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1.
Behav Brain Res ; 379: 112348, 2020 02 03.
Article in English | MEDLINE | ID: mdl-31711897

ABSTRACT

Dopamine (DA) is a critical neurotransmitter involved in motivational processes. Tetrahydrobiopterin (BH4) is an essential cofactor for tyrosine hydroxylase, the rate-limiting enzyme in DA synthesis. Decreases in BH4 levels are observed in several DA-related neuropsychiatric diseases involving impairment in motivation. Yet, whether BH4 could be used to treat motivational deficits has not been comprehensively investigated. To investigate the effects of exogenous BH4 administration on the dopaminergic system and related behaviors, we acutely injected mice with BH4 (50 mg/kg). Passage of BH4 through the blood brain barrier and accumulation in brain was measured using the in situ brain perfusion technique. DA release was then recorded using in-vivo micro-dialysis and motivation was evaluated through operant conditioning paradigms in basal condition and after an amphetamine (AMPH) injection. First, we showed that BH4 crosses the blood-brain barrier and that an acute peripheral injection of BH4 is sufficient to increase the concentrations of biopterins in the brain, without affecting BH4- and DA-related protein expression. Second, we report that this increase in BH4 enhanced AMPH-stimulated DA release in the nucleus accumbens. Finally, we found that BH4-induced DA release led to improved performance of a motivational task. Altogether, these findings suggest that BH4, through its action on the dopaminergic tone, could be used as a motivational enhancer.


Subject(s)
Amphetamine/pharmacology , Behavior, Animal/drug effects , Biopterins/analogs & derivatives , Brain/drug effects , Brain/metabolism , Conditioning, Operant/drug effects , Dopamine Agents/pharmacology , Dopamine/metabolism , Motivation/drug effects , Amphetamine/administration & dosage , Animals , Biopterins/administration & dosage , Biopterins/pharmacology , Dopamine Agents/administration & dosage , Male , Mice , Mice, Inbred C57BL , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism
2.
eNeuro ; 4(3)2017.
Article in English | MEDLINE | ID: mdl-28580417

ABSTRACT

Increasing evidence suggest that consumption of high-fat diet (HFD) can impact the maturation of brain circuits, such as during adolescence, which could account for behavioral alterations associated with obesity. In the present study, we used behavioral sensitization to amphetamine to investigate the effect of periadolescent HFD exposure (pHFD) in rats on the functionality of the dopamine (DA) system, a central actor in food reward processing. pHFD does not affect responding to an acute injection, however, a single exposure to amphetamine is sufficient to induce locomotor sensitization in pHFD rats. This is paralleled by rapid neurobiological adaptations within the DA system. In pHFD-exposed animals, a single amphetamine exposure induces an increase in bursting activity of DA cells in the ventral tegmental area (VTA) as well as higher DA release and greater expression of (tyrosine hydroxylase, TH) in the nucleus accumbens (NAc). Post-synaptically, pHFD animals display an increase in NAc D2 receptors and c-Fos expression after amphetamine injection. These findings highlight the vulnerability of DA system to the consumption of HFD during adolescence that may support deficits in reward-related processes observed in obesity.


Subject(s)
Diet, High-Fat , Dopamine/metabolism , Nucleus Accumbens/metabolism , Ventral Tegmental Area/metabolism , Amphetamine/pharmacology , Animals , Animals, Newborn , Diet, High-Fat/adverse effects , Dopamine Agents/pharmacology , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/physiology , Locomotion/drug effects , Male , Nucleus Accumbens/drug effects , Proto-Oncogene Proteins c-fos/metabolism , Rats , Rats, Long-Evans , Receptors, Dopamine D2/metabolism , Tyrosine 3-Monooxygenase/metabolism , Ventral Tegmental Area/drug effects
3.
Mol Psychiatry ; 20(11): 1373-85, 2015 Nov.
Article in English | MEDLINE | ID: mdl-25560761

