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1.
Brain Res Bull ; 175: 63-68, 2021 10.
Article in English | MEDLINE | ID: mdl-34274430

ABSTRACT

Studies have shown that both aging and dopaminergic dysfunction affected spatial learning and memory. Systematic dopaminergic inhibition, by dopamine receptor (DR) antagonist treatment, impaired spatial delayed-response (SDR) performance, which mostly requires self/body centered egocentric reference frame, in rhesus monkeys. However, the influence of DR blocking on large scale maze learning, which mainly involves world centered allocentric reference frame, remains unclear. Moreover, the effects of aging on the process also remain unknown. Present study investigated the issues, using large scale mazes composed of 8 maze units. Maze No. 1 was used for adaptation and training. Mazes No. 2-4 were used to investigate influence of aging, by comparing learning performance between young and aged rhesus monkeys. Mazes No. 5-8 were used to investigate the effects of DR antagonist treatment, SKF-83566 (0.02, 0.2 mg/kg) and haloperidol (0.001, 0.01 mg/kg). The result showed similar learning performance between young and aged monkeys in mazes No. 2-4. In mazes No. 5-8, we also found similar learning performance after acute DR antagonist injection, compared with pre-treatment baseline performance in mazes No. 2-4, in both young and aged groups. The result showed similar maze learning performance between young and aged monkeys in mazes (No. 2-4), suggesting no significant influence of aging on allocentric spatial learning. We also found similar maze performance in both groups, after dopamine receptor antagonist treatment in mazes (No. 5-8) compared with pre-treatment baseline performance in mazes (No. 2-4), suggesting no significant influence of dopaminergic inhibition on allocentric spatial learning. Together, the present study potentially suggested insensitivity of allocentric spatial learning to cognitive aging and acute systematic dopaminergic inhibition.


Subject(s)
Aging/psychology , Dopamine Antagonists/pharmacology , Maze Learning/drug effects , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/administration & dosage , 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 , Administration, Intravenous , Animals , Haloperidol/administration & dosage , Haloperidol/pharmacology , Macaca mulatta , Male , Psychomotor Performance/drug effects , Psychomotor Performance/physiology , Spatial Navigation
2.
Sci Rep ; 11(1): 10577, 2021 05 19.
Article in English | MEDLINE | ID: mdl-34011976

ABSTRACT

There has been an increase in cases of drug addiction and prescription drug abuse worldwide. Recently, pregabalin abuse has been a focus for many healthcare agencies, as highlighted by epidemiological studies. We previously evaluated the possibility of pregabalin abuse using the conditioned place preference (CPP) paradigm. We observed that a 60 mg/kg dose could induce CPP in mice and that pregabalin-rewarding properties were mediated through glutamate neurotransmission. Notably, the dopaminergic reward circuitry is also known to play a crucial role in medication-seeking behavior. Therefore, this study aimed to explore the possible involvement of dopaminergic receptor-1 in pregabalin-induced CPP. Mice were randomly allocated to receive saline or the dopamine-1 receptor antagonist SKF-83566 (0.03 mg/kg, intraperitoneal). After 30 min, the mice received either saline or pregabalin (60 mg/kg) during the conditioning phase. Among the control groups that received saline or SKF-83566, the time spent in the two conditioning chambers was not significantly altered. However, among the pregabalin-treated group, there was a marked increase in the time spent in the drug-paired chamber compared to the time spent in the vehicle-paired chamber. Notably, blocking dopamine-1 receptors with SKF-83566 completely prevented pregabalin-induced place preference, thus demonstrating the engagement of the dopaminergic system in pregabalin-induced reward-related behavior.


Subject(s)
Anti-Anxiety Agents/pharmacology , Behavior, Animal/drug effects , Pregabalin/pharmacology , Receptors, Dopamine D1/antagonists & inhibitors , Reward , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/analogs & derivatives , Animals , Dopaminergic Neurons/drug effects , Male , Mice, Inbred BALB C , Random Allocation
3.
Int J Neuropsychopharmacol ; 24(9): 721-733, 2021 09 21.
Article in English | MEDLINE | ID: mdl-34049400

ABSTRACT

BACKGROUND: SKF83959, an atypical dopamine (DA) D1 receptor agonist, has been used to test the functions of DA-related receptor complexes in vitro, but little is known about its impact on conditioned behavior. The present study examined the effects of SKF83959 on operant behaviors and assayed the neurochemical mechanisms involved. METHODS: Male rats were trained and maintained on either a fixed-interval 30-second (FI30) schedule or a differential reinforcement of low-rate response 10-second (DRL10) schedule of reinforcement. After drug treatment tests, western blotting assayed the protein expressions of the calcium-/calmodulin-dependent protein kinase II (CaMKII) and the transcription factor cyclic AMP response element binding protein (CREB) in tissues collected from 4 selected DA-related areas. RESULTS: SKF83959 disrupted the performance of FI30 and DRL10 behaviors in a dose-dependent manner by reducing the total number of responses in varying magnitudes. Moreover, the distinct profiles of the behavior altered by the drug were manifested by analyzing qualitative and quantitative measures on both tasks. Western-blot results showed that phospho-CaMKII levels decreased in the nucleus accumbens and the dorsal striatum of the drug-treated FI30 and DRL10 subjects, respectively, compared with their vehicle controls. The phospho-CREB levels decreased in the nucleus accumbens and the hippocampus of drug-treated FI30 subjects but increased in the nucleus accumbens of drug-treated DRL10 subjects. CONCLUSIONS: Our results provide important insight into the neuropsychopharmacology of SKF83959, indicating that the drug-altered operant behavior is task dependent and related to regional-dependent changes of CaMKII-CREB signaling in the mesocorticolimbic DA systems.


