Early-life exposure to sex hormones promotes voluntary ethanol intake in adulthood. A vulnerability factor to drug addiction.

While there is extensive research on alcohol dependence, the factors that make an individual vulnerable to developing alcoholism haven't been explored much. In this study, we aim to investigate how neonatal exposure to sex hormones affects alcohol intake and the regulation of the mesolimbic pathway in adulthood. The study aimed to investigate the impact of neonatal exposure to a single dose of testosterone propionate (TP) or estradiol valerate (EV) on ethanol consumption in adult rats.

Collective and Coordinated Conformational Changes Determine Agonism or Antagonism at the Human Trace Amine-Associated Receptor 1.

The human trace amine-associated receptor (hTAAR1), a G protein-coupled receptor, has been postulated as a new target in the treatment of neuropsychiatric conditions. The mechanism associated with activation or inactivation by agonists or antagonists in hTAAR1 and other GPCRs has not yet been fully elucidated. In this study, we combined computational methods including homology modeling, docking, and molecular dynamic simulations to reveal novel conformational changes associated with agonist and antagonist interactions in hTAAR1.

Betel quid: New insights into an ancient addiction.

The use of areca nuts (areca) in the form of betel quids constitutes the fourth most common addiction in the world, associated with high risk for oral disease and cancer. Areca is a complex natural product, making it difficult to identify specific components associated with the addictive and carcinogenic properties. It is commonly believed that the muscarinic agonist arecoline is at the core of the addiction.

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 vivo microdialysis, optogenetics, or use of radioactivity are required to study monoamine function.

Identification of Critical Residues in the Carboxy Terminus of the Dopamine Transporter Involved in the G Protein βγ-Induced Dopamine Efflux.

The dopamine transporter (DAT) plays a crucial role in the regulation of brain dopamine (DA) homeostasis through the re-uptake of DA back into the presynaptic terminal. In addition to re-uptake, DAT is also able to release DA through a process referred to as DAT-mediated DA efflux. This is the mechanism by which potent and highly addictive psychostimulants, such as amphetamine (AMPH) and its analogues, increase extracellular DA levels in motivational and reward areas of the brain.

Angiotensin (1-7) delivered orally via probiotic, but not subcutaneously, benefits the gut-brain axis in older rats.

To (1) investigate the efficacy of multiple doses of an orally delivered probiotic bacteria Lactobacillus paracasei (LP) modified to express angiotensin (1-7) (LP-A) in altering physiologic parameters relevant to the gut-brain axis in older rats and to (2) compare this strategy with subcutaneous delivery of synthetic Ang(1-7) peptide on circulating Ang(1-7) concentrations and these gut-brain axis parameters. Male 24-month-old F344BN rats received oral gavage of LP-A, or subcutaneous injection of Ang(1-7) for 0×, 1×, 3×, or 7×/week over 4 weeks. Circulating RAS analytes, inflammatory cytokines, and tryptophan and its downstream metabolites were measured by ELISA, electrochemiluminescence, and LC-MS respectively.

Alterations of the gut microbiota with antibiotics protects dopamine neuron loss and improve motor deficits in a pharmacological rodent model of Parkinson's disease.

Parkinson's disease (PD) is a debilitating condition resulting in motor and non-motor symptoms affecting approximately 10 million people worldwide. Currently, there are no pharmacological treatments that can cure the condition or effectively halt its progression. The focus of PD research has been primarily on the neurobiological basis and consequences of dopamine (DA) neuron degeneration given that the loss of DA neurons projecting from the substantia nigra to the dorsal striatum results in the development of cardinal PD motor symptoms.

Programming of Dopaminergic Neurons by Early Exposure to Sex Hormones: Effects on Morphine-Induced Accumbens Dopamine Release, Reward, and Locomotor Behavior in Male and Female Rats.

Neonatal programming with sex hormones produces long-term functional changes in various tissues, including the brain. Previously, we demonstrated a higher content of dopamine and an increase in potassium-induced dopamine release in the nucleus accumbens of adult rats exposed to estradiol valerate. On the other hand, sex hormones also affect the opioid system increasing the expression of the μ opioid receptor and β-endorphins.

Clustered Kv2.1 decreases dopamine transporter activity and internalization.

The dopamine transporter (DAT) regulates dopamine neurotransmission via reuptake of dopamine released into the extracellular space. Interactions with partner proteins alter DAT function and thereby dynamically shape dopaminergic tone important for normal brain function. However, the extent and nature of these interactions are incompletely understood.

