Metabolic sensing in AgRP neurons integrates homeostatic state with dopamine signalling in the striatum

Agouti-related peptide (AgRP) neurons increase motivation for food, however whether metabolic sensing of homeostatic state in AgRP neurons potentiates motivation by interacting with dopamine reward systems is unexplored. As a model of impaired metabolic-sensing, we used the AgRP-specific deletion of carnitine acetyltransferase (Crat) in mice. We hypothesized that metabolic sensing in AgRP neurons is required to increase motivation for food reward by modulating accumbal or striatal dopamine release. Studies confirmed that Crat deletion in AgRP neurons (KO) impaired ex vivo glucose-sensing, as well as in vivo responses to peripheral glucose injection or repeated palatable food presentation and consumption. Impaired metabolic-sensing in AgPP neurons reduced acute dopamine release (seconds) to palatable food consumption and during operant responding, as assessed by GRAB-DA photometry in the nucleus accumbens, but not the dorsal striatum. Impaired metabolic-sensing in AgRP neurons suppressed radiolabelled 18F-fDOPA accumulation after ~30 minutes in the dorsal striatum but not the nucleus accumbens. Impaired metabolic sensing in AgRP neurons suppressed motivated operant responding for sucrose rewards during fasting. Thus, metabolic-sensing in AgRP neurons is required for the appropriate temporal integration and transmission of homeostatic hunger-sensing to dopamine signalling in the striatum.

Natural Products in Modulating Methamphetamine-Induced Neuronal Apoptosis

Methamphetamine (METH), an amphetamine-type psychostimulant, is highly abused worldwide. Chronic abuse of METH causes neurodegenerative changes in central dopaminergic neurons with numerous neuropsychiatric consequences. Neuronal apoptosis plays a critical role in METH-induced neurotoxicity and may provide promising pharmacological targets for preventing and treating METH addiction. In recent years, accumulating evidence has revealed that natural products may possess significant potentials to inhibit METH-evoked neuronal apoptosis. In this review, we summarized and analyzed the improvement effect of natural products on METH-induced neuronal apoptosis and their potential molecular mechanisms on modulating dopamine release, oxidative stress, mitochondrial-dependent apoptotic pathway, endoplasmic reticulum stress-mediated apoptotic pathway, and neuroinflammation. Hopefully, this review may highlight the potential value of natural products in modulating METH-caused neuronal apoptosis and provide useful information for future research and developments of novel and efficacious pharmacotherapies in this field.

Catalytic SrMoO4 nanoparticles and conducting polymer composite sensor for monitoring of K+-induced dopamine release from neuronal cells

Octahedral SrMoO4 nanoparticles (NPs) with a high degree of crystallinity and controlled size (250-350 nm) were synthesized for the first time by employing a facile hydrothermal method. The prepared NPs...

Effectiveness and relationship between biased and unbiased measures of dopamine release and clearance

Fast-scan cyclic voltammetry (FSCV) is an effective tool for measuring dopamine (DA) release and clearance throughout the brain, including the ventral and dorsal striatum. Striatal DA terminals are abundant with signals heavily regulated by release machinery and the dopamine transporter (DAT). Peak height is a common method for measuring release but can be affected by changes in clearance. The Michaelis-Menten model has been a standard in measuring DA clearance, but requires experimenter fitted modeling subject to experimenter bias. The current study presents the use of the first derivative (velocity) of evoked DA signals as an alternative approach for measuring dopamine release and clearance and can be used to distinguish the two measures. Maximal upwards velocity predicts reductions in DA peak height due to D2 and GABAB receptor stimulation and by alterations in calcium concentrations. The Michaelis-Menten maximal velocity (Vmax) measure, an approximation for DAT numbers, predicted maximal downward velocity in slices and in vivo. Dopamine peak height and upward velocity were similar between wildtype C57 (WT) and DAT knock out (DATKO) mice. In contrast, downward velocity was considerably reduced and exponential decay (tau) was increased in DATKO mice, supporting use of both measures for changes in DAT activity. In slices, the competitive DAT inhibitors cocaine, PTT and WF23 increased peak height and upward velocity differentially across increasing concentrations, with PTT and cocaine reducing these measures at high concentrations. Downward velocity and tau values decreased and increased respectively across concentrations, with greater potency and efficacy observed with WF23 and PTT. In vivo recordings demonstrated similar effects of WF23 and PTT on measures of release and clearance. Tau was a more sensitive measure at low concentrations, supporting its use as a surrogate for the Michaelis-Menten measure of apparent affinity (Km). Together, these results inform on the use of these measures for DA release and clearance.

Deficiency in endocannabinoid synthase DAGLB contributes to Parkinson's disease and dopaminergic neuron dysfunction

2-arachidonoyl-glycerol (2-AG), the most abundant endocannabinoid (eCB) in the brain, regulates diverse neural functions. However, whether 2-AG deficiency contributes to Parkinson's disease (PD) and nigral dopaminergic neurons (DANs) dysfunction is unclear. Diacylglycerol lipase A and B (DAGLA and DAGLB) mediate the biosynthesis of 2-AG. Using homozygosity mapping and whole-exome sequencing, we linked multiple homozygous loss-of-function mutations in DAGLB to a form of early-onset autosomal recessive PD. We then used RNA sequencing and fiber photometry with genetically encoded eCB sensors to demonstrate that DAGLB is the main 2-AG synthase in nigral DANs. Genetic knockdown of Daglb by CRISPR/Cas9 in mouse nigral DANs substantially reduces 2-AG levels in the substantia nigra (SN). The SN 2-AG levels are markedly correlated with the vigor of movement during the acquisition of motor skills, while Daglb-deficiency impairs motor learning. Conversely, pharmacological enhancement of 2-AG levels increases nigral DAN activity and dopamine release and improves motor learning. Together, we demonstrate that DAGLB-deficiency contributes to the etiopathogenesis of PD, reveal the importance of DAGLB-mediated 2-AG biosynthesis in nigral DANs in regulating neural activity and dopamine release, and provide preclinical evidence for the beneficial effects of 2-AG augmentation in PD treatment.

Dopamine and fear memory formation in the human amygdala

Learning which environmental cues that predict danger is crucial for survival and accomplished through Pavlovian fear conditioning. In humans and rodents alike, fear conditioning is amygdala-dependent and rests on similar neurocircuitry. Rodent studies have implicated a causative role for dopamine in the amygdala during fear memory formation, but the role of dopamine in aversive learning in humans is unclear. Here, we show dopamine release in the amygdala and striatum during fear learning in humans. Using simultaneous positron emission tomography and functional magnetic resonance imaging, we demonstrate that the amount of dopamine release is linked to strength of conditioned fear responses and linearly coupled to learning-induced activity in the amygdala. Thus, like in rodents, formation of amygdala-dependent fear memories in humans seems to be facilitated by endogenous dopamine release, supporting an evolutionary conserved neurochemical mechanism for aversive memory formation.