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1.
Cereb Cortex ; 31(4): 2187-2204, 2021 03 05.
Article in English | MEDLINE | ID: mdl-33264389

ABSTRACT

Dopamine receptors play an important role in motivational, emotional, and motor responses. In addition, growing evidence suggests a key role of hippocampal dopamine receptors in learning and memory. It is well known that associative learning and synaptic plasticity of CA3-CA1 requires the dopamine D1 receptor (D1R). However, the specific role of the dopamine D2 receptor (D2R) on memory-related neuroplasticity processes is still undefined. Here, by using two models of D2R loss, D2R knockout mice (Drd2-/-) and mice with intrahippocampal injections of Drd2-small interfering RNA (Drd2-siRNA), we aimed to investigate how D2R is involved in learning and memory as well as in long-term potentiation of the hippocampus. Our studies revealed that the genetic inactivation of D2R impaired the spatial memory, associative learning, and the classical conditioning of eyelid responses. Similarly, deletion of D2R reduced the activity-dependent synaptic plasticity in the hippocampal CA1-CA3 synapse. Our results demonstrate the first direct evidence that D2R is essential in behaving mice for trace eye blink conditioning and associated changes in hippocampal synaptic strength. Taken together, these results indicate a key role of D2R in regulating hippocampal plasticity changes and, in consequence, acquisition and consolidation of spatial and associative forms of memory.


Subject(s)
CA1 Region, Hippocampal/metabolism , CA3 Region, Hippocampal/metabolism , Neuronal Plasticity/physiology , Receptors, Dopamine D2/deficiency , Spatial Memory/physiology , Synapses/metabolism , Animals , Avoidance Learning/physiology , Female , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , RNA, Small Interfering/administration & dosage , Receptors, Dopamine D2/genetics , Synapses/genetics
2.
Cell Rep ; 31(3): 107527, 2020 04 21.
Article in English | MEDLINE | ID: mdl-32320647

ABSTRACT

Cocaine drastically elevates dopamine (DA) levels in the striatum, a brain region that is critical to the psychomotor and rewarding properties of the drug. DA signaling regulates intrastriatal circuits connecting medium spiny neurons (MSNs) with afferent fibers and interneurons. While the cocaine-mediated increase in DA signaling on MSNs is well documented, that on cholinergic interneurons (ChIs) has been more difficult to assess. Using combined pharmacological, chemogenetic, and cell-specific ablation approaches, we reveal that the D2R-dependent inhibition of acetylcholine (ACh) signaling is fundamental to cocaine-induced changes in behavior and the striatal genomic response. We show that the D2R-dependent control of striatal ChIs enables the motor, sensitized, and reinforcing properties of cocaine. This study highlights the importance of the DA- and D2R-mediated inhibitory control of ChIs activity in the normal functioning of striatal networks.


Subject(s)
Cholinergic Neurons/drug effects , Cocaine/pharmacology , Corpus Striatum/drug effects , Dopamine/metabolism , Interneurons/drug effects , Acetylcholine/metabolism , Animals , Cholinergic Neurons/metabolism , Corpus Striatum/metabolism , Female , Interneurons/metabolism , Mice , Mice, Knockout , Muscarinic Antagonists/pharmacology , Receptors, Dopamine D2/deficiency , Receptors, Dopamine D2/metabolism , Receptors, Muscarinic/metabolism , Signal Transduction/drug effects , Transcriptome/drug effects
3.
J Neurosci ; 39(38): 7551-7563, 2019 09 18.
Article in English | MEDLINE | ID: mdl-31371425

ABSTRACT

Mental disorders are caused by genetic and environmental factors. We here show that deficiency of an isoform of dopamine D2 receptor (D2R), D2LR, causes stress vulnerability in mouse. This occurs through dysfunction of serotonin [5-hydroxytryptamine (5-HT)] 1A receptor (5-HT1AR) on serotonergic neurons in the mouse brain. Exposure to forced swim stress significantly increased anxiety- and depressive-like behaviors in D2LR knock-out (KO) male mice compared with wild-type mice. Treatment with 8-OH-DPAT, a 5-HT1AR agonist, failed to alleviate the stress-induced behaviors in D2LR-KO mice. In forced swim-stressed D2LR-KO mice, 5-HT efflux in the medial prefrontal cortex was elevated and the expression of genes related to 5-HT levels was upregulated by the transcription factor PET1 in the dorsal raphe nucleus. Notably, D2LR formed a heteromer with 5-HT1AR in serotonergic neurons, thereby suppressing 5-HT1AR-activated G-protein-activated inwardly rectifying potassium conductance in D2LR-KO serotonergic neurons. Finally, D2LR overexpression in serotonergic neurons in the dorsal raphe nucleus alleviated stress vulnerability observed in D2LR-KO mice. Together, we conclude that disruption of the negative feedback regulation by the D2LR/5-HT1A heteromer causes stress vulnerability.SIGNIFICANCE STATEMENT Etiologies of mental disorders are multifactorial, e.g., interactions between genetic and environmental factors. In this study, using a mouse model, we showed that genetic depletion of an isoform of dopamine D2 receptor, D2LR, causes stress vulnerability associated with dysfunction of serotonin 1A receptor, 5-HT1AR in serotonergic neurons. The D2LR/5-HT1AR inhibitory G-protein-coupled heteromer may function as a negative feedback regulator to suppress psychosocial stress.


