (PFC), amygdala and hippocampus display a coordinated activity during acquisition of associative fear memories. Evidence indicates that PFC engagement in aversive memory formation does not progress linearly as previously thought. Instead, it seems to be recruited at specific time windows after memory acquisition, which has implications for the treatment of post-traumatic stress disorders. Cannabidiol (CBD), the major non-psychotomimetic phytocannabinoid of the Cannabis sativa plant, is known to modulate contextual fear memory acquisition in rodents. However, it is still not clear how CBD interferes with PFC-dependent processes during post-training memory consolidation. Here, we tested whether intra-PFC infusions of CBD immediately after or 5h following contextual fear conditioning was able to interfere with memory consolidation. Neurochemical and cellular correlates of the CBD treatment were evaluated by the quantification of extracellular levels of dopamine (DA), serotonin, and their metabolites in the PFC and by measuring the cellular expression of activity-dependent transcription factors in cortical and limbic regions. Our results indicate that bilateral intra-PFC CBD infusion impaired contextual fear memory consolidation when applied 5h after conditioning, but had no effect when applied immediately after it. This effect was associated with a reduction in DA turnover in the PFC following retrieval 5days after training. We also observed that post-conditioning infusion of CBD reduced c-fos and zif-268 protein expression in the hippocampus, PFC, and thalamus. Our findings support that CBD interferes with contextual fear memory consolidation by reducing PFC influence on cortico-limbic circuits.

Brain monoamine levels and behaviour of young and adult chickens genetically selected on feather pecking

Severe feather pecking (SFP) in chickens is a detrimental behaviour with possibly neurochemical deficits at its base. Recent neurological studies depicted conflicting results on the role of serotonin (5-hydroxytryptamine, 5-HT) and dopamine (DA) in the development and display of feather pecking. We studied brain monoamine levels and behaviour in domestic chickens divergently genetically selected on feather pecking behaviour, the Low Feather Pecking (LFP) and High Feather Pecking (HFP) lines, both at a young age and when adult, to elucidate the role of 5-HT and DA in feather pecking. Also pecking behaviour and the behavioural response to challenging test situations was determined. At 8 weeks of age, HFP had lower 5-HT and DA turnover in several brain areas than LFP, whereas these differences had disappeared or were even reversed at 25 weeks of age. Line differences in central monoamine activity were found both in emotion-regulating and motor-regulating areas. As expected from previous generations, HFP exceeded LFP in most types of pecking at other birds, including severe feather pecking. Furthermore, HFP responded more actively in most behavioural tests conducted, and seem more impulsive or (hyper)active in their way of coping with challenges. This paper shows different developmental trajectories of the neurochemical systems (5-HT and DA) for chickens divergently selected on feather pecking behaviour, and a remarkable reversion of differences in monoamine activity at a later stage of life. Whether this is a cause or consequence of SFP needs further investigation.

A study of the age-related effects of lactational atrazine exposure

A growing number of reports have demonstrated that the widely-used herbicide Atrazine (ATR) can cause injury to dopamine (DA) neurons, but the exact mechanism remains unclear. In this study, we examined the effects of lactational ATR exposure in Sprague-Dawley rats on dopaminergic neuron health later in life.Compared with control rats, rats exposed to ATR during a critical period of neural development showed decreased striatal DA content and increased rates of DA turnover. The expression of Monoamine oxidase (MAO), which is associated with DA degradation, was up-regulated, and the expression of Vesicular Monoamine Transporter 2 (VMAT2), which is associated with DA transport, was down-regulated. The expression of transcription factor Nuclear Receptor Related Factor 1 (Nurr1), which is associated with DA neuron development, was down-regulated. Increased age (6–12 months old) increased the statistical significance of the differences of the above indicators in the ATR-treated rats compared to the control rats (P<0.05).Taken together, our results indicate that ATR exposure during the critical neural development period causes a down-regulation of Nurr1, which in turn affects Nurr1 target genes, including MAO, VMAT2 and DAT, which are involved in DA degradation and transport. Reduced expression of these genes impairs the capacity for vesicular storage or reuptake of DA, causing decreased levels of striatal DA, which can ultimately lead to DA neuron injury. DA neuron injuries become more severe over time, which suggests that aging can synergistically promote the ATR-associated DA neuron injuries.

Inhibition of neuronal mitochondrial complex I or lysosomal glucocerebrosidase is associated with increased dopamine and serotonin turnover

Parkinson's disease (PD) is a neurodegenerative disorder caused by loss of dopaminergic and serotoninergic signalling. A number of pathogenic mechanisms have been implicated including loss of mitochondrial function at the level of complex I, and lysosomal metabolism at the level of lysosomal glucocerebrosidase (GBA1). In order to investigate further the potential involvement of complex I and GBA1 in PD, we assessed the impact of loss of respective enzyme activities upon dopamine and serotonin turnover. Using SH-SY5Y cells, complex I deficiency was modelled by using rotenone whilst GBA1 deficiency was modelled by the use of conduritol B epoxide (CBE). Dopamine, its principal metabolites, and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the extracellular medium were quantified by HPLC. Inhibition of complex I significantly increased extracellular concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-HIAA. Comparable results were observed with CBE. These results suggest increased monoamine oxidase activity and provide evidence for involvement of impaired complex I or GBA1 activity in the dopamine/serotonin deficiency seen in PD. Use of extracellular media may also permit relatively rapid assessment of dopamine/serotonin metabolism and permit screening of novel therapeutic agents.