Monoamine Function Research Articles

PARAPHILIA AND MAJOR DEPRESSIVE DISORDERS: PREVALENCE AND PATHOGENESIS

Introduction - Paraphilia disorders are defined as an abnormal intense sexual deviant followed by behaviors to fulfill fierce sexual erotic activities. Major depressive disorder (MDD) is a mood disorder marked by the appearance of a depressed mood, decreased interest, poor cognitive function, and vegetative symptoms including sleep or eating disorders. There is a study about the prevalence of paraphilia in the US, 15,9%. Meanwhile, there is about 6,1% of the prevalence of depressive disorders in Indonesia. According to DSM-5, Paraphilias, and paraphilia-related disorders, depressive disorders are the most frequent comorbid axis I diagnoses with a lifetime prevalence of life by 56%. Based on these case numbers, this study aims to discuss the correlation between these two events. Methods - Researchers used several journals and textbooks discussing the prevalence and pathogenesis of paraphilia and major depressive disorders; and the correlation between these two disorders. Results - Paraphilias are rarely diagnosed in clinical settings because many cases of paraphilia are related to illegal and criminal acts (such as sexual harassment), and reporting methods are unreliable, meanwhile depression is ubiquitous in both high and low-income countries. This shows that any government needs to be aware of the effects of depressive disorders. Those who have not sought treatment are still high, amounting to 87 to 91% of depressive disorders that have not sought treatment. Discuss - There is a significant correlation between paraphilia and major depressive disorder, MDD is one of the paraphilia-related disorders comorbid axis I diagnosis with a lifespan prevalence of 56%. From the pathogenesis, monoamine neurotransmitters dopamine, norepinephrine, and serotonin serve a modulatory role in human sexual motivation, appetitive, and consummatory behavior. Conclusion - In pathogenesis, there's a degradation in function, amount, and production of neurotransmitter monoamine, dopamine, norepinephrine, and serotonin that cause the person with paraphilia usually show symptoms such as mood changes, decreased interest, depression, decreased cognitive function, and the appearance of vegetative-related symptoms such as impaired appetite or sleep activity. Keywords: paraphilias, depression, pathogenesis.

Individual differences in the boldness of female zebrafish are associated with alterations in serotonin function.

One of the most prevalent axes of behavioral variation in both humans and animals is risk taking, where individuals that are more willing to take risk are characterized as bold while those that are more reserved are regarded as shy. Brain monoamines (i.e. serotonin, dopamine and noradrenaline) have been found to play a role in a variety of behaviors related to risk taking. Using zebrafish, we investigated whether there was a relationship between monoamine function and boldness behavior during exploration of a novel tank. We found a correlation between serotonin metabolism (5-HIAA:5-HT ratio) and boldness during the initial exposure to the tank in female animals. The DOPAC:DA ratio correlated with boldness behavior on the third day in male fish. There was no relationship between boldness and noradrenaline. To probe differences in serotonergic function in bold and shy fish, we administered a selective serotonin reuptake inhibitor, escitalopram, and assessed exploratory behavior. We found that escitalopram had opposing effects on thigmotaxis in bold and shy female animals: the drug caused bold fish to spend more time near the center of the tank and shy fish spent more time near the periphery. Taken together, our findings indicate that variation in serotonergic function has sex-specific contributions to individual differences in risk-taking behavior.

Neuroendocrine functions of monoamines in invertebrates: Focus on bivalve molluscs

Monoamines (MA) such as serotonin, catecholamines (dopamine, norepinephrine, epinephrine), and trace amines (octopamine, tyramine), are neurotransmitters and neuroendocrine modulators in vertebrates, that contribute to adaptation to the environment. Although MA are conserved in evolution, information is still fragmentary in invertebrates, given the diversity of phyla and species. However, MA are crucial in homeostatic processes in these organisms, where the absence of canonical endocrine glands in many groups implies that the modulation of physiological functions is essentially neuroendocrine.In this review, we summarize available information on MA systems in invertebrates, with focus on bivalve molluscs, that are widespread in different aquatic environments, where they are subjected to a variety of environmental stimuli. Available data are reviewed on the presence of the different MA in bivalve tissues, their metabolism, target cells, signaling pathways, and the physiological functions modulated in larval and adult stages. Research gaps and perspectives are highlighted, in order to enrich the framework of knowledge on MA neuroendocrine functions, and on their role in adaptation to ongoing and future environmental changes.

