Opioid use disorder (OUD) has become a considerable global public health challenge; however, potential medications for the management of OUD that are effective, safe, and nonaddictive are not available. Accumulating preclinical evidence indicates that antagonists of the dopamine D₃ receptor (D₃R) have effects on addiction in different animal models. We have previously reported that YQA14, a D₃R antagonist, exhibits very high affinity and selectivity for D₃Rs over D₂Rs, and is able to inhibit cocaine- or methamphetamine-induced reinforcement and reinstatement in self-administration tests. In the present study, our results illustrated that YQA14 dose-dependently reduced infusions under the fixed-ratio 2 procedure and lowered the breakpoint under the progressive-ratio procedure in heroin self-administered rats, also attenuated heroin-induced reinstatement of drug-seeking behavior. On the other hand, YQA14 not only reduced morphine-induced expression of conditioned place preference but also facilitated the extinguishing process in mice. Moreover, we elucidated that YQA14 attenuated opioid-induced reward or reinforcement mainly by inhibiting morphine-induced up-regulation of dopaminergic neuron activity in the ventral tegmental area and decreasing dopamine release in the nucleus accumbens with a fiber photometry recording system. These findings suggest that D₃R might play a very important role in opioid addiction, and YQA14 may have pharmacotherapeutic potential in attenuating opioid-induced addictive behaviors dependent on the dopamine system.
Rats ; Mice ; Animals ; Analgesics, Opioid ; Dopamine ; Heroin/pharmacology* ; Dopamine Antagonists/pharmacology* ; Receptors, Dopamine D3/metabolism* ; Morphine/pharmacology* ; Behavior, Addictive/drug therapy* ; Self Administration

BACKGROUND: Models of attention deficit hyperactivity disorder(ADHD) that have proposed a hypodopaminergic state resulting in hypofunction of the prefrontal circuitry have assumed a unitary dopamine system, which largely ignores the distinct functional differences between mesocortical dopamine system and nigrostriatal dopamine system. PURPOSE: The author's goal was to develop a pathophysiological model for ADHD with greater explanotory power than dopaminergic hypofunction hypothesis in prefronal circuitry. MATERIALS AND METHODS: Published clinical findings on ADHD were integrated with data from genetic, pharmacological, neuroimaging studies in human and animals. RESULTS: Molecular genetic studies suggest that three genes may increase the susceptibility to ADHD. The three candidate genes associated with ADHD are each involved in dopaminergic function, and this consistent with the neurobiologic studies implicating catecholamines in the etiology of ADHD. Pharmacological data also provide compelling support for dopamine and noradrenergic hypothesis of ADHD. Neuroimaging studies lend substantial support for the hypothesis that right-sided abnormalities of prefrontal-basal ganglia circuit would be found in ADHD. CONCLUSIONS: The present hypothesis takes advantage of the major differences between the two pertinent dopamine systems. Mesocortical dopamine system, which largely lacks inhibitory autoreceptors, is ideally positioned to regulate cortical inputs, thus improving the signal-to-noise ratio for biologically valued signals. In this circuit, therapeutic doses of stimulants are hypothesized to increase postsynaptic dopamine effects and enhance executive functions. By contrast, symptoms of hyperactivity/impulsivity in ADHD are hypothesized to be associated with relative overactivity of nigrostriatal circuit. This nigrostriatal circuit is tightly regulated by inhibitory autoreceptoors as well as by long distance feedback from the cortex, and slow diffusion of therapeutic doses of stimulant via oral administration is hypothesized to produce a net inhibition of dopaminergic neurotransmission and improves hyperactivity.
Administration, Oral ; Animals ; Attention Deficit Disorder with Hyperactivity* ; Autoreceptors ; Catecholamines ; Diffusion ; Dopamine ; Dopamine Agents ; Executive Function ; Ganglia ; Humans ; Molecular Biology ; Neuroimaging ; Signal-To-Noise Ratio ; Synaptic Transmission