Subject(s)
Brain/metabolism , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, Dopamine D2/deficiency , Serotonergic Neurons/metabolism , Stress, Psychological/metabolism , Animals , Male , Mice , Mice, Knockout
4.
Proc Natl Acad Sci U S A ; 115(45): E10730-E10739, 2018 11 06.
Article in English | MEDLINE | ID: mdl-30348762

ABSTRACT

Impulsivity is closely associated with addictive disorders, and changes in the brain dopamine system have been proposed to affect impulse control in reward-related behaviors. However, the central neural pathways through which the dopamine system controls impulsive behavior are still unclear. We found that the absence of the D2 dopamine receptor (D2R) increased impulsive behavior in mice, whereas restoration of D2R expression specifically in the central amygdala (CeA) of D2R knockout mice (Drd2-/-) normalized their enhanced impulsivity. Inhibitory synaptic output from D2R-expressing neurons in the CeA underlies modulation of impulsive behavior because optogenetic activation of D2R-positive inhibitory neurons that project from the CeA to the bed nucleus of the stria terminalis (BNST) attenuate such behavior. Our identification of the key contribution of D2R-expressing neurons in the CeA → BNST circuit to the control of impulsive behavior reveals a pathway that could serve as a target for approaches to the management of neuropsychiatric disorders associated with impulsivity.


Subject(s)
Central Amygdaloid Nucleus/metabolism , Impulsive Behavior , Neural Pathways/metabolism , RNA, Messenger/genetics , Receptors, Dopamine D2/genetics , Septal Nuclei/metabolism , Animals , Central Amygdaloid Nucleus/physiopathology , Choice Behavior , Dopamine/metabolism , Gene Expression Regulation , Male , Mice , Mice, Knockout , Neural Pathways/physiopathology , Neurons/metabolism , Neurons/pathology , Neuropsychological Tests , Optogenetics , RNA, Messenger/antagonists & inhibitors , RNA, Messenger/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Reaction Time , Receptors, Dopamine D2/deficiency , Septal Nuclei/physiopathology , Signal Transduction
5.
CNS Neurol Disord Drug Targets ; 17(7): 522-527, 2018.
Article in English | MEDLINE | ID: mdl-29952269

ABSTRACT

BACKGROUND: Pridopidine, a compound in clinical trials for Huntington's disease treatment, was originally synthesized as a dopamine D2 receptor (D2R) ligand, but later found to possess higher affinity for the sigma-1 receptor (S1R). However, the putative contributions of D2R and S1R to the behavioral profile of acutely administered pridopidine have not been investigated. OBJECTIVE: The present study sought to compare the effects of acute pridopidine on wild-type vs. D2R and S1R knockout mice, at high (60 mg/kg) and low (6 mg/kg) doses. METHOD: Pridopidine effects on basal and phencyclidine-induced locomotor activity was measured in the open field test. Additionally, the actions of pridopidine on prepulse inhibition was measured in animals treated with saline or phencyclidine. RESULTS: Whereas inhibition of spontaneous and phencyclidine-induced locomotion was readily observed at 60 mg/kg pridopidine, neither locomotor stimulation in habituated mice, nor any effects on prepulse inhibition were detected upon pridopidine treatment. Surprisingly, inhibition of spontaneous locomotion was unaffected by both D2R and S1R deletion. CONCLUSION: The present results suggest the involvement of additional targets, besides D2R and S1R, in mediating locomotor inhibition by pridopidine.


Subject(s)
Dopamine Agents/pharmacology , Locomotion/drug effects , Piperidines/pharmacology , Receptors, Dopamine D2/deficiency , Receptors, sigma/deficiency , Receptors, sigma/metabolism , Acoustic Stimulation/adverse effects , Analysis of Variance , Animals , Dose-Response Relationship, Drug , Excitatory Amino Acid Antagonists/toxicity , Exploratory Behavior/drug effects , Mice , Mice, Knockout , Phencyclidine/toxicity , Prepulse Inhibition/drug effects , Receptors, Dopamine D2/genetics , Receptors, sigma/genetics , Time Factors , Sigma-1 Receptor
6.
Behav Brain Res ; 341: 129-134, 2018 04 02.
Article in English | MEDLINE | ID: mdl-29287910

ABSTRACT

Impulsivity associated with abnormal dopamine (DA) function has been observed in several disorders, including addiction. Choice impulsivity is the preference for small, immediate rewards over larger rewards after a delay, caused by excessive discounting of future rewards. Addicts have abnormally high discount rates and prefer the smaller rewards sooner. While impulsivity has been inversely correlated with DA D2 receptor (D2R) availability in the midbrain and striatum, it is difficult to mechanistically link the two, due to the diverse neuroanatomical localization of D2Rs, which are found throughout the brain, in many types of neurons and neuronal subcompartments. To determine if ventral tegmental area (VTA) D2R hypofunction is linked to impulsivity, we knocked down D2 receptors from the VTA, using an adeno-associated viral (AAV) vector that delivers short hairpin RNAs (shRNA) targeted against the D2R. The D2R knockdown is restricted to neurons whose cell bodies reside in the VTA, leaving postsynaptic D2Rs intact in the striatum, prefrontal cortex, and other mesocorticolimbic structures. Rats were trained in a delay-discounting task to assess impulsive choice until a stable discounting curve was obtained, and then received bilateral VTA infusions of the D2R shRNA or a scrambled control virus. Over the next six weeks, the discounting curve of the VTA D2R knockdown rats shifted to the left, indicating a preference for the smaller, immediate reward, whereas the curve for control rats remained stable and unchanged. Together these results demonstrate that a decrease in VTA D2Rs enhances choice impulsivity.