Brain Monoamine Dysfunction in Response to Predator Scent Stress Accompanies Stress-Susceptibility in Female Rats.

Post-traumatic stress disorder (PTSD) is prevalent in women; however, preclinical research on PTSD has predominantly been conducted in male animals. Using a predator scent stress (PSS) rodent model of PTSD, we sought to determine if stress-susceptible female rats show altered monoamine concentrations in brain regions associated with PTSD: the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and dorsal (dHIPP) and ventral (vHIPP) hippocampus. Female Sprague-Dawley rats were exposed to a single, 10-min PSS exposure and tested for persistent anhedonia, fear, and anxiety-like behavior over four weeks. Rats were phenotyped as stress-Susceptible based on sucrose consumption in the sucrose preference task and time spent in the open arms of the elevated plus maze. Brain tissue was collected, and norepinephrine, dopamine, serotonin, and their metabolites were quantified using high-performance liquid chromatography. Stress-susceptibility in female rats was associated with increased dopamine and serotonin turnover in the mPFC. Susceptibility was also associated with elevated dopamine turnover in the NAc and increased norepinephrine in the vHIPP. Our findings suggest that stress-susceptibility after a single stress exposure is associated with long-term effects on monoamine function in female rats. These data suggest interventions that decrease monoamine turnover, such as MAOIs, may be effective in the treatment of PTSD in women.

Positron emission tomography studies in adult patients with attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, motor hyperactivity, impulsivity, and psychosocial as well as cognitive dysfunction. Although characteristic clinical manifestations have been described, no definitive biomarkers to diagnose ADHD have been established. In this review article, we summarize positron emission tomography (PET) studies conducted in adult patients with ADHD. We found that, although, disturbances of dopamine, serotonin, and norepinephrine functions have been implicated in ADHD, no characteristic findings have been identified from PET studies in patients with ADHD. Several previous PET studies on the central dopaminergic transmission-related ligands in patients with ADHD have shown altered binding of dopamine markers in the basal ganglia. However, no consistent results were observed in the binding characteristics for dopamine transporters and receptors. Findings from PET studies with ligands related to serotonin and norepinephrine pathways showed either unclear clinical significance or low replicability. Therefore, whether alterations of monoamine function may be involved in the pathophysiological mechanism remains to be clarified. The limitations of previous PET studies include their small sample sizes, focus on several kinds of existing ligands, and a questionable validity of the diagnosis (lack of biological diagnostic criteria). To determine the characteristic findings for diagnosing ADHD, further research is needed, and particularly, studies that evaluate new active ligands with specific binding to monoamine pathways should be undertaken.

Comprehensive Preclinical Assessment of Sensory, Functional, Motivational-Affective, and Neurochemical Outcomes in Neuropathic Pain: The Case of the Sigma-1 Receptor.