Subject(s)
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/analogs & derivatives , Behavior, Animal/drug effects , Calcium-Calmodulin-Dependent Protein Kinase Type 2/drug effects , Conditioning, Operant/drug effects , Dopamine Agonists/pharmacology , Neostriatum/drug effects , Nucleus Accumbens/drug effects , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/administration & dosage , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology , Animals , Dopamine Agonists/administration & dosage , Male , Rats , Rats, Wistar , Receptors, Dopamine D1/agonists
4.
Oncol Rep ; 45(5)2021 05.
Article in English | MEDLINE | ID: mdl-33760205

ABSTRACT

Recent studies have reported the important roles of dopamine receptors in the early development and progression of glioblastoma (GBM). The present research aimed to explore the antineoplastic effect and intrinsic pathways of action of dopamine receptor D1 agonist SKF83959 on GBM cells. Flow cytometric analysis revealed a significant level of apoptotic cell death under SKF83959 treatment. SKF83959 administration increased intracellular calcium levels and oxidative stress through the phospholipase C/inositol trisphosphate pathway. The downstream calpains were activated and dysregulated by the increased calcium levels. The mitochondrial membrane potential­dependent staining assay revealed decreased mitochondrial transmembrane potential in GBM cells under SKF83959 treatment. The mitochondrial/cytosolic fraction and western blotting further demonstrated mitochondrial dysfunction and endoplasmic reticulum stress, followed by apoptosis. The calpain inhibitor, calpastatin, significantly reversed the increase in mitochondrial injury and endoplasmic reticulum stress and eventually ameliorated GBM cell apoptosis during SKF83959 treatment. Finally, the in vivo inhibitory efficacy of SKF83959 was verified in GBM xenograft models. In addition, immunohistochemistry and western blotting both revealed increased expression of calpains in xenograft GBM tissues. These results suggested a potential therapeutic target for human GBM treatment regarding calpain expression and activity regulation.


Subject(s)
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/analogs & derivatives , Brain Neoplasms/therapy , Calpain/metabolism , Glioblastoma/therapy , Receptors, Dopamine D1/agonists , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/therapeutic use , Aged , Animals , Apoptosis/drug effects , Brain/drug effects , Brain/pathology , Brain/surgery , Brain Neoplasms/pathology , Cell Line, Tumor , Chemotherapy, Adjuvant/methods , Endoplasmic Reticulum Stress/drug effects , Female , Glioblastoma/pathology , Humans , Male , Membrane Potential, Mitochondrial/drug effects , Middle Aged , Mitochondria/drug effects , Mitochondria/pathology , Neurosurgical Procedures , Receptors, Dopamine D1/metabolism , Signal Transduction/drug effects , Xenograft Model Antitumor Assays
5.
Chin J Physiol ; 64(1): 1-15, 2021.
Article in English | MEDLINE | ID: mdl-33642339

ABSTRACT

Dopamine (DA) is important for the performance of operant behavior as revealed by psychopharmacological studies that manipulate the activity of DA subtype receptors. However, the effects of SKF83959, an atypical DA D1 receptor agonist, on operant behavior and the underlying pharmacological mechanisms remain unclear. The present study sought to determine whether blockade of DA D1- and D2-subtyped receptors would reverse the operant behavior altered by SKF83959. Male rats were trained to respond on either a fixed-interval 30 s (FI30) schedule or a differential reinforcement of low-rate response 10 s (DRL10) schedule, two timing-relevant tasks but with distinct reinforcement contingencies. Pharmacological evaluation was conducted with injection of a selective D1 (or D2) receptor antagonist alone or in combined with SKF83959 (1.0 mg/kg) following a stable baseline of behavioral performance. The results showed that SKF83959 treatment alone significantly disrupted the performance of FI30 and DRL10 behaviors mainly by showing the decreases of the response-related measures, and the distinct profiles of the behavior altered by the drug were manifested by the qualitative analysis of inter-response time data on both tasks. The effects of SKF83959 were not significantly affected/reversed by the pretreatment of either SCH23390 or eticlopride injected at the doses of 0.02 and 0.06 mg/kg; however, a subtle reversal effect was observed in the treatment of low-dose eticlopride. Despite that these results confirm the FI30 and DRL10 behaviors changed by SKF83959, the absence of pharmacological reversal effect by DA receptor antagonist suggests that either D1- or D2-subtyped receptors may not play a critical role in the alteration of timing-relevant operant behavior produced by SKF83959.