OBJECTIVES: It has been suggested that dopamine as well as serotonin were related to the pathophysiology of obsessive-compulsive disorder (OCD). Thus, many studies were performed to nivestigate brain regions and their association with dopamine in OCD patients. Recently, we have been able to monitor the density of the dopamine transporter (DAT) in the basal ganglia using I-123N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(4-chlorophenyl) tropane (I-123 IPT) SPECT, to evaluate the activity of the presynaptic dopamine function. In present study, we investigated the DAT density of the basal ganglia using I-123 IPT SPECT in patients with OCD. METHODS: Fifteen patients with OCD and nineteen normal control group were included in this study. We performed brain SPECT 2 hours after the intravenous administration of I-123N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(4-chlorophenyl) tropane (I-123 IPT) and carried out both quantitative and qualitative analyses using the SPECT, which were reconstructed for the assessment of the specific/nonspecific DAT binding ratio in basal ganglia. We then investigated the correlation between the severity of OCD symptoms assessed with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and the specific/nonspecific DAT binding ratio of basal ganglia. RESULTS: Patients with OCD showed a significantly increased specific/nonspecific DAT binding ratio in right basal ganglia compared with normal controls and did not show a significantly increased specific/nonspecific DAT binding ratio, and an increased tendency in the specific/nonspecific DAT binding ratio in left basal ganglia (Rt:Z=2.584, P=0.009, Lt:=1.873, P=0.060). We found no significant correlation between the total scores of the Y-BOCS and the specific/nonspecific DAT binding ratio of basal ganglia. CONCLUSIONS: The data of this study suggest that dopamine in basal ganglia plays an important role in fronto-subcortical circuit, which are already known as a site of the pathophysiological mechanism of OCD.
Administration, Intravenous ; Basal Ganglia* ; Brain ; Dopamine Plasma Membrane Transport Proteins* ; Dopamine* ; Humans ; Obsessive-Compulsive Disorder* ; Serotonin ; Tomography, Emission-Computed, Single-Photon*

OBJECTIVES: Previous studies in patients with Tourette's disorder suggested presynaptic dopaminergic dysfunction, demonstrating increased dopamine densities. In present study, we investigated dopamine transporter densities using I-123N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(4-chlorophenyl)tropane(I-123-IPT)-SPECT in drug-naive children with Tourette's disorder and postulated that dopamine transporter density reflected dopamine concentrations. METHODS: Eight drug-naive children with Tourette's disorder and six normal children were included in the with the brain SPECT 2 hours after an intravenous administration of I-123-IPT. Obtained SPECT data were reconstructed for the assessment of specific/nonspecific dopamine transporter binding ratio of basal ganglia and were evaluated both quantitatively and qualitatively. We investigated correlation between total tic severity of children with Tourette's disorder assessed with YGTSS and specific/nonspecific binding ratio of basal ganglia. RESULTS: Drug-naive children with Tourette's disorder had a significantly greater increase of speciffic/nonspecific dopamine transporter binding ratio of left basal ganglia than normal children. However, no significant differences in specific/nonspecific dopamine transporter binding ratio of right basal ganglia were found between children with Tourette's disorder and normal children. Also, we found no significant correlation between total tic severity of children with Tourette's disorder and specific/ nonspecific binding ratio of basal ganglia. CONCLUSION: These findings support the hypothesis of dopamine dysregulation in presynaptic dopamine function of the basal ganglia in the pathophysiology of Tourette's disorder.
Administration, Intravenous ; Basal Ganglia* ; Brain ; Child* ; Dopamine Plasma Membrane Transport Proteins* ; Dopamine* ; Humans ; Tics ; Tomography, Emission-Computed, Single-Photon* ; Tourette Syndrome*

Controlled mechanical ventilation (CMV) with positive and expiratory pressure (PEEP) is often used to improve the pulmonary gas exchange in patients with acute respiratory distress syndrome. However, this ventilatory technique may induce hemodynamic and hormonal changes which may lead to vital organ dysfunction, such as oliguria. Low dose dopamine, acting as a dopaminergic receptor agonist, may improve vital organ perfusions, i.e. renal, mesenteric and coronary perfusions. The purpose of this current study was to evaluate the effects of low dose dopamine on renal function and hemodynamic change during controlled mechanical ventilation with PEEP. The study was performed on 10 patients treated with PEEP in the surgical intensive care unit. Starting with 0 cmH2O of PEEP and adding 4 cmH2O of PEEP at 4-hour intervals until it reached 12 cmH2O of PEEP, dopamine, 2 ug/kg/min, was selectively, administered, intravenously during the last two hours of each four hour intervals. Following each procedure, hemodynamic parameters, urine output, creatinine clearance and fractional excretion of sodium were measured. The cardiac index and mean arterial pressure had both decreased, but the mean pulmonary arterial pressure was increased at 12 cmH2O of PEEP compared with 0 cmH2O of PEEP in both groups with and without low dose dopamine. The main result of this study was that low dose dopamine attenuated the decrease of the cardiac index, urine output and creatinine clearance induced by mechanical ventilation with PEEP at 12 cmH2O.
Adult ; Aged ; Dopamine/therapeutic use ; Dopamine/administration & dosage* ; Dose-Response Relationship, Drug ; Female ; Hemodynamics/drug effects ; Human ; Kidney/physiopathology* ; Kidney/drug effects* ; Male ; Middle Age ; Positive-Pressure Respiration*

