Neurotransmitter imaging with radiopharmaceuticals plays major role for understanding of neurological and psychiatric disorders such as Parkinson's disease and depression. Radiopharmaceuticals for neurotransmitter imaging can be divided to dopamine transporter imaging radiopharmaceuticals and serotonin trnasporter imaging radiopharmaceuticals. Many kinds of new dopamine transporter imaging radiopharmcaeuticals has a tropane ring and they showed different biological properties according to the substituted functional group on tropane ring. After the first clinical trials with [123I]beta-CIT, alkyl chain substituent introduced to tropane ring amine to decrease time for imaging acquisition and to increase selectivity. From these results, [123I]PE2I, [18F]FE-CNT, [123I]FP-CIT and [18F]FP-CIT were developed and they showed high uptake on the dopamine transporter rich regions and fast peak uptake equilibrium time within 4 hours after injection. [11C]McN 5652 was developed for serotonin trnasporter imaging but this compound showed slow kinetics and high background radioactivity. To overcome these problems, new diarylsulfide backbone derivatives such as ADAM, ODAM, AFM, and DASB were developed. In these candidates, [11C]AFM and [11C]DASB showed high binding affinity to serotonin transporter and fast in vivo kinetics. This paper gives an overview of current status on dopamine and serotonin transporter imaging radiopharmaceuitcals and the development of new lead compounds as potential radiopharmaceuticals by medicinal chemistry.
Chemistry, Pharmaceutical ; Depression ; Dopamine ; Dopamine Plasma Membrane Transport Proteins ; Kinetics ; Neurotransmitter Agents* ; Parkinson Disease ; Radioactivity ; Radiopharmaceuticals* ; Serotonin ; Serotonin Plasma Membrane Transport Proteins ; Tomography, Emission-Computed, Single-Photon

This article is to review neurobiology of attention-deficit/hyperactivity disorder (ADHD) and pharmacological properties of Osmotic-Controlled Release Oral delivery System Methylphenidate (OROS MPH)(Concerta Oros(R)) in celebration of its one-decade clinical experiences in Korea. ADHD is a highly heritable neurodevelopmental disorder, characterized by age-inappropriate inattention, hyperactivity and impulsiveness. The symptoms of ADHD are consistent with dysfunction of the prefrontal cortex (PFC). The PFC functions such as working memory and executive function are powerfully modulated by the catecholamine neurotransmitters, dopamine (DA) and norepinephrine (NE). Methylphenidate (MPH) is a first line treatment for children and adolescents with ADHD in Korea. MPH improves the PFC functions with the mechanism of action being modulation of DA and NE tones by blocking both dopamine transporter (DAT) and norepinephrine transporter (NET). Stimulation of D1 and NE alpha2 receptors on the postsynaptic neurons may be its main mechanisms of action which improve working memory and behavioral inhibition in patients with ADHD. OROS MPH, one of long-acting MPH, employs an osmotic-releasing oral system (OROS), which has been designed to have 12 hour duration of effect, which permits oncedaily dosing, which has been shown to be as effective as 3-times-a-day immediate-release formulation of MPH (IR MPH). Recently there is growing evidence that OROS MPH has positive effects even on adults with ADHD, in multidimensional aspects; cognitively, emotionally and functionally.
Adolescent ; Adult ; Child ; Dopamine ; Dopamine Plasma Membrane Transport Proteins ; Executive Function ; Humans ; Korea ; Memory, Short-Term ; Methylphenidate ; Neurobiology ; Neurons ; Neuropharmacology ; Neurotransmitter Agents ; Norepinephrine ; Norepinephrine Plasma Membrane Transport Proteins ; Phenazines ; Prefrontal Cortex

This article is to review neurobiology of attention-deficit/hyperactivity disorder (ADHD) and pharmacological properties of Osmotic-Controlled Release Oral delivery System Methylphenidate (OROS MPH)(Concerta Oros(R)) in celebration of its one-decade clinical experiences in Korea. ADHD is a highly heritable neurodevelopmental disorder, characterized by age-inappropriate inattention, hyperactivity and impulsiveness. The symptoms of ADHD are consistent with dysfunction of the prefrontal cortex (PFC). The PFC functions such as working memory and executive function are powerfully modulated by the catecholamine neurotransmitters, dopamine (DA) and norepinephrine (NE). Methylphenidate (MPH) is a first line treatment for children and adolescents with ADHD in Korea. MPH improves the PFC functions with the mechanism of action being modulation of DA and NE tones by blocking both dopamine transporter (DAT) and norepinephrine transporter (NET). Stimulation of D1 and NE alpha2 receptors on the postsynaptic neurons may be its main mechanisms of action which improve working memory and behavioral inhibition in patients with ADHD. OROS MPH, one of long-acting MPH, employs an osmotic-releasing oral system (OROS), which has been designed to have 12 hour duration of effect, which permits oncedaily dosing, which has been shown to be as effective as 3-times-a-day immediate-release formulation of MPH (IR MPH). Recently there is growing evidence that OROS MPH has positive effects even on adults with ADHD, in multidimensional aspects; cognitively, emotionally and functionally.
Adolescent ; Adult ; Child ; Dopamine ; Dopamine Plasma Membrane Transport Proteins ; Executive Function ; Humans ; Korea ; Memory, Short-Term ; Methylphenidate ; Neurobiology ; Neurons ; Neuropharmacology ; Neurotransmitter Agents ; Norepinephrine ; Norepinephrine Plasma Membrane Transport Proteins ; Phenazines ; Prefrontal Cortex