Subject(s)
Delay Discounting/physiology , Impulsive Behavior/physiology , Receptors, Dopamine D2/deficiency , Ventral Tegmental Area/metabolism , Animals , Dependovirus/genetics , Gene Knockdown Techniques , Genetic Vectors , Male , Neurons/metabolism , RNA, Small Interfering/administration & dosage , RNA, Small Interfering/metabolism , Random Allocation , Rats, Sprague-Dawley , Receptors, Dopamine D2/genetics , Reward
7.
Br J Pharmacol ; 174(24): 4751-4770, 2017 Dec.
Article in English | MEDLINE | ID: mdl-28963856

ABSTRACT

BACKGROUND AND PURPOSE: Dopamine has multiple anti-inflammatory effects, but its role and molecular mechanism in acute pancreatitis (AP) are unclear. We investigated the role of dopamine signalling in the inflammatory response in AP. EXPERIMENTAL APPROACH: Changes in pancreatic dopaminergic system and effects of dopamine, antagonists and agonists of D1 and D2 dopamine receptors were analysed in wild-type and pancreas-specific Drd2-/- mice with AP (induced by caerulein and LPS or L-arginine) and pancreatic acinar cells with or without cholecystokinin (CCK) stimulation. The severity of pancreatitis was assessed by measuring serum amylase and lipase and histological assessments. The NF-κB signalling pathway was evaluated, and macrophage and neutrophil migration assessed by Transwell assay. KEY RESULTS: Pancreatic dopamine synthetase and metabolic enzyme levels were increased, whereas D1 and D2 receptors were decreased in AP. Dopamine reduced inflammation in CCK-stimulated pancreatic acinar cells by inhibiting the NF-κB pathway. Moreover, the protective effects of dopamine were blocked by a D2 antagonist, but not a D1 antagonist. A D2 agonist reduced pancreatic damage and levels of p-IκBα, p-NF-κBp65, TNFα, IL-1ß and IL-6 in AP. Pancreas-specific Drd2-/- aggravated AP. Also, the D2 agonist activated PP2A and inhibited the phosphorylation of Akt, IKK, IκBα and NF-κB and production of inflammatory cytokines and chemokines. Furthermore, it inhibited the migration of macrophages and neutrophils by reducing the expression of CCL2 and CXCL2. A PP2A inhibitor attenuated these protective effects of the D2 agonist. CONCLUSIONS AND IMPLICATIONS: D2 receptors control pancreatic inflammation in AP by inhibiting NF-κB activation via a PP2A-dependent Akt signalling pathway.


Subject(s)
Inflammation/metabolism , NF-kappa B/metabolism , Pancreatitis/metabolism , Protein Phosphatase 2/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Receptors, Dopamine D2/metabolism , Acute Disease , Animals , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Receptors, Dopamine D2/deficiency , Signal Transduction
8.
Pharmacol Rep ; 69(2): 235-241, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28119185

ABSTRACT

BACKGROUND: The human dopamine D2 receptor gene has three polymorphic variants that alter its amino acid sequence: alanine substitution by valine in position 96 (V96A), proline substitution by serine in position 310 (P310S) and serine substitution by cysteine in position 311 (S311C). Their functional role has never been the object of extensive studies, even though there is some evidence that their occurrence correlates with schizophrenia. METHODS: The HEK293 cell line was transfected with dopamine D1 and D2 receptors (or genetic variants of the D2 receptor), coupled to fluorescent proteins which allowed us to measure the extent of dimerization of these receptors, using a highly advanced biophysical approach (FLIM-FRET). Additionally, Fluoro-4 AM was used to examine changes in the level of calcium release after ligand stimulation of cells expressing different combinations of dopamine receptors. RESULTS: Using FLIM-FRET experiments we have shown that in HEK 293 expressing dopamine receptors, polymorphic mutations in the D2 receptor play a role in dimmer formation with the dopamine D1 receptor. The association level of dopamine receptors is affected by ligand administration, with variable effects depending on polymorphic variant of the D2 dopamine receptor. We have found that the level of heteromer formation is reflected by calcium ion release after ligand stimulation and have observed variations of this effect dependent on the polymorphic variant and the ligand. CONCLUSION: The data presented in this paper support the hypothesis on the role of calcium signaling regulated by the D1-D2 heteromer which may be of relevance for schizophrenia etiology.