Subject(s)
Dopamine Agonists , Receptors, Dopamine D1 , 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 , Behavior, Animal , Dopamine Agonists/pharmacology , Male , Rats , Rats, Sprague-Dawley
6.
Cell ; 184(4): 931-942.e18, 2021 02 18.
Article in English | MEDLINE | ID: mdl-33571431

ABSTRACT

The D1- and D2-dopamine receptors (D1R and D2R), which signal through Gs and Gi, respectively, represent the principal stimulatory and inhibitory dopamine receptors in the central nervous system. D1R and D2R also represent the main therapeutic targets for Parkinson's disease, schizophrenia, and many other neuropsychiatric disorders, and insight into their signaling is essential for understanding both therapeutic and side effects of dopaminergic drugs. Here, we report four cryoelectron microscopy (cryo-EM) structures of D1R-Gs and D2R-Gi signaling complexes with selective and non-selective dopamine agonists, including two currently used anti-Parkinson's disease drugs, apomorphine and bromocriptine. These structures, together with mutagenesis studies, reveal the conserved binding mode of dopamine agonists, the unique pocket topology underlying ligand selectivity, the conformational changes in receptor activation, and potential structural determinants for G protein-coupling selectivity. These results provide both a molecular understanding of dopamine signaling and multiple structural templates for drug design targeting the dopaminergic system.


Subject(s)
Receptors, Dopamine D1/chemistry , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/chemistry , Receptors, Dopamine D2/metabolism , Signal Transduction , 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 , Amino Acid Sequence , Conserved Sequence , Cryoelectron Microscopy , Cyclic AMP/metabolism , GTP-Binding Proteins/metabolism , HEK293 Cells , Humans , Ligands , Models, Molecular , Mutant Proteins/chemistry , Mutant Proteins/metabolism , Receptors, Adrenergic, beta-2/metabolism , Receptors, Dopamine D1/ultrastructure , Receptors, Dopamine D2/ultrastructure , Structural Homology, Protein
7.
Brain Res ; 1749: 147136, 2020 12 15.
Article in English | MEDLINE | ID: mdl-32980332

ABSTRACT

Fear-related anxiety disorders, such as social phobia and post-traumatic stress disorder, are partly explained by an uncontrollable state of fear. An emerging literature suggests dopamine receptor-1 (D1 receptor) in the amygdala is involved in the regulation of fear memory. An early study has reported that amygdaloid D1 receptor (D1R) is not coupled to the classic cAMP-dependent signal transduction. Here, we investigated whether SKF83959, a typical D1R agonist that mainly activates a D1-like receptor-dependent phosphatidylinositol (PI) signal pathway, facilitates fear extinction and reduces the return of extinguished fear. Interestingly, long-term loss of fearful memories can be induced through a combination of SKF83959 (1 mg/kg/day, i.p., once daily for one week) pharmacotherapy and extinction training. Furthermore, sub-chronic administration of SKF83959 after fear conditioning reduced fear renewal and reinstatement in the mice. We found that the activation D1R and PI signaling in the amygdala was responsible for the effect of SKF83959 on fear extinction. Additionally, SKF83959 significantly promoted the elevation of brain-derived neurotrophic factor (BDNF) expression, possibly by the cAMP response element binding protein (CREB) -directed gene transcription. Given the beneficial effects on extinction, SKF83959 may emerge as a candidate pharmacological approach for improving cognitive-behavioral therapy on fear-related anxiety disorders.


Subject(s)
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/analogs & derivatives , Amygdala/drug effects , Conditioning, Classical/drug effects , Dopamine Agonists/pharmacology , Extinction, Psychological/drug effects , Fear/drug effects , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology , Amygdala/metabolism , Animals , Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , Cyclic AMP Response Element-Binding Protein/genetics , Cyclic AMP Response Element-Binding Protein/metabolism , Male , Mice , Receptors, Dopamine D1/agonists
8.
Biol Sex Differ ; 11(1): 8, 2020 02 22.
Article in English | MEDLINE | ID: mdl-32087746

ABSTRACT

Depression and anxiety are more common among females than males and represent a leading cause of disease-related disability in women. Since the dopamine D1-D2 heteromer is involved in depression- and anxiety-like behavior, the possibility that the receptor complex may have a role in mediating sex differences in such behaviors and related biochemical signaling was explored.In non-human primate caudate nucleus and in rat striatum, females expressed higher density of D1-D2 heteromer complexes and a greater number of D1-D2 expressing neurons compared to males. In rat, the sex difference in D1-D2 expression levels occurred even though D1 receptor expression was lower in female than in male with no difference in D2 receptor expression. In behavioral tests, female rats showed faster latency to depressive-like behavior and a greater susceptibility to the pro-depressive and anxiogenic-like effects of D1-D2 heteromer activation by low doses of SKF 83959, all of which were ameliorated by the selective heteromer disrupting peptide, TAT-D1. The sex difference observed in the anxiety test correlated with differences in low-frequency delta and theta oscillations in the nucleus accumbens. Analysis of signaling pathways revealed that the sex difference in D1-D2 heteromer expression led to differences in basal and heteromer-stimulated activities of two important signaling pathways, BDNF/TrkB and Akt/GSK3/ß-catenin.These results suggest that the higher D1-D2 heteromer expression in female may significantly increase predisposition to depressive-like and anxiety-like behavior in female animals.