ABSTRACT

Hetero-oligomers of G-protein-coupled receptors have become the subject of intense investigation, because their purported potential to manifest signaling and pharmacological properties that differ from the component receptors makes them highly attractive for the development of more selective pharmacological treatments. In particular, dopamine D1 and D2 receptors have been proposed to form hetero-oligomers that couple to Gαq proteins, and SKF83959 has been proposed to act as a biased agonist that selectively engages these receptor complexes to activate Gαq and thus phospholipase C. D1/D2 heteromers have been proposed as relevant to the pathophysiology and treatment of depression and schizophrenia. We used in vitro bioluminescence resonance energy transfer, ex vivo analyses of receptor localization and proximity in brain slices, and behavioral assays in mice to characterize signaling from these putative dimers/oligomers. We were unable to detect Gαq or Gα11 protein coupling to homomers or heteromers of D1 or D2 receptors using a variety of biosensors. SKF83959-induced locomotor and grooming behaviors were eliminated in D1 receptor knockout (KO) mice, verifying a key role for D1-like receptor activation. In contrast, SKF83959-induced motor responses were intact in D2 receptor and Gαq KO mice, as well as in knock-in mice expressing a mutant Ala(286)-CaMKIIα that cannot autophosphorylate to become active. Moreover, we found that, in the shell of the nucleus accumbens, even in neurons in which D1 and D2 receptor promoters are both active, the receptor proteins are segregated and do not form complexes. These data are not compatible with SKF83959 signaling through Gαq or through a D1/D2 heteromer and challenge the existence of such a signaling complex in the adult animals that we used for our studies.


Subject(s)
Dopamine Agonists/pharmacology , GTP-Binding Protein alpha Subunits, Gq-G11/metabolism , Protein Multimerization/physiology , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/metabolism , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/analogs & derivatives , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology , Animals , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Dopamine Antagonists/pharmacology , GTP-Binding Protein alpha Subunits, Gq-G11/genetics , Grooming/drug effects , HEK293 Cells , Humans , Luminescent Proteins/genetics , Luminescent Proteins/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Models, Molecular , Motor Activity/drug effects , Motor Activity/genetics , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Phosphorylation/drug effects , Protein Multimerization/drug effects , Protein Structure, Tertiary , Receptors, Dopamine D1/genetics , Receptors, Dopamine D2/genetics
4.
Mol Psychiatry ; 19(12): 1295-304, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25070539

ABSTRACT

Convergent dopamine and glutamate signalling onto the extracellular signal-regulated kinase (ERK) pathway in medium spiny neurons (MSNs) of the striatum controls psychostimulant-initiated adaptive processes underlying long-lasting behavioural changes. We hypothesised that the physical proximity of dopamine D1 (D1R) and glutamate NMDA (NMDAR) receptors, achieved through the formation of D1R/NMDAR complexes, may act as a molecular bridge that controls the synergistic action of dopamine and glutamate on striatal plasticity and behavioural responses to drugs of abuse. We found that concomitant stimulation of D1R and NMDAR drove complex formation between endogenous D1R and the GluN1 subunit of NMDAR. Conversely, preventing D1R/GluN1 association with a cell-permeable peptide (TAT-GluN1C1) left individual D1R and NMDAR-dependent signalling intact, but prevented D1R-mediated facilitation of NMDAR-calcium influx and subsequent ERK activation. Electrophysiological recordings in striatal slices from mice revealed that D1R/GluN1 complexes control the D1R-dependent enhancement of NMDAR currents and long-term potentiation in D1R-MSN. Finally, intra-striatal delivery of TAT-GluN1C1 did not affect acute responses to cocaine but reduced behavioural sensitization. Our findings uncover D1R/GluN1 complexes as a major substrate for the dopamine-glutamate interaction in MSN that is usurped by addictive drugs to elicit persistent behavioural alterations. They also identify D1R/GluN1 complexes as molecular targets with a therapeutic potential for the vast spectrum of psychiatric diseases associated with an imbalance between dopamine and glutamate transmission.