Subject(s)
Genetic Variation/genetics , Protein Multimerization/genetics , Receptors, Dopamine D1/genetics , Receptors, Dopamine D2/deficiency , Calcium/metabolism , Calcium Signaling/genetics , Cell Line , HEK293 Cells , Humans , Schizophrenia/genetics
9.
PLoS One ; 11(9): e0162875, 2016.
Article in English | MEDLINE | ID: mdl-27622550

ABSTRACT

Corydalis yanhusuo. W.T. extracts (YHS) are widely used for the treatment of pain and inflammation. There are a few studies that assessed the effects of YHS in pain assays; however, none of these studies has systematically compared its activities in the different pain animal modes namely: acute, inflammatory and chronic pain. Furthermore, little is known about the mechanism of YHS activity in these assays. The aim of this study was to systematically evaluate the antinociceptive properties of YHS by testing it in four standardized pain assays and to investigate its mechanism. YHS antinociceptive properties were analyzed in the tail flick, the formalin paw licking, the von Frey filament and the hot box assays after spinal nerve ligation, which monitors acute nociceptive, persistent inflammatory and chronic neuropathic pain, respectively. YHS pharmacological profile was determined by screening it against a battery of G-protein coupled receptors and its mechanism of action was studied using knock-out mice. Our study shows that YHS, at a non-sedative dose, increases the tail flick latency in the tail flick assay without resulting in development of tolerance. YHS also decreases paw licking time in the formalin assay. Further, YHS increases paw withdraw threshold and latency in the von Frey filament and the hot box assays, respectively. In vitro, YHS exhibits prominent dopamine receptor antagonistic properties. In dopamine D2 receptor knockout mice, its antinociceptive effects are attenuated in acute and neuropathic pain but not inflammatory pain assays. Our results therefore indicate that YHS effectively attenuates acute, inflammatory and neuropathic pain, without causing tolerance. The effects on acute and neuropathic pain, but not inflammatory pain, are at least partially mediated through dopamine D2 receptor antagonism. Since YHS is a dietary supplement commercially available in the United States, our data suggest that it might be a candidate for alternative pain treatment.


Subject(s)
Analgesics/pharmacology , Corydalis , Acute Pain/drug therapy , Analgesics/isolation & purification , Animals , Drug Tolerance , Drugs, Chinese Herbal/pharmacology , Inflammation/drug therapy , Male , Mice , Mice, 129 Strain , Mice, Knockout , Neuralgia/drug therapy , Pain Measurement/methods , Receptors, Dopamine D2/deficiency , Receptors, Dopamine D2/genetics
10.
ACS Chem Neurosci ; 6(2): 297-305, 2015 Feb 18.
Article in English | MEDLINE | ID: mdl-25393953

ABSTRACT

Disruption to dopamine homeostasis during brain development has been implicated in a variety of neuropsychiatric disorders, including depression and schizophrenia. Inappropriate expression or activity of GABAergic interneurons are common features of many of these disorders. We discovered a persistent upregulation of GAD67+ and parvalbumin+ neurons within the anterior cingulate cortex of dopamine D2 receptor knockout mice, while other GABAergic interneuron markers were unaffected. Interneuron distribution and number were not altered in the striatum or in the dopamine-poor somatosensory cortex. The changes were already present by postnatal day 14, indicating a developmental etiology. D2eGFP BAC transgenic mice demonstrated the presence of D2 receptor expression within a subset of parvalbumin-expressing cortical interneurons, suggesting the possibility of a direct cellular mechanism through which D2 receptor stimulation regulates interneuron differentiation or survival. D2 receptor knockout mice also exhibited decreased depressive-like behavior compared with wild-type controls in the tail suspension test. These data indicate that dopamine signaling modulates interneuron number and emotional behavior and that developmental D2 receptor loss or blockade could reveal a potential mechanism for the prodromal basis of neuropsychiatric disorders.


Subject(s)
Gyrus Cinguli/cytology , Gyrus Cinguli/metabolism , Interneurons/cytology , Interneurons/metabolism , Parvalbumins/metabolism , Receptors, Dopamine D2/deficiency , Animals , Cell Count , Depression/metabolism , Depression/pathology , Emotions/physiology , Female , GABAergic Neurons/cytology , GABAergic Neurons/metabolism , Glutamate Decarboxylase/metabolism , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Gyrus Cinguli/growth & development , Immunohistochemistry , In Situ Hybridization, Fluorescence , Male , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Neuropsychological Tests , Receptors, Dopamine D2/genetics
11.
J Psychopharmacol ; 28(10): 973-7, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25122042

ABSTRACT

Whether the dopamine Drd-2 receptor is necessary for the behavioural action of antipsychotic drugs is an important question, as Drd-2 antagonism is responsible for their debilitating motor side effects. Using Drd-2 null mice (Drd2 -/-) it has previously been shown that Drd-2 is not necessary for antipsychotic drugs to reverse D-amphetamine disruption of latent inhibition (LI), a behavioural measure of learning to ignore irrelevant stimuli. Weiner's 'two-headed' model indicates that antipsychotics not only reverse LI disruption, 'disrupted LI', but also potentiate LI when low/absent in controls, 'persistent' LI. We investigated whether antipsychotic drugs haloperidol or clozapine potentiated LI in wild-type controls or Drd2 -/-. Both drugs potentiated LI in wild-type but not in Drd2 -/- mice, suggesting moderation of this effect of antipsychotics in the absence of Drd-2. Haloperidol potentiated LI similarly in both Drd1 -/- and wild-type mice, indicating no such moderation in Drd1 -/-. These data suggest that antipsychotic drugs can have either Drd-2 or non-Drd-2 effects on learning to ignore irrelevant stimuli, depending on how the abnormality is produced. Identification of the non-Drd-2 mechanism may help to identify novel non-Drd2 based therapeutic strategies for psychosis.


