Nicotinamide riboside first alleviates symptoms but later downregulates dopamine metabolism in proteasome inhibition mouse model of Parkinson's disease.

Parkinson's disease (PD) is associated with a reduction in 26/20S proteasome and mitochondrial function and depletion of dopamine. Activation of mitochondrial function with the NAD precursor nicotinamide riboside (NR) is a potential therapeutic for PD. However, despite recently started clinical trials, analysis of NR in mammalian animal PD models is lacking and data in simpler PD models is limited.

Increased Physiological GDNF Levels Have No Effect on Dopamine Neuron Protection and Restoration in a Proteasome Inhibition Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disease that comprises a range of motor and nonmotor symptoms. Glial cell line-derived neurotrophic factor (GDNF) promotes the survival of dopamine neurons and , and intracranial delivery of GDNF has been tested in six clinical trials for treating PD. However, clinical trials with ectopic GDNF have yielded variable results, which could in part result from abnormal expression site and levels caused by ectopic overexpression.

Elevated endogenous GDNF induces altered dopamine signalling in mice and correlates with clinical severity in schizophrenia.

Presynaptic increase in striatal dopamine is the primary dopaminergic abnormality in schizophrenia, but the underlying mechanisms are not understood. Here, we hypothesized that increased expression of endogenous GDNF could induce dopaminergic abnormalities that resemble those seen in schizophrenia. To test the impact of GDNF elevation, without inducing adverse effects caused by ectopic overexpression, we developed a novel in vivo approach to conditionally increase endogenous GDNF expression.

The overexpression of GDNF in nucleus accumbens suppresses alcohol-seeking behavior in group-housed C57Bl/6J female mice.

Background: Craving for alcohol, in other words powerful desire to drink after withdrawal, is an important contributor to the development and maintenance of alcoholism. Here, we studied the role of GDNF (glial cell line-derived neurotrophic factor) and BDNF (brain-derived neurotrophic factor) on alcohol-seeking behavior in group-housed female mice.

Methods: We modeled alcohol-seeking behavior in C57Bl/6J female mice.

Repeated Ethanol Exposure Alters DNA Methylation Status and Dynorphin/Kappa-Opioid Receptor Expression in Nucleus Accumbens of Alcohol-Preferring AA Rats.

Growing evidence suggests that epigenetic mechanisms, such as DNA methylation and demethylation, and histone modifications, are involved in the development of alcohol and drug addiction. However, studies of alcohol use disorder (AUD) that are focused on epigenetic DNA modifications and gene expression changes remain conflicting. Our aim was to study the effect of repeated ethanol consumption on epigenetic regulatory enzymes such as DNA methyltransferase and demethylase enzymes and whether those changes affected dynorphin/kappa-opioid receptor system in the Nucleus Accumbens (NAc).

Female C57BL/6J Mice Show Alcohol-Seeking Behaviour after Withdrawal from Prolonged Alcohol Consumption in the Social Environment.

Aims: Recently we developed a model to study alcohol-seeking behaviour after withdrawal in a social context in female mice. The model raised several questions that we were eager to address to improve methodology.

Methods: In our model, female mice were group-housed in automated cages with three conditioned (CS+) corners and water in both sides of one separate non-conditioned corner.

The Effect of LPS and Ketoprofen on Cytokines, Brain Monoamines, and Social Behavior in Group-Housed Pigs.

Poor health is a risk factor for damaging behaviors, but the mechanisms behind this link are unknown. Injection of pigs with lipopolysaccharide (LPS) can be used to model aspects of poor health. Recent studies have shown that LPS-injected pigs perform more tail- and ear-directed behavior compared to saline-injected pigs and suggest that pro-inflammatory cytokines may play a role in these behaviors.

The role of opioidergic system in modulating cost/benefit decision-making in alcohol-preferring AA rats and Wistar rats.

Research has highlighted the association of a positive family history of alcoholism with a positive treatment response to opioid antagonists in those with a gambling disorder. However, the role of the opioidergic system in gambling behavior is not well understood, and preclinical studies are needed to clarify this. In this study, Alko Alcohol (AA) and Wistar rats went through operant lever pressing training where the task was to choose the more profitable of two options.

ADHD-like behaviors caused by inactivation of a transcription factor controlling the balance of inhibitory and excitatory neuron development in the mouse anterior brainstem.