Chronic pain remains a major health problem and is currently facing slow drug innovation. New drug treatments should address not only the sensory-discriminative but also functional and motivational-affective components of chronic pain. In a mouse model of neuropathic pain induced by partial sciatic nerve ligation (PSNL), we analyzed sensory and functional-like outcomes by hindpaw mechanical stimulation and automated gait analysis (CatWalk). We characterized over time a reward-seeking task based on diminished motivation for natural reinforcers (anhedonic-like behavior). To differentiate the appetitive ("wanting") and consummatory ("liking") aspects of motivational behavior, we quantified the latency and number of approaches to eat white chocolate, as well as the eating duration and amount consumed. We explored a putative chronic pain-induced dysregulation of monoamine function by measuring monoamine levels in the nucleus accumbens (NAc), a well-known brain reward area. Finally, we investigated the role of sigma-1 receptor (σ1R) modulation, a nonopioid target, in these multiple dimensions by genetic deletion and pharmacological dose-response studies. After 6 weeks, PSNL increased the approach latency and reduced the consumption of white chocolate in 20-25% of the mice, while around 50-60% had one or the other parameter affected independently. After 10 weeks, sham-operated mice also displayed anhedonic-like behavior. PSNL was associated with reduced extracellular baseline dopamine and increased norepinephrine in the NAc and with a suppression of increased dopamine and serotonin efflux in response to the rewarding stimulus. Genetic and pharmacological blockade of σ1R relieved these multiple alterations in nerve-injured mice. We comprehensively describe sensory, functional, and depression-like impairment of key components of motivated behavior associated with nerve injury. We provide a neurochemical substrate for the depressed mesocorticolimbic reward processing in chronic pain, with a potentially increased translational value. Our results also highlight σ1R for the therapeutic intervention of neuropathic pain.

A Plate-Based Assay for the Measurement of Endogenous Monoamine Release in Acute Brain Slices.

Monoamine neurotransmitters are associated with numerous neurologic and psychiatric ailments. Animal models of such conditions have shown alterations in monoamine neurotransmitter release and uptake dynamics. Technically complex methods such as electrophysiology, Fast Scan Cyclic Voltammetry (FSCV), imaging, in vivomicrodialysis, optogenetics, or use of radioactivity are required to study monoamine function. The method presented here is an optimized two-step approach for detecting monoamine release in acute brain slices using a 48-well plate containing tissue holders for examining monoamine release, and high-performance liquid chromatography coupled with electrochemical detection (HPLC-ECD) for monoamine release measurement. Briefly, rat brain sections containing regions of interest, including prefrontal cortex, hippocampus, and dorsal striatum were obtained using a tissue slicer or vibratome. These regions of interest were dissected from the whole brain and incubated in an oxygenated physiological buffer. Viability was examined throughout the experimental time course, by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The acutely dissected brain regions were incubated in varying drug conditions that are known to induce monoamine release through the transporter (amphetamine) or through the activation of exocytotic vesicular release (KCl). After incubation, the released products in the supernatant were collected and analyzed through an HPLC-ECD system. Here, basal monoamine release is detected by HPLC from acute brain slices. This data supports previous in vivo and in vitro results showing that AMPH and KCl induce monoamine release. This method is particularly useful for studying mechanisms associated with monoamine transporter-dependent release and provides an opportunity to screen compounds affecting monoamine release in a rapid and low-cost manner.

MicroPET/CT assessment of neurochemical effects in the brain after long-term methylphenidate treatment in nonhuman primates