PURPOSE: Attention deficit hyperactivity disorder (ADHD) has been known as psychiatric disorder in childhood associated with dopamine dysregulation. In present study, we investigated changes in dopamine transporter (DAT) density of the basal ganglias using I-123 N- (3-iodopropen-2-yl) -2-carbomethoxy-3beta- (4-chlorophenyl) tropane [I-123 IPT] SPECT in children with ADHD before and after methylphenidate treatment. MATERIALS AND METHOD: Nine drug-naive children with ADHD and seven normal children were included in the study. We performed brain SPECT two hours after the intravenous administration of I-123 IPT and made both quantitative and qualitative analyses using the obtained SPECT data, which were reconstructed for the assessment of specific/nonspecific DAT binding ratios in the basal ganglia. All children with ADHD reperformed [123I]IPT SPECT after treatment with methylphenidate (0.7mg/kg/d) during about 8 weeks. SPECT data reconstructed for the assessment of specific/nonspecific DAT binding ratio of the basal ganglia were compared between before and after treatment methylphenidate. We investigated correlation between the change of ADHD symptom severity assessed with ADHD rating scale-IV and specific/nonspecific DAT binding ratio of basal ganglia. RESULTS: Children with ADHD had a significantly greater specific/nonspecific DAT binding ratio of the basal ganglia comparing to normal children (Right: z = 2.057, p = 0.041; Left: z = 2.096, p = 0.032). Under treatment with methylphenidate in all children with ADHD, specific/nonspecific DAT binding ratio of both basal ganglia decreased significantly greater than before treatment with methylphenidate (Right: t = 3.239, p = 0.018; Left: t = 3.133, p = 0.020). However, no significant correlation between the change of ADHD symptom severity scores and specific/nonspecific DAT binding ratio of the basal ganglia were found. CONCLUSIONS: These findings support the complex dysregulation of the dopaminergic neurotransmitter system in children with ADHD.
Administration, Intravenous ; Attention Deficit Disorder with Hyperactivity* ; Basal Ganglia* ; Brain ; Child* ; Dopamine Plasma Membrane Transport Proteins* ; Dopamine* ; Humans ; Methylphenidate ; Neurotransmitter Agents ; Tomography, Emission-Computed, Single-Photon

OBJECTIVE: ADHD has been known as a psychiatric disorder in childhood associated with dopamine dysregulation. In the present study, we investigated dopamine transporter (DAT) density using I-123N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(4-chlorophenyl) tropane (I-123-IPT)-SPECT in children with ADHD on the hypothesis that alterations of DAT density in the basal ganglia were suggestive of dopaminergic dysfunction in children with ADHD. METHODS: Nine drug-naive children with ADHD and six normal children were included in the study. We performed brain SPECT two hours after the intravenous administration of I-123-IPT and made both quantitative and qualitative analyses using the obtained SPECT data, which were reconstructed for the assessment of specific/nonspecific DAT binding ratios in the basal ganglia. We then investigated the correlation between ADHD Rating Scale (ARS) scores of children with ADHD and specific/nonspecific DAT binding ratios in the basal ganglia. RESULTS: Children with ADHD had significantly greater specific/nonspecific DAT binding ratio of the basal ganglia comparing to normal children. However, no significant correlation were found between ARS scores of children with ADHD and specific/nonspecific DAT binding ratio of basal ganglia in children with ADHD. CONCLUSION: These findings support the complex dysregulation of the dopaminergic neurotransmitter system in children with ADHD.
Administration, Intravenous ; Attention Deficit Disorder with Hyperactivity* ; Basal Ganglia* ; Brain ; Child* ; Dopamine Plasma Membrane Transport Proteins* ; Dopamine* ; Humans ; Neurotransmitter Agents ; Tomography, Emission-Computed, Single-Photon*