Subject(s)
Cocaine/pharmacology , Corpus Striatum/drug effects , Dopamine Uptake Inhibitors/pharmacology , Neuronal Plasticity/drug effects , Receptors, Dopamine D1/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Calcium/metabolism , Corpus Striatum/physiology , Dopamine/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Male , Mice, Inbred C57BL , Mice, Knockout , Neuronal Plasticity/physiology , Neurons/drug effects , Neurons/physiology , Receptors, Dopamine D1/genetics , Tissue Culture Techniques
5.
Mol Psychiatry ; 18(9): 1025-33, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23711983

ABSTRACT

A decrease in dopamine D2 receptor (D2R) binding in the striatum is one of the most common findings in disorders that involve a dysregulation of motivation, including obesity, addiction and attention deficit hyperactivity disorder. As disruption of D2R signaling in the ventral striatum--including the nucleus accumbens (NAc)--impairs motivation, we sought to determine whether potentiating postsynaptic D2R-dependent signaling in the NAc would improve motivation. In this study, we used a viral vector strategy to overexpress postsynaptic D2Rs in either the NAc or the dorsal striatum. We investigated the effects of D2R overexpression on instrumental learning, willingness to work, use of reward value representations and modulation of motivation by reward associated cues. Overexpression of postsynaptic D2R in the NAc selectively increased motivation without altering consummatory behavior, the representation of the value of the reinforcer, or the capacity to use reward associated cues in flexible ways. In contrast, D2R overexpression in the dorsal striatum did not alter performance on any of the tasks. Thus, consistent with numerous studies showing that reduced D2R signaling impairs motivated behavior, our data show that postsynaptic D2R overexpression in the NAc specifically increases an animal's willingness to expend effort to obtain a goal. Taken together, these results provide insight into the potential impact of future therapeutic strategies that enhance D2R signaling in the NAc.


Subject(s)
Gene Expression Regulation/physiology , Motivation/physiology , Nucleus Accumbens/metabolism , Receptors, Dopamine D2/metabolism , Analysis of Variance , Animals , Conditioning, Classical , Conditioning, Operant , Genetic Vectors/physiology , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Microtubule-Associated Proteins/metabolism , Reward , Tritium/metabolism
6.
Hippocampus ; 21(11): 1169-79, 2011 Nov.
Article in English | MEDLINE | ID: mdl-20848600

ABSTRACT

Although the importance of cAMP-response element binding protein (CREB) phosphorylation in long-term memory formation is well documented for hippocampus-dependent tasks, little is known about the changes in phosphorylated CREB (pCREB) that occur during the process of extinction. The purpose of this study was to characterize the temporal patterns of pCREB in the CA1 and the amygdala after the extinction of previously acquired spatial information in the water maze. Mice were trained to find a hidden platform located at a fixed position and then were given extinction sessions in which the platform was either absent (NoPF) or relocated every day (RandomPF). We show that water maze spatial training evoked a biphasic response of pCREB in the CA1, with two different peaks occurring 15 min and 8 h postacquisition. The extinction of the original spatial preference significantly reduced the two peaks of CA1 pCREB in both RandomPF and NoPF groups whereas CA1 pCREB at 60 min post-training remained unaffected. Moreover, the early and late phases of extinction training produced regionally dissociable effects on pCREB in the CA1 and the lateral nucleus of the amygdala. These findings provide new insights on the molecular dynamics and anatomical dissociations underlying spatial memory and extinction learning.


Subject(s)
CA1 Region, Hippocampal/physiology , Cyclic AMP Response Element-Binding Protein/metabolism , Extinction, Psychological/physiology , Memory/physiology , Animals , Blotting, Western , Immunohistochemistry , Male , Maze Learning/physiology , Mice , Mice, Inbred C57BL , Phosphorylation
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