Methylphenidate (MPH) is a psychostimulant approved by the FDA to treatment Attention-Deficit Hyperactivity Disorder (ADHD). MPH is believed to exert its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. We used a quantitative non-invasive PET imaging technique to study the effects of long-term methylphenidate use on the central nervous system (CNS). We conducted microPET/CT scans on young adult male rhesus monkeys to monitor changes in the dopaminergic system. We used [18F] AV-133, a ligand for the vesicular monoamine transporter 2 (VMAT2), and [18F]FESP a ligand for the D2 and 5HT2 receptors. In this study we evaluated the effects if chronic MPH treatment in the nonhuman primates (NHP). Two-year-old, male rhesus monkeys were orally administered MPH diluted in the electrolyte replenisher, Prang, twice a day, five days per week (M-F) over an 8-year period. The dose of MPH was gradually escalated from 0.15 mg/kg initially to 2.5 mg/kg/dose for the low dose group, and 1.5 mg/kg to 12.5 mg/kg/dose for the high dose group (Rodriguez et al., 2010). Scans were performed on Mondays, about 60 h after their last treatment, to avoid the acute effects of MPH. Tracers were injected intravenously ten minutes before microPET/CT scanning. Sessions lasted about 120 min. The Logan reference tissue model was used to determine the Binding Potential (BP) of each tracer in the striatum with the cerebellar cortex time activity curve as an input function. Both MP treatment groups had a lower [18F] AV-133 BP, although this failed to reach statistical significance. MPH treatment did not have a significant effect on The BP of [18F] FESP in the striatum. Long-term administration of MPH did not significant change any of the marker of monoamine function used here. These data suggest that, despite lingering concerns, long-term use of methylphenidate does not negatively impact monoamine function. This study also demonstrates that microPET imaging can distinguish differences in binding potentials of a variety of radiotracers in the CNS of NHPs. This approach may provide minimally-invasive biomarkers of neurochemical processes associated with chronic exposure to CNS medications. (Supported by NCTR).

Genetic or Toxicant-Induced Disruption of Vesicular Monoamine Storage and Global Metabolic Profiling in Caenorhabditis elegans.

The proper storage and release of monoamines contributes to a wide range of neuronal activity. Here, we examine the effects of altered vesicular monoamine transport in the nematode Caenorhabditis elegans. The gene cat-1 is responsible for the encoding of the vesicular monoamine transporter (VMAT) in C. elegans and is analogous to the mammalian vesicular monoamine transporter 2 (VMAT2). Our laboratory has previously shown that reduced VMAT2 activity confers vulnerability on catecholamine neurons in mice. The purpose of this article was to determine whether this function is conserved and to determine the impact of reduced VMAT activity in C. elegans. Here we show that deletion of cat-1/VMAT increases sensitivity to the neurotoxicant 1-methyl-4-phenylpyridinium (MPP+) as measured by enhanced degeneration of dopamine neurons. Reduced cat-1/VMAT also induces changes in dopamine-mediated behaviors. High-resolution mass spectrometry-based metabolomics in the whole organism reveals changes in amino acid metabolism, including tyrosine metabolism in the cat-1/VMAT mutants. Treatment with MPP+ disrupted tryptophan metabolism. Both conditions altered glycerophospholipid metabolism, suggesting a convergent pathway of neuronal dysfunction. Our results demonstrate the evolutionarily conserved nature of monoamine function in C. elegans and further suggest that high-resolution mass spectrometry-based metabolomics can be used in this model to study environmental and genetic contributors to complex human disease.

Combined approaches for evaluation of xenoestrogen neural toxicity and thyroid dysfunction: Screening of oxido-nitrosative markers, DNA fragmentation, and biogenic amine degradation.

Anthropogenic chemicals such as parabens and triclosan are used in personal care products. Duetotheir ability to decrease or prevent bacterial contamination and act as preservatives, these chemicals are used in cosmetic manufacturing processes to increase the shelf life of products. In this study, we assessed the side effects of environmental estrogens (such as the xenoestrogen butylparaben and the antimicrobial agent and preservative triclosan) on thyroid function, brain monoamine levels, and DNA aberration. Forty-two male albino rats were divided into seven groups with six members each: the first group served as control; the second and the third groups were treated with butylparaben 10 and 50 mg/kg body weight, respectively; the fourth and fifth groups were treated with triclosan 10 and 50 mg/kg body weight, respectively; and the sixth and seventh groups were treated with butylparaben plus triclosan 10 and 50 mg/kg body weight, respectively. After 60 days, blood samples were collected and brain specimens were divided into striatum, midbrain, cortex, and thalamus. Thyroid function and levels of monoamines and monoamine metabolites were determined for each brain area. Comet assay was used for brain tissue analysis. The results showed that butylparaben and triclosan and their combinations induced hypothyroidism and disrupted monoamine levels, leading to a decrease in catecholamine and serotonin levels, and accelerated production of 5-hydroxyindoleacetic acid. The obtained data indicate that anthropogenic chemicals such as butylparaben and triclosan have harmful effects on thyroid and brain function and accelerate cell destruction and mutation, as evidenced by single-stranded DNA breaks in the comet assay.