Subject(s)
Anxiety/metabolism , Caudate Nucleus/metabolism , Depression/metabolism , Nucleus Accumbens/metabolism , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/metabolism , Sex Characteristics , Signal Transduction , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/administration & dosage , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/analogs & derivatives , Animals , Anxiety/physiopathology , Behavior, Animal , Brain-Derived Neurotrophic Factor/metabolism , Caudate Nucleus/drug effects , Chlorocebus aethiops , Depression/physiopathology , Female , Glycogen Synthase Kinase 3/metabolism , Male , Nucleus Accumbens/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Rats, Sprague-Dawley , Receptor, trkB/metabolism , Receptors, Dopamine D1/agonists , Receptors, Dopamine D2/agonists , Signal Transduction/drug effects , beta Catenin/metabolism
9.
Cell Calcium ; 80: 103-111, 2019 06.
Article in English | MEDLINE | ID: mdl-30999216

ABSTRACT

The entorhinal cortex plays an important role in temporal lobe processes including learning and memory, object recognition, and contextual information processing. The alteration of the strength of synaptic inputs to the lateral entorhinal cortex may therefore contribute substantially to sensory and mnemonic functions. The neuromodulatory transmitter dopamine exerts powerful effects on excitatory glutamatergic synaptic transmission in the entorhinal cortex. Interestingly, inputs from midbrain dopamine neurons appear to specifically target clusters of excitatory cells located in the superficial layers of the entorhinal cortex. We have previously demonstrated that dopamine facilitates synaptic transmission through the activation of D1-like receptors. This facilitation of synaptic transmission is dependent on both activation of classical D1-like-receptors, and upon activation of dopamine receptors linked to increases in phospholipase C, inositol triphosphate (IP3), and intracellular calcium. In the present study we combined electrophysiological recordings of evoked excitatory postsynaptic currents with imaging of intracellular calcium using the fluorescent indicator fluo-4 to monitor calcium transients evoked by dopamine in electrophysiologically identified putative fan and pyramidal cells of the lateral entorhinal cortex. Bath application of dopamine (1 µM), or the phosphatidylinositol (PI)-linked D1-like-receptor agonist SKF83959 (5 µM), induced reliable and reversible increases in fluo-4 fluorescence and excitatory postsynaptic currents in fan cells, but not in pyramidal cells. In contrast, application of the classical D1-like-receptor agonist SKF38393 (10 µM) did not result in significant increases in fluorescence. Blocking release of calcium from internal stores by loading cells with the IP3 receptor blocker heparin (1 mM) or the ryanodine receptor blocker dantrolene (20 µM) abolished both the calcium transients and the facilitation of evoked synaptic currents induced by dopamine. Dopamine also induced calcium transients in fan cells when calcium was excluded from the extracellular medium, further indicating that the calcium transients are linked to release from internal stores. These results indicate that following D1-like-receptor binding, dopamine selectively induces transient elevations in intracellular calcium via activation of IP3 and ryanodine receptors, and that these elevations are linked to the facilitation of synaptic responses in putative layer II entorhinal cortex fan cells.


Subject(s)
Calcium/metabolism , Dopamine/metabolism , Dopaminergic Neurons/physiology , Entorhinal Cortex/physiology , Excitatory Postsynaptic Potentials/physiology , 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 , Calcium Signaling , Cells, Cultured , Dopamine Agonists/pharmacology , Entorhinal Cortex/pathology , Male , Rats , Rats, Inbred Strains , Receptors, Dopamine D1/metabolism
10.
Neuropharmacology ; 144: 358-367, 2019 01.
Article in English | MEDLINE | ID: mdl-30439417

ABSTRACT

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique used to modulate neuronal excitability via externally applied electric fields. Despite the positive effects of tDCS in a wide range of neurological disorders in humans, its mechanism of action remains poorly understood. Here we investigated cellular and molecular mechanisms underlying the aftereffects of anodal tDCS on the induction of long-term potentiation (LTP), a cellular correlate of learning and memory, at Schaffer collateral-CA1 synapses. We found that hippocampal CA1 LTP was enhanced in slices from rats subjected to anodal tDCS with no significant changes in basal synaptic function. The enhancing effect of tDCS on LTP was still maintained 12 h after stimulation. Treatment of ex vivo hippocampal slices from tDCS-treated rats with tropomyosin receptor kinase B (TrkB) inhibitor ANA-12, but not D1 receptor antagonist SKF-83566 or ß2-adrenergic receptor antagonist propranolol, efficiently prevented tDCS-induced enhancement of LTP. The tDCS-treated rats exhibited higher levels of brain derived neurotrophic factor (BDNF) in the hippocampal CA1 region compared to sham-treated rats. Anodal tDCS also enhances memory performance in hippocampal-dependent passive avoidance learning task, and this enhancement can be blocked by ANA-12 pretreatment. Altogether, our results underscore the importance of BDNF/TrkB-mediated metaplastic effect of anodal tDCS on the induction of hippocampal CA1 LTP.