Subject(s)
Antipsychotic Agents/pharmacology , Clozapine/pharmacology , Dopamine D2 Receptor Antagonists/pharmacology , Haloperidol/pharmacology , Inhibition, Psychological , Learning/drug effects , Receptors, Dopamine D2/deficiency , Animals , Mice , Mice, Knockout , Receptors, Dopamine D1/deficiency , Receptors, Dopamine D1/genetics , Receptors, Dopamine D2/genetics , Receptors, Dopamine D2/metabolism
12.
Invest Ophthalmol Vis Sci ; 55(9): 5537-44, 2014 Aug 05.
Article in English | MEDLINE | ID: mdl-25097246

ABSTRACT

PURPOSE: This study used dopamine D2 receptor (D2R) knockout (KO) mice to investigate the role of D2R activity in the development of form-deprivation myopia (FDM). Sulpiride, a D2R antagonist, was administered systemically into wild-type (WT) mice to validate the involvement of D2R in FDM development. METHODS: The D2R KO and WT C57BL/6 mice were subjected to FDM. Wild-type mice received daily intraperitoneal injections of sulpiride, 8 µg/g body weight, for a period of 4 weeks. The body weight, refraction, corneal radius of curvature, and ocular axial components were measured at week 4 of the experiment. Differences in all ocular parameters between the experimental and control groups were compared statistically. RESULTS: Form-deprivation myopia in D2R KO mice (FD-KO) was significantly reduced compared with their WT littermates (interocular difference, -2.12 ± 0.91 diopter [D] in FD-KO versus -5.35 ± 0.83 D in FD-WT, P = 0.014), with a smaller vitreous chamber depth (0.008 ± 0.006 vs. 0.026 ± 0.006 mm, P = 0.044) and axial length (-0.001 ± 0.007 vs. 0.027 ± 0.008 mm, P = 0.007). Furthermore, FDM was attenuated in animals treated with sulpiride (-2.01 ± 0.31 D in FD-sulpiride versus -4.06 ± 0.30 D in FD-DMSO, P < 0.001) compared with those treated with vehicle, with a retardation in growth of vitreous chamber depth (-0.001 ± 0.006 vs. 0.022 ± 0.004 mm, P = 0.003) and axial length (-0.004 ± 0.007 vs. 0.027 ± 0.005 mm, P = 0.001). CONCLUSIONS: Genetic and pharmacological inactivation of D2R attenuates FDM development in mice, suggesting that dopamine acting on D2R appears to promote the development of FDM in C57BL/6 mice. Further studies are required to confirm these results using animal models in which retinal D2R is selectively blocked.


Subject(s)
Form Perception/physiology , Myopia/physiopathology , Receptors, Dopamine D2/physiology , Analysis of Variance , Animals , Disease Models, Animal , Dopamine Antagonists/pharmacology , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, Dopamine D2/deficiency , Refraction, Ocular/physiology , Sulpiride/pharmacology
13.
Neuron ; 81(1): 153-64, 2014 Jan 08.
Article in English | MEDLINE | ID: mdl-24411738

ABSTRACT

Structural plasticity in the adult brain is essential for adaptive behavior. We have found a remarkable anatomical plasticity in the basal ganglia of adult mice that is regulated by dopamine D2 receptors (D2Rs). By modulating neuronal excitability, striatal D2Rs bidirectionally control the density of direct pathway collaterals in the globus pallidus that bridge the direct pathway with the functionally opposing indirect pathway. An increase in bridging collaterals is associated with enhanced inhibition of pallidal neurons in vivo and disrupted locomotor activation after optogenetic stimulation of the direct pathway. Chronic blockade with haloperidol, an antipsychotic medication used to treat schizophrenia, decreases the extent of bridging collaterals and rescues the locomotor imbalance. These findings identify a role for bridging collaterals in regulating the concerted balance of striatal output and may have important implications for understanding schizophrenia, a disease involving excessive activation of striatal D2Rs that is treated with D2R blockers.