Vesicular monoamine transporter 2 mediates fear behavior in mice.

A subset of people exposed to a traumatic event develops post-traumatic stress disorder (PTSD), which is associated with dysregulated fear behavior. Genetic variation in SLC18A2, the gene that encodes vesicular monoamine transporter 2 (VMAT2), has been reported to affect risk for the development of PTSD in humans. Here, we use transgenic mice that express either 5% (VMAT2-LO mice) or 200% (VMAT2-HI mice) of wild-type levels of VMAT2 protein. We report that VMAT2-LO mice have reduced VMAT2 protein in the hippocampus and amygdala, impaired monoaminergic vesicular storage capacity in both the striatum and frontal cortex, decreased monoamine metabolite abundance and a greatly reduced capacity to release dopamine upon stimulation. Furthermore, VMAT2-LO mice showed exaggerated cued and contextual fear expression, altered fear habituation, inability to discriminate threat from safety cues, altered startle response compared with wild-type mice and an anxiogenic-like phenotype, but displayed no deficits in social function. By contrast, VMAT2-HI mice exhibited increased VMAT2 protein throughout the brain, higher vesicular storage capacity and greater dopamine release upon stimulation compared with wild-type controls. Behaviorally, VMAT2-HI mice were similar to wild-type mice in most assays, with some evidence of a reduced anxiety-like responses. Together, these data show that presynaptic monoamine function mediates PTSD-like outcomes in our mouse model, and suggest a causal link between reduced VMAT2 expression and fear behavior, consistent with the correlational relationship between VMAT2 genotype and PTSD risk in humans. Targeting this system is a potential strategy for the development of pharmacotherapies for disorders like PTSD.

Reduced home cage and social activity in Pou3f2⊿ mice

Pou3f2/Brn2 is a transcription factor that helps to determine the cellular identity of neocortical or hypothalamic neurons. Mammalian Pou3f2 contains three homopolymeric amino acids that are not present in amphibian Pou3f2. These amino acids contribute to monoamine function, which may play specific roles in mammalian development and behavior. Previous work has indicated that Pou3f2⊿ mice, which lack the homopolymeric amino acids, exhibited declined maternal activity and impaired object and spatial recognition. The current study, analyzed weight gain, brain development, home cage activity, social interaction, and response to novel objects in Pou3f2⊿ mice to determine which aspects of behavior were affected by monoamine dysregulation. Compared to their wild type counterparts, Pou3f2⊿ mice showed decreased social interaction and reduced home cage activity during their active phase. However, they showed normal weight gain, brain development, and responses to novelty. These results indicate that monoamine dysregulation in Pou3f2⊿ mice may specifically affect basal activity and social development, without altering non-social motivation.

Vapor Cannabis Exposure Promotes Genetic Plasticity in the Rat Hypothalamus

It is well established that cannabis use promotes appetite. However, how cannabis interacts with the brain’s appetite center, the hypothalamus, to stimulate feeding behavior is unknown. A growing body of evidence indicates that the hypothalamic transcriptome programs energy balance. Here, we tested the hypothesis that cannabis targets alternative polyadenylation (APA) sites within hypothalamic transcripts to regulate transcriptomic function. To do this, we used a novel cannabis vapor exposure model to characterize feeding in adult male Long Evans rats and aligned this behavioral response with APA events using a Whole Transcriptome Termini Sequencing (WTTS-Seq) approach as well as functional RNA abundance measurements with real-time quantitative polymerase chain reactions. We found that vapor cannabis exposure promoted food intake in free-feeding and behaviorally sated rats, validating the appetite stimulating properties of cannabis. Our WTTS-Seq analysis mapped 59 unique cannabis-induced hypothalamic APAs that occurred primarily within exons on transcripts that regulate synaptic function, excitatory synaptic transmission, and dopamine signaling. Importantly, APA insertions regulated RNA abundance of Slc6a3, the dopamine transporter, suggesting a novel genetic link for cannabis regulation of brain monoamine function. Collectively, these novel data indicate that a single cannabis exposure rapidly targets a key RNA processing mechanism linked to brain transcriptome function.