Subject(s)
Brain-Derived Neurotrophic Factor/metabolism , CA1 Region, Hippocampal/metabolism , Long-Term Potentiation/physiology , Memory/physiology , Transcranial Direct Current Stimulation , 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 , Adrenergic beta-Antagonists/pharmacology , Animals , Avoidance Learning/drug effects , Avoidance Learning/physiology , Azepines/pharmacology , Benzamides/pharmacology , CA1 Region, Hippocampal/drug effects , Long-Term Potentiation/drug effects , Male , Memory/drug effects , Propranolol/pharmacology , Random Allocation , Rats, Sprague-Dawley , Receptor, trkB/antagonists & inhibitors , Receptor, trkB/metabolism , Receptors, Dopamine D1/antagonists & inhibitors , Receptors, Dopamine D1/metabolism , Synapses/drug effects , Synapses/metabolism , Tissue Culture Techniques
11.
Biol Pharm Bull ; 41(3): 427-434, 2018.
Article in English | MEDLINE | ID: mdl-29491219

ABSTRACT

Patients with Alzheimer's disease (AD) always have cognitive impairments. In this study we investigated whether 6-chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) has improvements on cognitive dysfunction. The scopolamine model of dementia was used to investigate the anti-amnesic activities of SKF83959, and then, Western blotting and pharmacological inhibitor were used to assay the anti-amnesic mechanisms of SKF83959. It was found that SKF83959 administration significantly improved the scopolamine-induced memory impairments in the passive avoidance task, Y-maze test, and Morris water maze task. Moreover, SKF83959 treatment significantly antagonized the down-regulating effects of scopolamine on brain-derived neurotrophic factor (BDNF) signaling cascade in the hippocampus, but not cortex. Importantly, the usage of K252a, a selective inhibitor of tyrosine kinase B (TrkB), significantly attenuated the protective effects of SKF83959 in the scopolamine model. Collectively, this study shows that SKF83959 has beneficial effects in the scopolamine model of dementia by modulation of hippocampal BDNF signaling, implying a novel and potential therapeutic agent for treating dementia in AD.


Subject(s)
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/analogs & derivatives , Dementia/chemically induced , Dementia/drug therapy , Muscarinic Antagonists , Scopolamine , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/therapeutic use , Amnesia/chemically induced , Amnesia/drug therapy , Amnesia/psychology , Animals , Avoidance Learning/drug effects , Brain-Derived Neurotrophic Factor/drug effects , Carbazoles/pharmacology , Dementia/psychology , Hippocampus/drug effects , Indole Alkaloids/pharmacology , Male , Maze Learning/drug effects , Memory/drug effects , Mice , Mice, Inbred ICR , Protein-Tyrosine Kinases/antagonists & inhibitors , Psychomotor Performance/drug effects , Signal Transduction/drug effects
12.
Eur J Neurosci ; 46(4): 2015-2025, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28677227

ABSTRACT

Deficits in neuronal network synchrony in hippocampus and prefrontal cortex have been widely demonstrated in disorders of cognitive dysfunction, including schizophrenia and Alzheimer's disease. The atypical dopamine agonist SKF 83959 has been shown to increase brain-derived neurotrophic factor signalling and suppress activity of glycogen synthase kinase-3 in PFC, two processes important to learning and memory. The purpose of this study was to therefore evaluate the impact of SKF 83959 on oscillatory deficits in methylazoxymethanol acetate (MAM) rat model of schizophrenia. To achieve this, local field potentials were recorded simultaneously from the hippocampus and prefrontal cortex of anesthetized rats at 15 and 90 min following both acute and repeated administration of SKF 83959 (0.4 mg/kg). In MAM rats, but not controls, repeated SKF 83959 treatment increased signal amplitude in hippocampus and enhanced the spectral power of low frequency delta and theta oscillations in this region. In PFC, SKF 83959 increased delta, theta and gamma spectral power. Increased HIP-PFC theta coherence was also evident following acute and repeated SKF 83959. In apparent contradiction to these oscillatory effects, in MAM rats, SKF 83959 inhibited spatial learning and induced a significant increase in thigmotactic behaviour. These findings have uncovered a previously unknown role for SKF 83959 in the positive regulation of hippocampal-prefrontal cortical oscillatory network activity. As SKF 83959 is known to have affinity for a number of receptors, delineating the receptor mechanisms that mediate the positive drug effects on neuronal oscillations could have significant future implications in disorders associated with cognitive dysfunction.


Subject(s)
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/analogs & derivatives , Cognitive Dysfunction/drug therapy , Disease Models, Animal , Dopamine Agonists/pharmacology , Hippocampus/drug effects , Nerve Net/drug effects , Prefrontal Cortex/drug effects , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/therapeutic use , Animals , Cognitive Dysfunction/physiopathology , Dopamine Agonists/therapeutic use , Hippocampus/physiology , Male , Maze Learning/drug effects , Maze Learning/physiology , Nerve Net/physiology , Prefrontal Cortex/physiology , Rats , Rats, Sprague-Dawley , Receptors, Dopamine/physiology
13.
Autophagy ; 13(8): 1404-1419, 2017 Aug 03.
Article in English | MEDLINE | ID: mdl-28613975