Subject(s)
Basal Ganglia/cytology , Nerve Net/physiology , Neural Pathways/physiology , Neurons/physiology , Receptors, Dopamine D2/physiology , Action Potentials/drug effects , Action Potentials/genetics , Animals , Basal Ganglia/drug effects , Basal Ganglia/physiology , Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics , Corpus Striatum/cytology , Corpus Striatum/physiology , Dopamine Antagonists/pharmacology , Doxycycline/pharmacology , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Globus Pallidus/cytology , Globus Pallidus/physiology , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Haloperidol/pharmacology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutation/genetics , Nerve Net/drug effects , Neural Pathways/drug effects , Neurons/drug effects , Potassium Channels, Inwardly Rectifying/genetics , Potassium Channels, Inwardly Rectifying/metabolism , Receptors, Dopamine D1/genetics , Receptors, Dopamine D2/deficiency , Time Factors
14.
Behav Pharmacol ; 25(1): 32-43, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24366314

ABSTRACT

This study examined whether repeated administration of caffeine would induce behavioural sensitization and overexpression of cocaine-regulated and amphetamine-regulated transcript (CART) peptides in mice. The involvement of dopaminergic receptors and adenosine receptors in caffeine-induced behavioural sensitization and CART overexpression was studied. The relevance of D1R and D2R, and A1R and A(2A)R in the overexpression of CART peptides in mouse striatum was also evaluated. Repeated administration of caffeine induced behavioural sensitization in mice. Significant increases in CART mRNA levels were observed on day 3 and peaked at day 5 of caffeine administration, and then decreased gradually. Higher proportions of CART⁺ cells were observed in the dorsolateral and ventrolateral part of the caudate putamen than in the nucleus accumbens shell and core. The behavioural sensitization induced by caffeine was inhibited by dopaminergic receptor antagonists and adenosine receptor agonists. D1R and D2R, and cyclic AMP (cAMP)/protein kinase A (PKA)/phospho-cAMP response element-binding protein (pCREB) signalling were activated by caffeine, but A1R and A(2A)R were inhibited. Overexpression of caffeine-induced CART peptides and pCREB activity were blocked by N-cyclopentyladenosine (CPA, an A1R agonist) and 4-[2-[[6-amino-9-(N-ethyl-ß-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid hydrochloride (CGS 21680, an A(2A)R agonist), but not by R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390, a D1R antagonist) or raclopride (a D2R antagonist). Caffeine-induced overexpression of CART peptides was associated with the inhibition of A1R and A(2A)R, and the activation of cAMP/PKA/pCREB signalling. Moreover, the A(2A)R-D2R heterodimer might be involved in the overexpression of CART peptides induced by caffeine.


Subject(s)
Behavior, Animal/drug effects , Caffeine/pharmacology , Central Nervous System Stimulants/pharmacology , Gene Expression Regulation/drug effects , Motor Activity/drug effects , Nerve Tissue Proteins/metabolism , Animals , Benzazepines/pharmacology , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Cyclic AMP-Dependent Protein Kinases/metabolism , Dopamine Antagonists/pharmacology , Dose-Response Relationship, Drug , Gene Expression Regulation/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/genetics , Nerve Tissue Proteins/genetics , Receptors, Dopamine D2/deficiency , Time Factors
15.
Nat Neurosci ; 16(8): 1042-8, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23817550

ABSTRACT

Dopaminergic (DA) signaling governs the control of complex behaviors, and its deregulation has been implicated in a wide range of diseases. Here we demonstrate that inactivation of the Fto gene, encoding a nucleic acid demethylase, impairs dopamine receptor type 2 (D2R) and type 3 (D3R) (collectively, 'D2-like receptor')-dependent control of neuronal activity and behavioral responses. Conventional and DA neuron-specific Fto knockout mice show attenuated activation of G protein-coupled inwardly-rectifying potassium (GIRK) channel conductance by cocaine and quinpirole. Impaired D2-like receptor-mediated autoinhibition results in attenuated quinpirole-mediated reduction of locomotion and an enhanced sensitivity to the locomotor- and reward-stimulatory actions of cocaine. Analysis of global N(6)-methyladenosine (m(6)A) modification of mRNAs using methylated RNA immunoprecipitation coupled with next-generation sequencing in the midbrain and striatum of Fto-deficient mice revealed increased adenosine methylation in a subset of mRNAs important for neuronal signaling, including many in the DA signaling pathway. Several proteins encoded by these mRNAs had altered expression levels. Collectively, FTO regulates the demethylation of specific mRNAs in vivo, and this activity relates to the control of DA transmission.


Subject(s)
Dopamine/physiology , Dopaminergic Neurons/enzymology , Mesencephalon/physiology , Mixed Function Oxygenases/physiology , Oxo-Acid-Lyases/physiology , Adenine/metabolism , Alpha-Ketoglutarate-Dependent Dioxygenase FTO , Animals , Cocaine/pharmacology , Corpus Striatum/physiology , Dopaminergic Neurons/physiology , Exploratory Behavior/drug effects , Exploratory Behavior/physiology , Female , G Protein-Coupled Inwardly-Rectifying Potassium Channels/physiology , Locomotion/drug effects , Locomotion/physiology , Male , Methylation , Methyltransferases/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mixed Function Oxygenases/deficiency , Mixed Function Oxygenases/genetics , Oxo-Acid-Lyases/deficiency , Oxo-Acid-Lyases/genetics , Phenotype , Quinpirole/pharmacology , RNA Processing, Post-Transcriptional , RNA, Messenger/metabolism , Receptors, Dopamine D2/deficiency , Receptors, Dopamine D2/physiology , Receptors, Dopamine D3/physiology , Reward , Signal Transduction/drug effects
16.
Neuroscience ; 248: 479-87, 2013 Sep 17.
Article in English | MEDLINE | ID: mdl-23811070