The neural circuits regulating motivation and movement include midbrain dopaminergic neurons and associated inhibitory GABAergic and excitatory glutamatergic neurons in the anterior brainstem. Differentiation of specific subtypes of GABAergic and glutamatergic neurons in the mouse embryonic brainstem is controlled by a transcription factor Tal1. This study characterizes the behavioral and neurochemical changes caused by the absence of Tal1 function.

Inactivation of the GATA Cofactor ZFPM1 Results in Abnormal Development of Dorsal Raphe Serotonergic Neuron Subtypes and Increased Anxiety-Like Behavior.

Serotonergic neurons in the dorsal raphe (DR) nucleus are associated with several psychiatric disorders including depression and anxiety disorders, which often have a neurodevelopmental component. During embryonic development, GATA transcription factors GATA2 and GATA3 operate as serotonergic neuron fate selectors and regulate the differentiation of serotonergic neuron subtypes of DR. Here, we analyzed the requirement of GATA cofactor ZFPM1 in the development of serotonergic neurons using conditional mouse mutants.

Chronic 2-Fold Elevation of Endogenous GDNF Levels Is Safe and Enhances Motor and Dopaminergic Function in Aged Mice.

Glial cell line-derived neurotrophic factor (GDNF) supports function and survival of dopamine neurons that degenerate in Parkinson's disease (PD). Ectopic delivery of GDNF in clinical trials to treat PD is safe but lacks significant therapeutic effect. In pre-clinical models, ectopic GDNF is effective but causes adverse effects, including downregulation of tyrosine hydroxylase, only a transient boost in dopamine metabolism, aberrant neuronal sprouting, and hyperactivity.

MANF Ablation Causes Prolonged Activation of the UPR without Neurodegeneration in the Mouse Midbrain Dopamine System.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) localized protein that regulates ER homeostasis and unfolded protein response (UPR). The biology of endogenous MANF in the mammalian brain is unknown and therefore we studied the brain phenotype of MANF-deficient female and male mice at different ages focusing on the midbrain dopamine system and cortical neurons. We show that a lack of MANF from the brain led to the chronic activation of UPR by upregulation of the endoribonuclease activity of the inositol-requiring enzyme 1α (IRE1α) pathway.

Glial cell line-derived neurotrophic factor receptor Rearranged during transfection agonist supports dopamine neurons in Vitro and enhances dopamine release In Vivo.

Background: Motor symptoms of Parkinson's disease (PD) are caused by degeneration and progressive loss of nigrostriatal dopamine neurons. Currently, no cure for this disease is available. Existing drugs alleviate PD symptoms but fail to halt neurodegeneration.

Cerebral dopamine neurotrophic factor-deficiency leads to degeneration of enteric neurons and altered brain dopamine neuronal function in mice.

Cerebral dopamine neurotrophic factor (CDNF) is neuroprotective for nigrostriatal dopamine neurons and restores dopaminergic function in animal models of Parkinson's disease (PD). To understand the role of CDNF in mammals, we generated CDNF knockout mice (Cdnf), which are viable, fertile, and have a normal life-span. Surprisingly, an age-dependent loss of enteric neurons occurs selectively in the submucosal but not in the myenteric plexus.

The selective κ-opioid receptor antagonist JDTic attenuates the alcohol deprivation effect in rats.

The mechanisms behind relapse to ethanol intake in recovering alcoholics are still unclear. The negative reinforcing effects contributing to ethanol addiction, including relapse, are considered to be partly driven by the κ-opioidergic system. As the κ-opioidergic system interacts with the mesolimbic reward pathway, the aim of the study was to clarify the role of nucleus accumbens shell κ-opioidergic mechanisms in relapse to ethanol intake by using the alcohol deprivation effect (ADE) paradigm.

Abnormal behavior, striatal dopamine turnover and opioid peptide gene expression in histamine-deficient mice.

Hypothalamic histaminergic neurons regulate a variety of homeostatic, metabolic and cognitive functions. Recent data have suggested a modulatory role of histamine and histamine receptors in shaping striatal activity and connected the histaminergic system to neuropsychiatric disorders. We characterized exploratory behavior and striatal neurotransmission in mice lacking the histamine producing enzyme histidine decarboxylase (Hdc).

Downregulation of tyrosine hydroxylase phenotype after AAV injection above substantia nigra: Caution in experimental models of Parkinson's disease.