ABSTRACT

Dopamine agonists such as bromocriptine and cabergoline have been successfully used in the treatment of pituitary prolactinomas and other neuroendocrine tumors. However, their therapeutic mechanisms are not fully understood. In this study we demonstrated that DRD5 (dopamine receptor D5) agonists were potent inhibitors of pituitary tumor growth. We further found that DRD5 activation increased production of reactive oxygen species (ROS), inhibited the MTOR pathway, induced macroautophagy/autophagy, and led to autophagic cell death (ACD) in vitro and in vivo. In addition, DRD5 protein was highly expressed in the majority of human pituitary adenomas, and treatment of different human pituitary tumor cell cultures with the DRD5 agonist SKF83959 resulted in growth suppression, and the efficacy was correlated with the expression levels of DRD5 in the tumors. Furthermore, we found that DRD5 was expressed in other human cancer cells such as glioblastomas, colon cancer, and gastric cancer. DRD5 activation in these cell lines suppressed their growth, inhibited MTOR activity, and induced autophagy. Finally, in vivo SKF83959 also inhibited human gastric cancer cell growth in nude mice. Our studies revealed novel mechanisms for the tumor suppressive effects of DRD5 agonists, and suggested a potential use of DRD5 agonists as a novel therapeutic approach in the treatment of different human tumors and cancers.


Subject(s)
Autophagy , Pituitary Neoplasms/metabolism , Pituitary Neoplasms/pathology , Receptors, Dopamine D5/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 , Autophagosomes/drug effects , Autophagosomes/metabolism , Autophagosomes/ultrastructure , Autophagy/drug effects , Cabergoline , Cell Line, Tumor , Cell Proliferation/drug effects , Ergolines/pharmacology , Ergolines/therapeutic use , Humans , Mice, Nude , Pituitary Neoplasms/drug therapy , Pituitary Neoplasms/ultrastructure , Rats , Reactive Oxygen Species/metabolism , Receptors, Dopamine D5/genetics , Superoxide Dismutase/metabolism , TOR Serine-Threonine Kinases/metabolism
14.
Neuroimage ; 152: 119-129, 2017 05 15.
Article in English | MEDLINE | ID: mdl-28259782

ABSTRACT

fMRI was used to study late effects of dopamine D1/5 receptor activation on hippocampal signal processing and signal propagation to several target regions. The dopamine D1/5 receptor agonists SKF83959 and SKF38393 were intraperitoneally applied without, immediately before or 7 days after electrical stimulation of the right perforant pathway with bursts of high-frequency pulses. Control animals received a 0.9% NaCl solution. One day after D1/5 receptor activation, the perforant pathway was stimulated and the induced BOLD responses in the right hippocampus and its target regions, left hippocampus (l-HC) and medial prefrontal cortex (mPFC), were measured. Depending on the temporal relation between dopamine receptor activation and the first perforant pathway stimulation the induced BOLD response pattern differed. When applied without concurrent perforant pathway stimulation, the agonists caused region-selective increases in the induced BOLD responses: the effect of SKF83959 was evident in the mPFC whereas that of SKF38393 was confined to the l-HC. When applied in conjunction with perforant pathway stimulation, either agonist caused increased BOLD responses in both regions. In contrast, when applied 7 days after perforant pathway stimulation, neither SKF83959 nor SKF38393 modified the BOLD responses in the mPFC or l-HC 1day later. These findings suggest that (i) activation of dopamine D1/5 receptors alone is sufficient to modify stimulus-induced BOLD responses in target regions of the right hippocampus 24h later, and (ii), the history of previous stimulations crucially affects the impact of dopamine receptor activation on stimulus-induced BOLD responses.


Subject(s)
Hippocampus/physiology , Receptors, Dopamine D1/physiology , Receptors, Dopamine D5/physiology , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/administration & dosage , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/analogs & derivatives , Animals , Brain Mapping , Dopamine Agonists/administration & dosage , Electric Stimulation , Hippocampus/drug effects , Magnetic Resonance Imaging , Male , Perforant Pathway/physiology , Prefrontal Cortex/drug effects , Prefrontal Cortex/physiology , Rats, Wistar , Receptors, Dopamine D1/agonists , Receptors, Dopamine D5/agonists
15.
Neuropsychopharmacology ; 41(8): 2072-81, 2016 07.
Article in English | MEDLINE | ID: mdl-26763483

ABSTRACT

Dopamine is critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine's function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in appetitive tasks. A parallel and growing literature indicates that dopamine signaling is involved in consolidation of memories into stable representations in aversive tasks such as fear conditioning. Relatively little is known about how dopamine may modulate memories that form during extinction, when organisms learn that the relation between previously associated events is severed. We investigated whether fear and reward extinction share common mechanisms that could be enhanced with dopamine D1/5 receptor activation. Pharmacological activation of dopamine D1/5 receptors (with SKF 81297) enhanced extinction of both cued and contextual fear. These effects also occurred in the extinction of cocaine-induced conditioned place preference, suggesting that the observed effects on extinction were not specific to a particular type of procedure (aversive or appetitive). A cAMP/PKA biased D1 agonist (SKF 83959) did not affect fear extinction, whereas a broadly efficacious D1 agonist (SKF 83822) promoted fear extinction. Together, these findings show that dopamine D1/5 receptor activation is a target for the enhancement of fear or reward extinction.