ABSTRACT

D2 receptor null mutant (Drd2(-/-)) mice have altered responses to the rewarding and locomotor effects of psychostimulant drugs, which is evidence of a necessary role for D2 receptors in these behaviors. Furthermore, work with mice that constitutively express only the D2 receptor short form (D2S), as a result of genetic deletion of the long form (D2L), provides the basis for a current model in which D2L is thought to be the postsynaptic D2 receptor on medium spiny neurons in the basal forebrain, and D2S the autoreceptor that regulates the activity of dopamine neurons and dopamine synthesis and release. Because constitutive genetic deletion of the D2 or D2L receptor may cause compensatory changes that influence functional outcomes, our approach is to identify aspects of the abnormal phenotype of a Drd2(-/-) mouse that can be normalized by virus-mediated D2 receptor expression. Drd2(-/-) mice are deficient in basal and methamphetamine-induced locomotor activation and lack D2 receptor agonist-induced activation of G protein-regulated inward rectifying potassium channels (GIRKs) in dopaminergic neurons. Here we show that virus-mediated expression of D2L in the nucleus accumbens significantly restored methamphetamine-induced locomotor activation, but not basal locomotor activity, compared to mice receiving the control virus. It also restored the effect of methamphetamine to decrease time spent in the center of the activity chamber in female but not male Drd2(-/-) mice. Furthermore, the effect of expression of D2S was indistinguishable from D2L. Similarly, virus-mediated expression of either D2S or D2L in substantia nigra neurons restored D2 agonist-induced activation of GIRKs. In this acute expression system, the alternatively spliced forms of the D2 receptor appear to be equally capable of acting as postsynaptic receptors and autoreceptors.


Subject(s)
Locomotion/drug effects , Neurons/metabolism , Nucleus Accumbens/cytology , Receptors, Dopamine D2/metabolism , Animals , Behavior, Animal/drug effects , Dopamine Agonists/pharmacology , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/metabolism , Female , G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism , Gene Expression Regulation/drug effects , Gene Transfer Techniques , Male , Methamphetamine/pharmacology , Mice , Mice, Knockout , Neurons/drug effects , Receptors, Dopamine D2/agonists , Receptors, Dopamine D2/deficiency
17.
Nat Commun ; 4: 1579, 2013.
Article in English | MEDLINE | ID: mdl-23481387

ABSTRACT

Dopaminergic systems are implicated in stress-related behaviour. Here we investigate behavioural responses to chronic stress in dopamine D2 receptor knockout mice and find that anxiety-like behaviours are increased compared with wild-type mice. Repeated stress exposure suppresses cocaine-induced behavioural sensitization, cocaine-seeking and relapse behaviours in dopamine D2 receptor knockout mice. Cocaine challenge after drug withdrawal in cocaine-experienced wild-type or dopamine D2 receptor knockout mice is associated with inhibition of long-term depression in the nucleus accumbens, and chronic stress during withdrawal prevents inhibition after cocaine challenge in cocaine-experienced dopamine D2 receptor knockout mice, but not in wild-type mice. Lentiviral-induced knockdown of dopamine D2 receptors in the nucleus accumbens of wild-type mice does not affect basal locomotor activity, but confers stress-induced inhibition of the expression of cocaine-induced behavioural sensitization. Stressed mice depleted of dopamine D2 receptors do not manifest long-term depression inhibition. Our results suggest that dopamine D2 receptors have roles in regulating synaptic modification triggered by stress and drug addiction.


Subject(s)
Behavior, Addictive/metabolism , Behavior, Addictive/physiopathology , Behavior, Animal , Neuronal Plasticity , Receptors, Dopamine D2/metabolism , Stress, Psychological/metabolism , Stress, Psychological/physiopathology , Animals , Anxiety/complications , Anxiety/metabolism , Anxiety/physiopathology , Behavior, Addictive/etiology , Behavior, Animal/drug effects , Central Nervous System Sensitization/drug effects , Cocaine/pharmacology , Conditioning, Psychological/drug effects , Electric Stimulation , Gene Knockdown Techniques , In Vitro Techniques , Lentivirus/metabolism , Maze Learning/drug effects , Mice , Neuronal Plasticity/drug effects , Nucleus Accumbens/drug effects , Nucleus Accumbens/pathology , Nucleus Accumbens/physiopathology , Receptors, Dopamine D2/deficiency , Restraint, Physical , Stress, Psychological/complications
18.
Genes Brain Behav ; 12(4): 397-404, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23521753

ABSTRACT

Dopamine signalling facilitates motivated behaviours, and the D2 dopamine receptor (D2R) is important in mother-infant interactions. D2R antagonists disrupt maternal behaviour and, in isolated rat pups, reduce ultrasonic vocalizations (USVs) that promote maternal interaction. Here, we examined the effects of genetic D2R signalling deficiency on pup-dam interaction with Drd2 knockout (D2R KO) mice. Using heterozygous (HET) cross littermates, the effect of pup genotype on isolation-induced USVs was quantified. Independent of parental genotype, D2R-deficient pups emitted fewer USVs than wild type (WT) littermates in a gene dose-dependent manner. Using reciprocal D2R KO-WT crosses, we examined how parental genotype affects pup USVs. Heterozygous pups from D2R KO dams produced fewer USVs than HET pups from WT dams. Also, exposure to USV-emitting pups increased plasma prolactin levels in WT dams but not in D2R KO dams, and KO dams showed delayed pup retrieval and nest building. These findings indicate the importance of the interaction between pup and dam genotypes on behaviour and further support the role of D2R signalling in maternal care.


