Functional Adaptation in the Brain Habenulo-Mesencephalic Pathway During Cannabinoid Withdrawal.

The mesolimbic reward system originating from dopamine neurons in the ventral tegmental area (VTA) of the midbrain shows a profound reduction in function during cannabinoid withdrawal. This condition may underlie aversive states that lead to compulsive drug seeking and relapse. The lateral habenula (LHb) exerts negative control over the VTA via the GABA rostromedial tegmental nucleus (RMTg), representing a potential convergence point for drug-induced opponent processes.

Presynaptic nanoscale components of retrograde synaptic signaling.

While our understanding of the nanoscale architecture of anterograde synaptic transmission is rapidly expanding, the qualitative and quantitative molecular principles underlying distinct mechanisms of retrograde synaptic communication remain elusive. We show that a particular form of tonic cannabinoid signaling is essential for setting target cell-dependent synaptic variability. It does not require the activity of the two major endocannabinoid-producing enzymes.

Cognitive performance in aged rats is associated with differences in distinctive neuronal populations in the ventral tegmental area and altered synaptic plasticity in the hippocampus.

Introduction: Deterioration of cognitive functions is commonly associated with aging, although there is wide variation in the onset and manifestation. Albeit heterogeneity in age-related cognitive decline has been studied at the cellular and molecular level, there is poor evidence for electrophysiological correlates. The aim of the current study was to address the electrophysiological basis of heterogeneity of cognitive functions in cognitively Inferior and Superior old (19-20 months) rats in the ventral tegmental area (VTA) and the hippocampus, having Young (12 weeks) rats as a control.

The PPARα agonist fenofibrate reduces the cytokine imbalance in a maternal immune activation model of schizophrenia.

Maternal infections during pregnancy may increase the risk of psychiatric disorders in offspring. We recently demonstrated that activation of peroxisome proliferator-activate receptor-α (PPARα), with the clinically available agonist fenofibrate (FEN), attenuates the neurodevelopmental disturbances induced by maternal immune activation (MIA) in rat offspring. We hypothesized that fenofibrate might reduce MIA-induced cytokine imbalance using a MIA model based on the viral mimetic polyriboinosinic-polyribocytidilic acid [poly (I:C)].

The Atypical Dopamine Transporter Inhibitor CE-158 Enhances Dopamine Neurotransmission in the Prefrontal Cortex of Male Rats: A Behavioral, Electrophysiological, and Microdialysis Study.

Background: Dopamine plays a key role in several physiological functions such as motor control, learning and memory, and motivation and reward. The atypical dopamine transporter inhibitor S,S stereoisomer of 5-(((S)-((S)-(3-bromophenyl)(phenyl)methyl)sulfinyl)methyl)thiazole (CE-158) has been recently reported to promote behavioral flexibility and restore learning and memory in aged rats.

Methods: Adult male rats were i.

Combined α- and D-receptor blockade activates noradrenergic and dopaminergic neurons, but extracellular dopamine in the prefrontal cortex is determined by uptake and release from noradrenergic terminals.

Experimental and clinical evidence indicates a deficit of release and function of dopamine in schizophrenia and suggests that α-adrenoceptor antagonists rescue dopamine deficit and improve the antipsychotic efficacy of D-receptor antagonists. In anesthetized male rats, we investigated how the blockade of α- and D-receptors by atipamezole and raclopride, respectively, modified the firing of noradrenergic neurons in the locus coeruleus (LC) and dopaminergic neurons in the ventral tegmental area (VTA). In freely moving rats, we studied how atipamezole and raclopride modified extracellular noradrenaline, dopamine, and DOPAC levels in the medial prefrontal cortex (mPFC) through microdialysis.

Low-Affinity/High-Selectivity Dopamine Transport Inhibition Sufficient to Rescue Cognitive Functions in the Aging Rat.

The worldwide increase in cognitive decline, both in aging and with psychiatric disorders, warrants a search for pharmacological treatment. Although dopaminergic treatment approaches represent a major step forward, current dopamine transporter (DAT) inhibitors are not sufficiently specific as they also target other transporters and receptors, thus showing unwanted side effects. Herein, we describe an enantiomerically pure, highly specific DAT inhibitor, S-CE-123, synthetized in our laboratory.