Adeno-associated virus (AAV) vector-mediated delivery of human α-synuclein (α-syn) gene in rat substantia nigra (SN) results in increased expression of α-syn protein in the SN and striatum which can progressively degenerate dopaminergic neurons. Therefore, this model is thought to recapitulate the neurodegeneration in Parkinson's disease. Here, using AAV to deliver α-syn above the SN in male and female rats resulted in clear expression of human α-syn in the SN and striatum.

The effect of lipopolysaccharide (LPS) on inflammatory markers in blood and brain and on behavior in individually-housed pigs.

Most of us have experienced deterioration of mood while ill. In humans, immune activation is associated with lethargy and social withdrawal, irritability and aggression; changes in social motivation could, in theory, lead to less functional interactions. This might also be the case for animals housed in close confinement.

Towards developing a model to study alcohol drinking and craving in female mice housed in automated cages.

It is about half a century ago when the so-called "Wise model" to study alcohol drinking behavior in rats was established. The model was based on voluntary intermittent access to increasing concentrations of alcohol. We aimed to establish a model of alcohol craving and used an extinction test on withdrawal days 1 and 10 to study motivation for alcohol.

The κ-opioid receptor antagonist JDTic decreases ethanol intake in alcohol-preferring AA rats.

Rationale: Studies suggest that the κ-opioidergic system becomes overactivated as ethanol use disorders develop. Nalmefene, a currently approved treatment for ethanol use disorders, may also elicit some of its main effects via the κ-opioidergic system. However, the exact role of κ-opioid receptors on regulating ethanol intake and contribution to the development of ethanol addiction remains to be elucidated.

Amphetamine primes enhanced motivation toward uncertain choices in rats with genetic alcohol preference.

Rationale: Comorbidity with gambling disorder (GD) and alcohol use disorder (AUD) is well documented.

Objective: The purpose of our study was to examine the influence of genetic alcohol drinking tendency on reward-guided decision making behavior of rats and the impact of dopamine releaser D-amphetamine on this behavior.

Methods: In this study, Alko alcohol (AA) and Wistar rats went through long periods of operant lever pressing training where the task was to choose the profitable of two options.

Combination of CDNF and Deep Brain Stimulation Decreases Neurological Deficits in Late-stage Model Parkinson's Disease.

Several neurotrophic factors (NTF) are shown to be neuroprotective and neurorestorative in pre-clinical animal models for Parkinson's disease (PD), particularly in models where striatal dopamine neuron innervation partially exists. The results of clinical trials on late-stage patients have been modest. Subthalamic deep brain stimulation (STN DBS) is a proven treatment for a selected group of advanced PD patients.

Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Elevates Stimulus-Evoked Release of Dopamine in Freely-Moving Rats.

Neurotrophic factors (NTFs) hold potential as disease-modifying therapies for neurodegenerative disorders like Parkinson's disease. Glial cell line-derived neurotrophic factor (GDNF), cerebral dopamine neurotrophic factor (CDNF), and mesencephalic astrocyte-derived neurotrophic factor (MANF) have shown neuroprotective and restorative effects on nigral dopaminergic neurons in various animal models of Parkinson's disease. To date, however, their effects on brain neurochemistry have not been compared using in vivo microdialysis.

Constitutive Ret signaling leads to long-lasting expression of amphetamine-induced place conditioning via elevation of mesolimbic dopamine.

Addictive drugs enhance dopamine release in the striatum, which can lead to compulsive drug-seeking after repeated exposure. Glial cell line-derived neurotrophic factor (GDNF) is an important regulator of midbrain dopamine neurons, and may play a mechanistic role in addiction-related behaviors. To elucidate the components of GDNF-signaling that contribute to addiction-related behaviors of place preference and its extinction, we utilized two genetically modified GDNF mouse models in an amphetamine-induced conditioned place preference (CPP) paradigm and evaluated how the behavioral findings correlate with dopamine signaling in the dorsal and ventral striatum.

Dopaminergic modulation of reward-guided decision making in alcohol-preferring AA rats.

R**esults from animal gambling models have highlighted the importance of dopaminergic neurotransmission in modulating decision making when large sucrose rewards are combined with uncertainty. The majority of these models use food restriction as a tool to motivate animals to accomplish operant behavioral tasks, in which sucrose is used as a reward. As enhanced motivation to obtain sucrose due to hunger may impact its reward-seeking effect, we wanted to examine the decision-making behavior of rats in a situation where rats were fed ad libitum.