Functional connectivity, behavioral and dopaminergic alterations 24 hours following acute exposure to synthetic bath salt drug methylenedioxypyrovalerone.

Among cathinone drugs known as bath salts, methylenedioxypyrovalerone (MDPV) exerts its potent actions via the dopamine (DA) system, and at intoxicating doses may produce adverse behavioral effects. Previous work by our group suggests that prolonged alterations in correlated neural activity between cortical and striatal areas could underlie, at least in part, the adverse reactions to this bath salt drug. In the present study, we assessed the effect of acute MDPV administration on brain functional connectivity at 1 and 24 h in rats.

Neonatal programming with testosterone propionate reduces dopamine transporter expression in nucleus accumbens and methylphenidate-induced locomotor activity in adult female rats.

Research in programming is focused on the study of stimuli that alters sensitive periods in development, such as prenatal and neonatal stages, that can produce long-term deleterious effects. These effects can occur in various organs or tissues such as the brain, affecting brain circuits and related behaviors. Our laboratory has demonstrated that neonatal programming with sex hormones affects the mesocorticolimbic circuitry, increasing the synthesis and release of dopamine (DA) in striatum and nucleus accumbens (NAcc).

The Molecular Chaperone Hsc70 Interacts with Tyrosine Hydroxylase to Regulate Enzyme Activity and Synaptic Vesicle Localization.

We previously reported that the vesicular monoamine transporter 2 (VMAT2) is physically and functionally coupled with Hsc70 as well as with the dopamine synthesis enzymes tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase, providing a novel mechanism for dopamine homeostasis regulation. Here we expand those findings to demonstrate that Hsc70 physically and functionally interacts with TH to regulate the enzyme activity and synaptic vesicle targeting. Co-immunoprecipitation assays performed in brain tissue and heterologous cells demonstrated that Hsc70 interacts with TH and aromatic amino acid decarboxylase.

Fast-scan cyclic voltammetry demonstrates that L-DOPA produces dose-dependent, regionally selective bimodal effects on striatal dopamine kinetics in vivo.

Parkinson's disease (PD) is a debilitating condition that is caused by a relatively specific degeneration of dopaminergic (DAergic) neurons of the substantia nigra pars compacta. L-DOPA was introduced as a viable treatment option for PD over 40 years ago and still remains the most common and effective therapy for PD. Though the effects of L-DOPA to augment striatal DA production are well known, little is actually known about how L-DOPA alters the kinetics of DA neurotransmission that contribute to its beneficial and adverse effects.

Neurobiological model of stimulated dopamine neurotransmission to interpret fast-scan cyclic voltammetry data.

Fast-scan cyclic voltammetry (FSCV) is an electrochemical method that can assess real-time in vivo dopamine (DA) concentration changes to study the kinetics of DA neurotransmission. Electrical stimulation of dopaminergic (DAergic) pathways can elicit FSCV DA responses that largely reflect a balance of DA release and reuptake. Interpretation of these evoked DA responses requires a framework to discern the contribution of DA release and reuptake.

Adolescent behavior and dopamine availability are uniquely sensitive to dietary omega-3 fatty acid deficiency.

Background: Understanding the nature of environmental factors that contribute to behavioral health is critical for successful prevention strategies in individuals at risk for psychiatric disorders. These factors are typically experiential in nature, such as stress and urbanicity, but nutrition--in particular dietary deficiency of omega-3 polyunsaturated fatty acids (n-3 PUFAs)-has increasingly been implicated in the symptomatic onset of schizophrenia and mood disorders, which typically occurs during adolescence to early adulthood. Thus, adolescence might be the critical age range for the negative impact of diet as an environmental insult.

Inhibition of dopamine transporter activity by G protein βγ subunits.

Uptake through the Dopamine Transporter (DAT) is the primary mechanism of terminating dopamine signaling within the brain, thus playing an essential role in neuronal homeostasis. Deregulation of DAT function has been linked to several neurological and psychiatric disorders including ADHD, schizophrenia, Parkinson's disease, and drug addiction. Over the last 15 years, several studies have revealed a plethora of mechanisms influencing the activity and cellular distribution of DAT; suggesting that fine-tuning of dopamine homeostasis occurs via an elaborate interplay of multiple pathways.

The zebrafish homologue of the human DYT1 dystonia gene is widely expressed in CNS neurons but non-essential for early motor system development.