Maternal immune activation impairs endocannabinoid signaling in the mesolimbic system of adolescent male offspring.

Prenatal infections can increase the risk of developing psychiatric disorders such as schizophrenia in the offspring, especially when combined with other postnatal insults. Here, we tested, in a rat model of prenatal immune challenge by the viral mimic polyriboinosinic-polyribocytidilic acid, whether maternal immune activation (MIA) affects the endocannabinoid system and endocannabinoid-mediated modulation of dopamine functions. Experiments were performed during adolescence to assess i) the behavioral endophenotype (locomotor activity, plus maze, prepulse inhibition of startle reflex); ii) the locomotor activity in response to Δ9-Tetrahydrocannabinol (THC) and iii) the properties of ventral tegmental area (VTA) dopamine neurons in vivo and their response to THC; iv) endocannabinoid-mediated synaptic plasticity in VTA dopamine neurons; v) the expression of cannabinoid receptors and enzymes involved in endocannabinoid synthesis and catabolism in mesolimbic structures and vi) MIA-induced neuroinflammatory scenario evaluated by measurements of levels of cytokine and neuroinflammation markers.

The Intranigral Infusion of Human-Alpha Synuclein Oligomers Induces a Cognitive Impairment in Rats Associated with Changes in Neuronal Firing and Neuroinflammation in the Anterior Cingulate Cortex.

Parkinson's disease (PD) is a complex pathology causing a plethora of non-motor symptoms besides classical motor impairments, including cognitive disturbances. Recent studies in the PD human brain have reported microgliosis in limbic and neocortical structures, suggesting a role for neuroinflammation in the development of cognitive decline. Yet, the mechanism underlying the cognitive pathology is under investigated, mainly for the lack of a valid preclinical neuropathological model reproducing the disease's motor and non-motor aspects.

A Novel and Selective Dopamine Transporter Inhibitor, -MK-26, Promotes Hippocampal Synaptic Plasticity and Restores Effort-Related Motivational Dysfunctions.

Dopamine (DA), the most abundant human brain catecholaminergic neurotransmitter, modulates key behavioral and neurological processes in young and senescent brains, including motricity, sleep, attention, emotion, learning and memory, and social and reward-seeking behaviors. The DA transporter (DAT) regulates transsynaptic DA levels, influencing all these processes. Compounds targeting DAT (e.

The potent α-adrenoceptor antagonist RS 79948 also inhibits dopamine D -receptors: Comparison with atipamezole and raclopride.

Neurochemical, electrophysiological and behavioral evidence indicate that the potent α-adrenoceptor antagonist RS 79948 is also a dopamine (DA) D receptor antagonist. Thus, results from ligand binding and adenylate cyclase activity indicate that RS 79948 binds to D receptors and antagonized D receptor-mediated inhibition of cAMP synthesis at nanomolar concentrations. Results from microdialysis indicated that RS 79948 shared with the selective α-adrenergic antagonist atipamezole the ability to increase the co-release of DA and norepinephrine (NE) from noradrenergic terminals in the medial prefrontal cortex (mPFC), except that RS 79948-induced DA release persisted after noradrenergic denervation, unlike atipamezole effect, indicating that RS 79948 releases DA from dopaminergic terminals as well.

Repurposing Peroxisome Proliferator-Activated Receptor Agonists in Neurological and Psychiatric Disorders.

Common pathophysiological mechanisms have emerged for different neurological and neuropsychiatric conditions. In particular, mechanisms of oxidative stress, immuno-inflammation, and altered metabolic pathways converge and cause neuronal and non-neuronal maladaptative phenomena, which underlie multifaceted brain disorders. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors modulating, among others, anti-inflammatory and neuroprotective genes in diverse tissues.

N-Acylethanolamine Acid Amidase Inhibition Potentiates Morphine Analgesia and Delays the Development of Tolerance.