Putative Trace-AmineAssociated Receptor 5 (TAAR5) Agonist α-NETA Increases Electrocorticogram Gamma-Rhythm in Freely Moving Rats.

Cortical gamma rhythm is involved in transmission of information (communication) between brain areas that are believed to be involved in the pathogenesis of cognitive dysfunctions. Trace amines represent a group of endogenous biogenic amines that are known to be involved in modulation of function of classical monoamines, such as dopamine. To evaluate potential modulatory influence of a specific receptor for trace amines Trace Amine-Associated Receptor 5 (TAAR5) on the dopamine system, we used HPLC measurements of dopamine and its metabolites in the mouse striatum following administration of the putative TAAR5 agonist α-NETA. Administration of α-NETA caused significant modulation of dopaminergic system as evidenced by an altered dopamine turnover rate in the striatum. Then, to evaluate potential modulatory influence of TAAR5 on the rat brain gamma rhythm, we investigated the changes of electrocorticogram (ECoG) spectral power in the gamma-frequency range (40-50Hz) following administration of the putative TAAR5 agonist α-NETA. In addition, we analyzed the changes of spatial synchronization of gamma oscillations of rat ECoG by multichannel recording. Significant complex changes were observed in the ECoG spectrum, including an increase in the spectral power in the ranges of delta (1Hz), theta (7Hz), and gamma rhythms (40-50Hz) after the introduction of α-NETA. Furthermore, a decrease in the spatial synchronization of gamma oscillations of 40-50Hz and its increase for theta oscillations of 7Hz were detected after the introduction of α-NETA. In conclusion, putative TAAR5 agonist α-NETA can modulate striatal dopamine transmission and cause significant alterations of gamma rhythm of brain activity in a manner consistent with schizophrenia-related deficits described in humans and experimental animals. These observations suggest a role of TAAR5 in the modulation of cognitive functions affected in brain pathologies.

Absence of gut microbiota during early life affects anxiolytic Behaviors and monoamine neurotransmitters system in the hippocampal of mice

The gut microbiome is composed of an enormous number of microorganisms, generally regarded as commensal bacteria. Resident gut bacteria are an important contributor to health and significant evidence suggests that the presence of healthy and diverse gut microbiota is important for normal cognitive and emotional processing. Here we measured the expression of monoamine neurotransmitter-related genes in the hippocampus of germ-free (GF) mice and specific-pathogen-free (SPF) mice to explore the effect of gut microbiota on hippocampal monoamine functioning. In total, 19 differential expressed genes (Htr7, Htr1f, Htr3b, Drd3, Ddc, Maob, Tdo2, Fos, Creb1, Akt1, Gsk3a, Pik3ca, Pla2g5, Cyp2d22, Grk6, Ephb1, Slc18a1, Nr4a1, Gdnf) that could discriminate between the two groups were identified. Interestingly, GF mice displayed anxiolytic-like behavior compared to SPF mice, which were not reversed by colonization with gut microbiota from SPF mice. Besides, colonization of adolescent GF mice by gut microbiota was not sufficient to reverse the altered gene expression associated with their GF status. Taking these findings together, the absence of commensal microbiota during early life markedly affects hippocampal monoamine gene-regulation, which was associated with anxiolytic behaviors and monoamine neurological signs.