Subject(s)
Extinction, Psychological/physiology , Fear/physiology , Receptors, Dopamine D1/physiology , Receptors, Dopamine D5/physiology , Reward , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/administration & dosage , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/analogs & derivatives , Animals , Benzazepines/administration & dosage , Cocaine/administration & dosage , Conditioning, Classical/drug effects , Cyclic AMP/metabolism , Extinction, Psychological/drug effects , Fear/drug effects , Male , Mice, Inbred C57BL , Receptors, Dopamine D1/agonists , Receptors, Dopamine D5/agonists , beta-Arrestins/metabolism
16.
PLoS One ; 10(7): e0131948, 2015.
Article in English | MEDLINE | ID: mdl-26133167

ABSTRACT

The lateral entorhinal cortex receives strong inputs from midbrain dopamine neurons that can modulate its sensory and mnemonic function. We have previously demonstrated that 1 µM dopamine facilitates synaptic transmission in layer II entorhinal cortex cells via activation of D1-like receptors, increased cAMP-PKA activity, and a resulting enhancement of AMPA-receptor mediated currents. The present study assessed the contribution of phosphatidylinositol (PI)-linked D1 receptors to the dopaminergic facilitation of transmission in layer II of the rat entorhinal cortex, and the involvement of phospholipase C activity and release of calcium from internal stores. Whole-cell patch-clamp recordings of glutamate-mediated evoked excitatory postsynaptic currents were obtained from pyramidal and fan cells. Activation of D1-like receptors using SKF38393, SKF83959, or 1 µM dopamine induced a reversible facilitation of EPSCs which was abolished by loading cells with either the phospholipase C inhibitor U-73122 or the Ca2+ chelator BAPTA. Neither the L-type voltage-gated Ca2+ channel blocker nifedipine, nor the L/N-type channel blocker cilnidipine, blocked the facilitation of synaptic currents. However, the facilitation was blocked by blocking Ca2+ release from internal stores via inositol 1,4,5-trisphosphate (InsP3) receptors or ryanodine receptors. Follow-up studies demonstrated that inhibiting CaMKII activity with KN-93 failed to block the facilitation, but that application of the protein kinase C inhibitor PKC(19-36) completely blocked the dopamine-induced facilitation. Overall, in addition to our previous report indicating a role for the cAMP-PKA pathway in dopamine-induced facilitation of synaptic transmission, we demonstrate here that the dopaminergic facilitation of synaptic responses in layer II entorhinal neurons also relies on a signaling cascade dependent on PI-linked D1 receptors, PLC, release of Ca2+ from internal stores, and PKC activation which is likely dependent upon both DAG and enhanced intracellular Ca2+. These signaling pathways may collaborate to enhance sensory and mnemonic function in the entorhinal cortex during tonic release of dopamine.


Subject(s)
Entorhinal Cortex/metabolism , Glutamic Acid/metabolism , Phosphatidylinositols/metabolism , Receptors, Dopamine/metabolism , Synaptic Transmission/physiology , 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 , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Dopamine/pharmacology , Dopamine Agonists/pharmacology , Entorhinal Cortex/drug effects , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , Male , Neurons/drug effects , Neurons/metabolism , Rats , Rats, Long-Evans , Synaptic Transmission/drug effects
17.
J Neurochem ; 134(5): 904-14, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26031312

ABSTRACT

Recent studies have shown that sigma-1 receptor orthodox agonists can inhibit neuroinflammation. SKF83959 (3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine), an atypical dopamine receptor-1 agonist, has been recently identified as a potent allosteric modulator of sigma-1 receptor. Here, we investigated the anti-inflammatory effects of SKF83959 in lipopolysaccharide (LPS)-stimulated BV2 microglia. Our results indicated that SKF83959 significantly suppressed the expression/release of the pro-inflammatory mediators, such as tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), inducible nitric oxide synthase (iNOS), and inhibited the generation of reactive oxygen species. All of these responses were blocked by selective sigma-1 receptor antagonists (BD1047 or BD1063) and by ketoconazole (an inhibitor of enzyme cytochrome c17 to inhibit the synthesis of endogenous dehydroepiandrosterone, DHEA). Additionally, we found that SKF83959 promoted the binding activity of DHEA with sigma-1 receptors, and enhanced the inhibitory effects of DHEA on LPS-induced microglia activation in a synergic manner. Furthermore, in a microglia-conditioned media system, SKF83959 inhibited the cytotoxicity of conditioned medium generated by LPS-activated microglia toward HT-22 neuroblastoma cells. Taken together, our study provides the first evidence that allosteric modulation of sigma-1 receptors by SKF83959 inhibits microglia-mediated inflammation. SKF83959 is a potent allosteric modulator of sigma-1 receptor. Our results indicated that SKF83959 enhanced the activity of endogenous dehydroepiandrosterone (DHEA) in a synergic manner, and inhibited the activation of BV2 microglia and the expression/release of the pro-inflammatory mediators, such as tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), inducible nitric oxide synthase (iNOS).