Opioids are essential drugs for pain management, although long-term use is accompanied by tolerance, necessitating dose escalation, and dependence. Pharmacological treatments that enhance opioid analgesic effects and/or attenuate the development of tolerance (with a desirable opioid-sparing effect in treating pain) are actively sought. Among them, N-palmitoylethanolamide (PEA), an endogenous lipid neuromodulator with anti-inflammatory and neuroprotective properties, was shown to exert anti-hyperalgesic effects and to delay the emergence of morphine tolerance.

Reinstatement of synaptic plasticity in the aging brain through specific dopamine transporter inhibition.

Aging-related neurological deficits negatively impact mental health, productivity, and social interactions leading to a pronounced socioeconomic burden. Since declining brain dopamine signaling during aging is associated with the onset of neurological impairments, we produced a selective dopamine transporter (DAT) inhibitor to restore endogenous dopamine levels and improve cognitive function. We describe the synthesis and pharmacological profile of (S,S)-CE-158, a highly specific DAT inhibitor, which increases dopamine levels in brain regions associated with cognition.

Repeated exposure to JWH-018 induces adaptive changes in the mesolimbic and mesocortical dopaminergic pathways, glial cells alterations, and behavioural correlates.

Background And Purpose: Spice/K2 herbal mixtures, containing synthetic cannabinoids such as JWH-018, have been marketed as marijuana surrogates since 2004. JWH-018 has cannabinoid CB receptor-dependent reinforcing properties and acutely increases dopaminergic transmission selectively in the NAc shell. Here, we tested the hypothesis that repeated administration of JWH-018 (i) modulates behaviour, (ii) affects dopaminergic transmission and its responsiveness to motivational stimuli, and (iii) is associated with a neuroinflammatory phenotype.

Prenatal THC Does Not Affect Female Mesolimbic Dopaminergic System in Preadolescent Rats.

Cannabis use among pregnant women is increasing worldwide along with permissive sociocultural attitudes toward it. Prenatal cannabis exposure (PCE), however, is associated with adverse outcome among offspring, ranging from reduced birth weight to child psychopathology. We have previously shown that male rat offspring prenatally exposed to Δ9-tetrahydrocannabinol (THC), a rat model of PCE, exhibit extensive molecular, cellular, and synaptic changes in dopamine neurons of the ventral tegmental area (VTA), resulting in a susceptible mesolimbic dopamine system associated with a psychotic-like endophenotype.

Endocannabinoid-Like Lipid Neuromodulators in the Regulation of Dopamine Signaling: Relevance for Drug Addiction.

The family of lipid neuromodulators has been rapidly growing, as the use of different -omics techniques led to the discovery of a large number of naturally occurring acylethanolamines (NAEs) and amino acids belonging to the complex lipid signaling system termed endocannabinoidome. These molecules exert a variety of biological activities in the central nervous system, as they modulate physiological processes in neurons and glial cells and are involved in the pathophysiology of neurological and psychiatric disorders. Their effects on dopamine cells have attracted attention, as dysfunctions of dopamine systems characterize a range of psychiatric disorders, i.

Noradrenergic Source of Dopamine Assessed by Microdialysis in the Medial Prefrontal Cortex.

Previous results indicate that dopamine (DA) release in the medial prefrontal cortex (mPFC) is modified by α adrenoceptor- but not D2 DA receptor- agonists and antagonists, suggesting that DA measured by microdialysis in the mPFC originates from noradrenergic terminals. Accordingly, noradrenergic denervation was found to prevent α-receptor-mediated rise and fall of extracellular DA induced by atipamezole and clonidine, respectively, in the mPFC. The present study was aimed to determine whether DA released by dopaminergic terminals in the mPFC is not detected by microdialysis because is readily taken up by norepinephrine transporter (NET).

Mesolimbic dopamine dysregulation as a signature of information processing deficits imposed by prenatal THC exposure.

Cannabis is the illicit drug most widely used by pregnant women worldwide. Its growing acceptance and legalization have markedly increased the risks of child psychopathology, including psychotic-like experiences, which lowers the age of onset for a first psychotic episode. As the majority of patients with schizophrenia go through a premorbid condition long before this occurs, understanding neurobiological underpinnings of the prodromal stage of the disease is critical to improving illness trajectories and therapeutic outcomes.