Differential change in cortical and hippocampal monoamines, and behavioral patterns in streptozotocin-induced type 1 diabetic rats.

Objective(s):Diabetes mellitus (DM) is a widespread metabolic disorder worldwide. Clinical physicians have found diabetic patients have mild to middle cognitive dysfunction and an alteration of brain monoaminergic function. This study explored the change in various patterns of behavioral models and brain monoamine function under streptozotocin (STZ)-induced type 1 diabetes.Materials and Methods:We established a type 1 DM model via intravenous injection with STZ (65 mg/kg) in rats. Three weeks after the STZ injection, various behavioral measurements including the inhibitory avoidance test, active avoidance test and Morris water maze were conducted. Finally, all rats were dissected and the concentrations of monoamines and their metabolites in cortex and hippocampus were measured by high performance liquid chromatography with electrochemical detection.Results:We found that STZ induced type 1 diabetes (hyperglycemia and lack of insulin) in rats. STZ-induced diabetic rats had cognitive impairment in acquisition sessions and long-term retention of the active avoidance test. STZ-induced diabetic rats also had cognitive impairment in spatial learning, reference and working memory of the Morris water maze. STZ significantly reduced concentrations of norepinephrine (NE) in the cortex and dopamine (DA) in the hippocampus, but increased concentrations of DA and serotonin (5-HT) in the cortex 35 days after injection. The concentration of 5-HT in the hippocampus was also significantly increased.Conclusion:The data suggested that this cognitive impairment after a short-term period of STZ injection might be related to cortical NE dysfunction, differential alteration of cortical and hippocampal DA function, and brain 5-HT hyperfunction.

P.2.023 - Impairment of learning and memory in mice overexpressing α- and γ-synuclein in dopaminergic neurons- implication in Parkinson’s disease

Introduction Idiopathic Parkinson’s disease (PD) is characterized by progressive brain pathology affecting several neurotransmitter systems, leading to a diverse profile of autonomic, motor, cognitive and psychiatric dysfunctions. Multiple convergent lines of evidence implicate the aggregation and accumulation of α-synuclein in the PD pathogenesis [1]. Moreover, post-translational changes of γ-synuclein increase the α-synuclein aggregation [2]. α- and γ-synuclein are members of the synuclein family of small cytoplasmic neuron-specific proteins, and have been suggested to modulate the function of monoamine transporters (DAT, SERT, NET) [3]. Previously, we reported that α-synuclein knockdown mice showed increased extracellular dopamine and serotonin levels –compared to control mice– in caudate-putamen (CPu) and medial prefrontal cortex (mPFC) after DAT or SERT blockade with nomifensine or citalopram, respectively (Alarcon-Aris et al., in review). Aims Given the role of monoamine neurotransmission in cognitive processes, in the present study we assessed the effects of over-expressing α- and γ-synuclein in mouse dopaminergic neurons on spatial and working memory. Methods We generated a mouse model overexpressing human wild-type α-synucleinor endogenous γ-synuclein in dopaminergic neurons from the substantia nigra compacta (SNc) and ventral tegmental area (VTA) using adeno-associated virus type-5 (AAV5-human-α-synuclein) or type-10 (AAV10-mouse-γ-synuclein) unilaterally injected in SNc/VTA. Behavioral tests were performed in mice at 4, 8 and 16 weeks post-infection using cognitive (novel object recognition, Morris water maze, passive avoidance tests) and motor paradigms (cylinder test, rotarod). Extracellular striatal dopamine levels were measured by in vivo microdialysis after implanting concentric dialysis probes, and analyzed by high precision liquid chromatography with electrochemical detection (+0.75 V). In situ hybridization was performed on fixed mice tissues, with 33P-dATP labeled probes in order to detect α- and γ-synuclein transcripts through autoradiography. Results AAV5-α-synuclein mice showed increased human α-synuclein mRNA levels in the ipsilateral SNc over time reaching a 278% of sham mice at 8 weeks post-infection. Similarly, AAV10-γ-synuclein mice reached to a maximal of 250% of sham mice. Overexpression of α- or γ-synuclein led to lower extracellular dopamine levels in CPu and mPFC compared to sham mice after local veratridine (sodium chanel activator agent, 50 µM) or nomifensine (DAT inhibitor, 1-10-50 µM) administration at 4 weeks post-infection. Moreover, overexpression of α- or γ-synuclein led to the impairment of working memory in mice as revealed by passive avoidance test (retention memory 35.5% and 45.9% shorter in AAV5-α-synuclein andAAV10-γ-synuclein mice, respectively) and novel object recognition test (reduction of 10% in time spent exploring novel object in both infected models) at 4-8 weeks post-infection. Likewise, these mice showed deficits in the spatial learning using the Morris water maze (F(1,28)=5.711, P=0.02 in AAV5-α-synuclein; F(1,28)=11.43, P=0.0021 in AAV10-γ-synuclein). These non-motor symptoms appeared earlier than motor deficits assessed by the cylinder test and rotarod. Conclusions Overall, these findings indicate that 1) α- and γ-synuclein are directly involved in the regulation of cognitive functions, likely through changes in monoamine functions, and 2) overexpression of α- or γ-synuclein in dopaminergic neurons mimics the temporal progression of clinical symptoms in PD, with early cognitive deficits appearing before motor symptoms.