Subject(s)
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/analogs & derivatives , Microglia/drug effects , Receptors, sigma/drug effects , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology , Allosteric Regulation , Animals , Anti-Inflammatory Agents/pharmacology , Cell Line , Culture Media, Conditioned/pharmacology , Dehydroepiandrosterone/metabolism , Enzyme Induction/drug effects , Ethylenediamines/pharmacology , Interleukin-10/metabolism , Ketoconazole/pharmacology , Lipopolysaccharides/pharmacology , Male , Mice , Microglia/pathology , Narcotic Antagonists/pharmacology , Neuroblastoma/pathology , Neuroimmunomodulation/drug effects , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/biosynthesis , Nitric Oxide Synthase Type II/genetics , Piperazines/pharmacology , Protein Binding/drug effects , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Receptors, sigma/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolism , Sigma-1 Receptor
18.
Br J Pharmacol ; 172(16): 4052-65, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25989224

ABSTRACT

BACKGROUND AND PURPOSE: Application of orthosteric sigma-1 receptor agonists as anti-seizure drugs has been hindered by questionable efficacy and potential adverse effects. Here, we have investigated the anti-seizure effects of the novel and potent allosteric modulator of sigma-1 receptors, SKF83959 and its derivative SOMCL-668 (3-methyl-phenyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol). EXPERIMENTAL APPROACH: The anti-seizure effects of SKF83959 were investigated in three mouse models, maximal electroshock seizures, pentylenetetrazole-induced convulsions and kainic acid-induced 'status epilepticus'. Also, in rats, the cortical epileptiform activity induced by topical application of picrotoxin was recorded in electrocorticograms. In rat hippocampal brain slices, effects of the drugs on the high potassium-evoked epileptiform local field potentials were studied. Anti-seizure activities of SOMCL-668, a newly developed sigma-1 receptor selective allosteric modulator, were also investigated. KEY RESULTS: SKF83959 (20, 40 mg·kg(-1) ) exhibited anti -seizure actitity in the three mouse models and reduced the cortical epileptiform activity without alteration of spontaneous motor activity and motor coordination. These effects were blocked by the sigma-1 receptor antagonist BD1047, but not the dopamine D1 receptor antagonist SCH23390. SKF83959 alone did not directly inhibit the epileptiform firing of CA3 neurons induced by high potassium in hippocampal slices, but did potentiate inhibition by the orthosteric sigma-1 receptor agonist SKF10047. Lastly, a selective sigma-1 receptor allosteric modulator SOMCL-668, which does not bind to dopamine receptors, exerted similar anti-seizure activities. CONCLUSIONS AND IMPLICATIONS: SKF83959 and SOMCL-668 displayed anti-seizure activities, indicating that allosteric modulation of sigma-1 receptors may provide a novel approach for discovering new anti-seizure drugs.


Subject(s)
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/analogs & derivatives , Anticonvulsants/therapeutic use , Benzazepines/therapeutic use , Receptors, sigma/metabolism , Seizures/drug therapy , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/therapeutic use , Animals , Anticonvulsants/pharmacology , Benzazepines/pharmacology , Hippocampus/drug effects , Hippocampus/physiology , Male , Mice, Inbred C57BL , Motor Activity/drug effects , Rats, Sprague-Dawley , Seizures/metabolism , Sigma-1 Receptor
19.
Brain Res ; 1615: 71-79, 2015 Jul 30.
Article in English | MEDLINE | ID: mdl-25912434

ABSTRACT

Dopamine, a key neurotransmitter mediating the rewarding effects, exerts some of its effects by modulating neuronal excitability of striatal medium spiny neurons. A D1-like dopamine receptor-dependent phosphatidylinositol signal pathway exists in the striatum, however little is known about its role in the dopaminergic modulation of striatal neuronal excitability. 3-Methyl-6-chloro-7, 8-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) is a selective D1 receptor agonist with high-affinity. Here, we observed its effect on the voltage-gated sodium channels (VGSCs) in primary cultured striatal neurons by whole cell patch-clamp technique. We found that SKF83959 induced an inhibition on VGSCs in a dose-dependent manner in striatal neurons (IC50 value: 3.31 ± 0.39 µM), which could be prevented by antagonist of D1 receptor, but not that of D2, α1 adrenergic, or cholinoceptor. The effect of SKF83959 on VGSCs was also prevented by pretreatment with inhibitors of phospholipase C (PLC) and protein kinases C (PKC), but the inositol-1,4,5-phosphate 3 (IP3) antagonist did not occlude SKF83959 (1µM)-induced reduction of VGSCs. These data indicate that SKF83959 inhibits VGSCs in cultured striatal neurons via D1-like receptor-phosphatidylinositol-PKC pathway, which may underlie the dopaminergic modulation on striatal neuronal excitability.


Subject(s)
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/analogs & derivatives , Corpus Striatum/metabolism , Neurons/metabolism , Receptors, Dopamine D1/metabolism , Type C Phospholipases/metabolism , Voltage-Gated Sodium Channels/metabolism , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology , Animals , Cells, Cultured , Corpus Striatum/drug effects , Dose-Response Relationship, Drug , Female , Male , Membrane Potentials/drug effects , Neurons/drug effects , Rats, Sprague-Dawley , Receptors, Dopamine D1/agonists , Signal Transduction/drug effects , Voltage-Gated Sodium Channel Blockers/pharmacology
20.
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
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