Neurophysiological and Neurochemical Effects of the Putative Cognitive Enhancer ()-CE-123 on Mesocorticolimbic Dopamine System.

Treatments for cognitive impairments associated with neuropsychiatric disorders, such as attention deficit hyperactivity disorder or narcolepsy, aim at modulating extracellular dopamine levels in the brain. CE-123 (5-((benzhydrylsulfinyl)methyl) thiazole) is a novel modafinil analog with improved specificity and efficacy for dopamine transporter inhibition that improves cognitive and motivational processes in experimental animals. We studied the neuropharmacological and behavioral effects of the -enantiomer of CE-123 (()-CE-123) and -modafinil in cognitive- and reward-related brain areas of adult male rats.

Prenatal THC exposure produces a hyperdopaminergic phenotype rescued by pregnenolone.

The increased legal availability of cannabis has led to a common misconception that it is a safe natural remedy for, among others, pregnancy-related ailments such as morning sickness. Emerging clinical evidence, however, indicates that prenatal cannabis exposure (PCE) predisposes offspring to various neuropsychiatric disorders linked to aberrant dopaminergic function. Yet, our knowledge of how cannabis exposure affects the maturation of this neuromodulatory system remains limited.

Inhibition of N-acylethanolamine acid amidase reduces nicotine-induced dopamine activation and reward.

Tobacco smoke is the leading preventable cause of death in the world and treatments aimed to increase success rate in smoking cessation by reducing nicotine dependence are sought. Activation of peroxisome proliferator-activated receptor-alpha (PPARα) by synthetic or endogenous agonists was shown to suppress nicotine-induced activation of mesolimbic dopamine system, one of the major neurobiological substrates of nicotine dependence, and nicotine-seeking behavior in rats and monkeys. An alternative indirect way to activate PPARα is inhibition of N-acylethanolamine acid amidase (NAAA), one of the major hydrolyzing enzyme for its endogenous agonists palmitoylethanolamide (PEA) and oleoylethanolamide (OEA).

Astrocytic Mechanisms Involving Kynurenic Acid Control Δ-Tetrahydrocannabinol-Induced Increases in Glutamate Release in Brain Reward-Processing Areas.

The reinforcing effects of Δ-tetrahydrocannabinol (THC) in rats and monkeys, and the reinforcement-related dopamine-releasing effects of THC in rats, can be attenuated by increasing endogenous levels of kynurenic acid (KYNA) through systemic administration of the kynurenine 3-monooxygenase inhibitor, Ro 61-8048. KYNA is a negative allosteric modulator of α7 nicotinic acetylcholine receptors (α7nAChRs) and is synthesized and released by astroglia, which express functional α7nAChRs and cannabinoid CB1 receptors (CB1Rs). Here, we tested whether these presumed KYNA autoreceptors (α7nAChRs) and CB1Rs regulate glutamate release.

Rationale for an adjunctive therapy with fenofibrate in pharmacoresistant nocturnal frontal lobe epilepsy.

Objective: Nocturnal frontal lobe epilepsy (NFLE) is an idiopathic partial epilepsy with a family history in about 25% of cases, with autosomal dominant inheritance (autosomal dominant NFLE [ADNFLE]). Traditional antiepileptic drugs are effective in about 55% of patients, whereas the rest remains refractory. One of the key pathogenetic mechanisms is a gain of function of neuronal nicotinic acetylcholine receptors (nAChRs) containing the mutated α4 or β2 subunits.

Endocannabinoid Signaling in Motivation, Reward, and Addiction: Influences on Mesocorticolimbic Dopamine Function.

Evidence suggests that the endocannabinoid system has been conserved in the animal kingdom for 500 million years, and this system influences many critical behavioral processes including associative learning, reward signaling, goal-directed behavior, motor skill learning, and action-habit transformation. Additionally, the neurotransmitter dopamine has long been recognized to play a critical role in the processing of natural rewards, as well as of motivation that regulates approach and avoidance behavior. This motivational role of dopamine neurons is also based upon the evidence provided by several studies investigating disorders of dopamine pathways such as drug addiction and Parkinson's disease.