Subject(s)
Maternal Behavior , Receptors, Dopamine D2/deficiency , Vocalization, Animal , Animals , Animals, Newborn , Heterozygote , Mice , Mice, Inbred C57BL , Mice, Knockout , Nesting Behavior , Phenotype , Prolactin/blood , Receptors, Dopamine D2/genetics , Sound
19.
J Neurosci ; 33(13): 5834-42, 2013 Mar 27.
Article in English | MEDLINE | ID: mdl-23536095

ABSTRACT

Competition between adult males for limited resources such as food and receptive females is shaped by the male pattern of pituitary growth hormone (GH) secretion that determines body size and the production of urinary pheromones involved in male-to-male aggression. In the brain, dopamine (DA) provides incentive salience to stimuli that predict the availability of food and sexual partners. Although the importance of the GH axis and central DA neurotransmission in social dominance and fitness is clearly appreciated, the two systems have always been studied unconnectedly. Here we conducted a cell-specific genetic dissection study in conditional mutant mice that selectively lack DA D2 receptors (D2R) from pituitary lactotropes (lacDrd2KO) or neurons (neuroDrd2KO). Whereas lacDrd2KO mice developed a normal GH axis, neuroDrd2KO mice displayed fewer somatotropes; reduced hypothalamic Ghrh expression, pituitary GH content, and serum IGF-I levels; and exhibited reduced body size and weight. As a consequence of a GH axis deficit, neuroDrd2KO adult males excreted low levels of major urinary proteins and their urine failed to promote aggression and territorial behavior in control male challengers, in contrast to the urine taken from control adult males. These findings reveal that central D2Rs mediate a neuroendocrine-exocrine cascade that controls the maturation of the GH axis and downstream signals that are critical for fitness, social dominance, and competition between adult males.


Subject(s)
Body Size/physiology , Growth Hormone/metabolism , Pituitary Gland/metabolism , Prolactin/metabolism , Receptors, Dopamine D2/metabolism , Analysis of Variance , Animals , Benzamides/pharmacokinetics , Body Size/drug effects , Body Size/genetics , Body Weight/drug effects , Body Weight/genetics , Case-Control Studies , Catatonia/chemically induced , Catatonia/metabolism , Dopamine Antagonists/pharmacology , Eating/drug effects , Eating/genetics , Eating/physiology , Female , Haloperidol/pharmacology , Insulin-Like Growth Factor I/metabolism , Intermediate Filament Proteins/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Nerve Tissue Proteins/genetics , Nestin , Oligodeoxyribonucleotides, Antisense/pharmacology , Pheromones/urine , Pituitary Gland/drug effects , Prolactin/genetics , Protein Binding/drug effects , Protein Binding/genetics , Proteins/metabolism , Radioimmunoassay , Receptors, Dopamine D2/deficiency , Receptors, Dopamine D2/genetics , Social Dominance , Territoriality , Tritium/pharmacokinetics
20.
Neuropsychopharmacology ; 38(8): 1512-20, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23422792

ABSTRACT

Drugs that induce psychosis, such as D-amphetamine (AMP), and those that alleviate it, such as antipsychotics, are suggested to exert behavioral effects via dopamine receptor D2 (D2). All antipsychotic drugs are D2 antagonists, but D2 antagonism underlies the severe and debilitating side effects of these drugs; it is therefore important to know whether D2 is necessary for their behavioral effects. Using D2-null mice (Drd2-/-), we first investigated whether D2 is required for AMP disruption of latent inhibition (LI). LI is a process of learning to ignore irrelevant stimuli. Disruption of LI by AMP models impaired attention and abnormal salience allocation consequent to dysregulated dopamine relevant to schizophrenia. AMP disruption of LI was seen in both wild-type (WT) and Drd2-/-. This was in contrast to AMP-induced locomotor hyperactivity, which was reduced in Drd2-/-. AMP disruption of LI was attenuated in mice lacking dopamine receptor D1 (Drd1-/-), suggesting that D1 may play a role in AMP disruption of LI. Further supporting this possibility, we found that D1 antagonist SKF83566 attenuated AMP disruption of LI in WT. Remarkably, both haloperidol and clozapine attenuated AMP disruption of LI in Drd2-/-. This demonstrates that antipsychotic drugs can attenuate AMP disruption of learning to ignore irrelevant stimuli in the absence of D2 receptors. Data suggest that D2 is not essential either for AMP to disrupt or for antipsychotic drugs to reverse AMP disruption of learning to ignore irrelevant stimuli and further that D1 merits investigation in the mediation of AMP disruption of these processes.


Subject(s)
Antipsychotic Agents/pharmacology , Dextroamphetamine/pharmacology , Inhibition, Psychological , Learning/drug effects , Learning/physiology , Receptors, Dopamine D2/deficiency , Animals , Female , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Time Factors
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