Opinion on monoaminergic contributions to traits and temperament.

This article critically reviews evidence relating temperamental traits and personality factors to the monoamine neurotransmitters, especially dopamine and serotonin. The genetic evidence is not yet considered to be conclusive and it is argued that basic neuroscience research on the neural basis of behaviour in experimental animals should be taken more into account. While questionnaire and lexical methodology including the 'Five Factor' theory has been informative (mostly for the traits relevant to social functioning, i.e. personality), biologically oriented approaches should be employed with more objective, theoretically grounded measures of cognition and behaviour, combined with neuroimaging and psychopharmacology, where appropriate. This strategy will enable specific functions of monoamines and other neuromodulators such as acetylcholine and neuropeptides (such as orexin) to be defined with respect to their roles in modulating activity in specific neural networks-leading to a more realistic definition of their interactive roles in complex, biologically based traits (i.e. temperament).This article is part of the theme issue 'Diverse perspectives on diversity: multi-disciplinary approaches to taxonomies of individual differences'.

Baseline-dependent effects of amphetamine on attention are associated with striatal dopamine metabolism

Psychostimulants, such as amphetamine, are widely used to treat attentional deficits. In humans, response to dopaminergic medications is complex with improvement often dependent on baseline performance. Our goal was to determine if attention in rats could be improved by low dose amphetamine in a baseline-dependent manner by examining the relationship between task performance, drug response and monoamine levels in corticostriatal tissue. Firstly, rats performed a signal detection task with varying signal durations before administration of saline, 0.1 or 0.25 mg/kg amphetamine. Following 0.1 mg/kg amphetamine, accuracy in poor performing individuals increased to that of high performing rats. Furthermore, baseline accuracy correlated with the magnitude of improvement after amphetamine. Secondly, neurochemical analysis of monoamine content and gene expression levels in the prefrontal cortex (PFC) and dorsal striatum (CPU) was conducted. CPU homovanillic acid and 5-hydroxyindoleacetic acid levels were increased in poor performers with a significant correlation between the expression of the dopamine transporter gene and baseline accuracy. No changes were found in the PFC. These results indicated poor performance was associated with greater response to amphetamine and altered DA and 5-HT neurotransmitter systems in CPU. These results suggest striatal monoamine function may be fundamental to explaining individual differences in psychostimulant response.

Hormonal Contraception and Risk for Depression

Changes in estrogen and progesterone can affect monoamine and GABA-ergic function and have been shown to increase depression in both experimental and