DYT1 dystonia is caused by mutation of the TOR1A gene, resulting in the loss of a single glutamic acid residue near the carboxyl terminal of TorsinA. The neuronal functions perturbed by TorsinA[ΔE] are a major unresolved issue in understanding the pathophysiology of dystonia, presenting a critical roadblock to developing effective treatments. We identified and characterized the zebrafish homologue of TOR1A, as a first step towards elucidating the functions of TorsinA in neurons, in vivo, using the genetically-manipulable zebrafish model.

Proteins interacting with monoamine transporters: current state and future challenges.

Plasma membrane and vesicular transporters for the biogenic amines, dopamine, norepinephrine, and serotonin, represent a group of proteins that play a crucial role in the regulation of neurotransmission. Clinically, mono amine transporters are the primary targets for the actions of many therapeutic agents used to treat mood disorders, as well as the site of action for highly addictive psychostimulants such as cocaine, amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine. Over the past decade, the use of approaches such as yeast two-hybrid and proteomics has identified a multitude of transporter interacting proteins, suggesting that the function and regulation of these transporters are more complex than previously anticipated.

Monoamine transporters: vulnerable and vital doorkeepers.

Transporters of dopamine, serotonin, and norepinephrine have been empirically used as medication targets for several mental illnesses in the last decades. These protein-targeted medications are effective only for subpopulations of patients with transporter-related brain disorders. Since the cDNA clonings in early 1990s, molecular studies of these transporters have revealed a wealth of information about the transporters' structure-activity relationship (SAR), neuropharmacology, cell biology, biochemistry, pharmacogenetics, and the diseases related to the human genes encoding these transporters among related regulators.

A biochemical and functional protein complex involving dopamine synthesis and transport into synaptic vesicles.

Synaptic transmission depends on neurotransmitter pools stored within vesicles that undergo regulated exocytosis. In the brain, the vesicular monoamine transporter-2 (VMAT(2)) is responsible for the loading of dopamine (DA) and other monoamines into synaptic vesicles. Prior to storage within vesicles, DA synthesis occurs at the synaptic terminal in a two-step enzymatic process.

The molecular chaperone Hsc70 interacts with the vesicular monoamine transporter-2.

Synaptic transmission depends on the efficient loading of transmitters into synaptic vesicles by vesicular neurotransmitter transporters. The vesicular monoamine transporter-2 (VMAT2) is essential for loading monoamines into vesicles and maintaining normal neurotransmission. In an effort to understand the regulatory mechanisms associated with VMAT2, we have embarked upon a systematic search for interacting proteins.

Physical and functional interaction between the dopamine transporter and the synaptic vesicle protein synaptogyrin-3.

Uptake through the dopamine transporter (DAT) represents the primary mechanism used to terminate dopaminergic transmission in brain. Although it is well known that dopamine (DA) taken up by the transporter is used to replenish synaptic vesicle stores for subsequent release, the molecular details of this mechanism are not completely understood. Here, we identified the synaptic vesicle protein synaptogyrin-3 as a DAT interacting protein using the split ubiquitin system.

Chronic methylphenidate treatment enhances striatal dopamine neurotransmission after experimental traumatic brain injury.

Traumatic brain injury (TBI) results in functional deficits that often are effectively treated clinically with the neurostimulant, methylphenidate (MPH). We hypothesized that daily MPH administration would reverse striatal neurotransmission deficits observed in the controlled cortical impact (CCI) model of TBI. CCI or naïve rats received daily injections of MPH (5 mg/kg) or saline for 14 days and were assessed on day 15 using fast scan cyclic voltammetry.

The orphan transporter Rxt1/NTT4 (SLC6A17) functions as a synaptic vesicle amino acid transporter selective for proline, glycine, leucine, and alanine.

Rxt1/NTT4 (SLC6A17) belongs to a gene family of "orphan transporters" whose substrates and consequently functions remain unidentified. Although Rxt1/NTT4 was previously thought to function as a sodium-dependent plasma membrane transporter, recent studies localized the protein to synaptic vesicles of glutamatergic and GABAergic neurons. Here, we provide evidence indicating that Rxt1/NTT4 functions as a vesicular transporter selective for proline, glycine, leucine, and alanine.

Glutamate and monoamine transporters: new visions of form and function.

Neurotransmitters are rapidly removed from the extracellular space primarily through the actions of plasma membrane transporters. This uptake process is not only essential in the termination of neurotransmission but also serves to replenish intracellular levels of transmitter for further release. Neurotransmitter transporters couple the inward movement of substrate to the movement of Na(+) down a concentration gradient and, in addition to their transport function, some carriers also display channel-like activities.