PURPOSE: Tourette's disorder (TD), which is characterized by multiple waxing and waning motor tics and one or more vocal tics, is known to be associated with abnormalities in the dopaminergic system. To testify our hypothesis that risperidone would improve tic symptoms of TD patients through the change of the dopaminergic system, we measured the dopamine transporter (DAT) densities between drug-naive children with TD and normal children, and investigated the DAT density before and after treatment with risperidone in drug-naive children with TD, using iodine-123 labelled N- (3-iodopropen-2-yl) -2beta-carbomethoxy -3beta- (4-chlorophenyl) tropane ([123I]IPT) single photon emission computed tomography (SPECT). MATERIALS AND METHODS: [123I]IPT SPECT imaging and Yale Global Tic Severity Scale-Korean version (YGTSS-K) for assessing the tic symptom severity were carried out before and after treatment with risperidone for 8 weeks in nine drug-naive children with TD. Eleven normal children also underwent SPECT imaging 2 hours after an intravenous administration of [123I]IPT. RESULTS: Drug-naive children with TD had a significantly greater increase in the specific/nonspecific DAT binding ratio of both basal ganglia compared with the normal children. However, no significant difference in the specific/nonspecific DAT binding ratio of the basal ganglia before and after treatment with risperidone in children with TD was found, although tic symptoms were significantly improved with risperidone. CONCLUSION: These findings suggest that DAT densities are directly associated with the pathophysiology of TD, however, that the effect of risperidone on tic symptoms in children with TD is not attributed to the change of dopaminergic system.
Administration, Intravenous ; Basal Ganglia ; Child* ; Dopamine Plasma Membrane Transport Proteins* ; Dopamine* ; Humans ; Risperidone* ; Tics ; Tomography, Emission-Computed, Single-Photon* ; Tourette Syndrome*

OBJECTIVES: ADHD has been known as psychiatric disorder in childhood associated with dopamine dysregulation. The symptoms of ADHD can be treated with methylphenidate, a potent blocker of the dopamine transporter (DAT). In present study, we investigated DAT density using I-123N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(4-chlorophenyl) tropane ([123I]IPT SPECT) in children with ADHD before and after treatment with methylphenidate. METHODS: Seven drug-naive children with ADHD and eight normal children were included in the study and performed SPECT 2 hours after an intravenous administration of [123I]IPT. All children with ADHD reperformed [123I]IPT SPECT after treatment with methylphenidate (0.7 mg/kg/d) during about 8 weeks. SPECT data reconstructed for the assessment of specific/ nonspecific DAT binding ratio of the basal ganglia were compared between before and after treatment methylphenidate. We investigated correlation between the change of ADHD symptom severity assessed with ADHD rating scale-IV and specific/ nonspecific DAT binding ratio of basal ganglia. RESULTS: Children with ADHD had a significantly greater increase of specific/nonspecific DAT binding ratio of right basal ganglia than normal children (Right:z=2.085, p=0.037;Left:z=1.506, p=0.132). Under treatment with methylphenidate in all children with ADHD, specific/nonspecific DAT binding ratio of both basal ganglia decreased significantly greater than before treatment with methylphenidate (Right:t=3.239, p=0.018;Left:t=3.133, p=0.020). However, no significant correlation between the change of ADHD symptom severity scores and specific/nonspecific DAT binding ratio of the basal ganglia were found. CONCLUSIONS: The data of this study using methylphenidate in children with ADHD support the complex dysregulation of the dopaminergic neurotransmitter system in children with ADHD.
Administration, Intravenous ; Attention Deficit Disorder with Hyperactivity* ; Basal Ganglia* ; Child* ; Dopamine Plasma Membrane Transport Proteins* ; Dopamine* ; Humans ; Methylphenidate* ; Neurotransmitter Agents ; Tomography, Emission-Computed, Single-Photon*

Although it has been accepted that metoclopramide provides the effects of antiemetics, enhance- ment of intestinal motility and acts as antagonist on dopamine receptor, there is still controversy over inhibitory action of plasma cholinesterase. We examined the effect of preoperative intravenous administration of metoclopramide 10mg (group 2,4) on the duration of neuromuscular block induced by an intubating dose (1 mg/kg) of succinylcholine. Forty female adult patients were devided into four groups, scheduled for cesarean section (group 3,4) or other elective operations (group 1,2). The 1 H2single twitch height of the adductor pollicis muacle was recorded on paper to 1 H2single twitch stimulus by a nerve stimulator (Accelograph). The patients in group 2 and 4 received metoclopramide 10 mg i.v followed by succinylcholine 1mg/kg, and the patients in group 1 and 3 received succinylcholine 1mg/kg alone. The time from disappearance of 1 H, single twitch height to reappearance of that did not significantly differ between group l and 3. However, there was significant prolongation of the time from disappearance of 1H2single twitch height to reappearance of that in patients who received metoclopramide followed by succinylcholine in group 2 and 4. Also, we examined the effect of preoperative intravenous administration of metoclopramide 10mg on the duration of neuromuscular block by 0.5mg/kg of succinylcholine in twenty female patients for elective operations (group 5,6). There was no significant prolongation of the time from disappearance of 1 H, single twitch height to reappearance of that.
Administration, Intravenous ; Adult ; Antiemetics ; Cesarean Section ; Cholinesterases ; Female ; Gastrointestinal Motility ; Humans ; Metoclopramide* ; Neuromuscular Blockade ; Plasma ; Pregnancy ; Receptors, Dopamine ; Succinylcholine*