OBJECTIVE: The definite causes of obsessive-compulsive disorder (OCD) are still unknown. Evidences from familial, twin and segregation studies support the role of a genetic component in the etiology of OCD. There are growing evidences that OCD has specific neurochemical and neuroanatomical basis. It has been shown that serotonergic neurons play the predominant pathophysiological role in OCD. Recently, it has also been proposed that neurotransmitters other than serotonin play a role in the pathophysiology of OCD, and a series of studies have provided evidence that dopamine is involved in some OCD patients. Therefore, the aims of this study were to investigate the association between dopamine receptor D4 (DRD4) and OCD. METHODS: One hundred and fifteen OCD patients and 160 normal controls participated in this study. Genomic DNA was extracted from their blood. The genotypes and allele frequencies of the DRD4 polymorphism between OCD group and control group were compared. OCD patients were classified into early onset group (age of onset <17) and late onset group (age of onset > or =17) according to their onset age and the genotype and allele frequency were compared between two groups. Using principal component analysis, we had already derived 4 factors from 13 main contents of YBOCS checklist in the previous study and in this study, we investigated the association between these three factors and DRD4 genotypes. RESULTS: In this case-control study, we could find that the L-genotype frequencies of DRD4 were significantly higher in OCD than in normal control groups (chi2 test, p=0.04). There were no difference in genotype frequencies between early onset OCD group and late onset OCD group. In OCD group, patients with L-genotype had higher scores for the religious/somatic factor than the other groups (t test, p=0.009). CONCLUSIONS: The L-genotype of DRD4 may have negative effects on the development of OCD and religious/somatic factor of the obsessive-compulsive symptoms.
Age of Onset ; Case-Control Studies ; Checklist ; DNA ; Dopamine Plasma Membrane Transport Proteins ; Dopamine* ; Gene Frequency ; Genotype ; Humans ; Neurotransmitter Agents ; Obsessive-Compulsive Disorder* ; Principal Component Analysis ; Receptors, Dopamine* ; Serotonergic Neurons ; Serotonin

To investigate the effect of Rehmanniae Radix on depression-like behavior and monoamine neurotransmitters of chronic unpredictable mild stress(CUMS) model rats. CUMS combined with isolated feeding was used to induce the depression model of rats. The depression-like behavior of rats was evaluated by sucrose preference test, open field test, and forced swim test. Hematoxylin-Eosin(HE) staining was used to investigate the pathological changes of neurons in the CA1 and CA3 area of hippocampus. Ultra performance liquid chromatography-tandem mass spectrometry(UPLC-MS) was used to detect the contents of 5-hydroxytryptamine(5-HT), 5-hydroxyindoleacetic acid(5-HIAA), dopamine(DA), 3,4-dihydroxyphenylacetic acid(DOPAC), homovanillic acid(HVA), norepinephrine(NE), and 3-methoxy-4-hydroxyphenyl glycol(MHPG) in rats. Western blot was used to detect the protein expressions of tryptophan hydroxylase 2(TPH2), serotonin transporter(SERT), and monoamine oxidase A(MAO-A) in the hippocampus of rats. Compared with the normal group, depressive-like behavior of rats was obvious in the model group. The arrangements of neurons in the CA1 and CA3 area of hippocampus were loose and disorderly. The levels of 5-HT, 5-HIAA, and 5-HT/5-HIAA in the hippocampal area were decreased(P<0.01). The protein expression of TPH2 was decreased(P<0.01), but those of SERT and MAO-A were increased(P<0.01). In the Rehmanniae Radix groups with 1.8 g·kg~(-1) and 7.2 g·kg~(-1), the depression-like behavior of CUMS rats and pathological changes of neurons in CA1, CA3 area of hippocampus were improved. The protein expression of TPH2(P<0.05, P<0.01) was increased, and those of SERT and MAO-A were down-regulated(P<0.05, P<0.01). The levels of 5-HT, 5-HIAA, and 5-HT/5-HIAA in hippocampus were increased(P<0.05, P<0.01). The changes in DA, DOPAC, HVA, DA/(DOPAC +HVA), NE, DHPG, and NE/DHPG were not statistically significant. The results suggested that Rehmanniae Radix improved depression-like behavior of CUMS rats, and the mechanism might be related to the regulation of synthesis, transportation, and metabolism of 5-HT neurotransmitter in the hippocampus.
3,4-Dihydroxyphenylacetic Acid/pharmacology* ; Animals ; Antidepressive Agents/therapeutic use* ; Chromatography, Liquid ; Depression/drug therapy* ; Disease Models, Animal ; Dopamine ; Eosine Yellowish-(YS)/pharmacology* ; Hematoxylin/pharmacology* ; Hippocampus/metabolism* ; Homovanillic Acid/pharmacology* ; Hydroxyindoleacetic Acid/metabolism* ; Methoxyhydroxyphenylglycol/pharmacology* ; Monoamine Oxidase/metabolism* ; Neurotransmitter Agents/metabolism* ; Norepinephrine/pharmacology* ; Plant Extracts ; Rats ; Rehmannia/chemistry* ; Serotonin/metabolism* ; Serotonin Plasma Membrane Transport Proteins/pharmacology* ; Stress, Psychological/metabolism* ; Tandem Mass Spectrometry ; Tryptophan Hydroxylase/metabolism*

OBJECTIVE: Dopamine transporter is member of family of Na/Cl dependent neurotransmitter transporter, 12 transmembrane domain that has high substrate specificity, affinity. It is related with dopamine reuptake in presynaptic vesicle. DAT has a VNTR in its 3'-untranslated region(UTR), 3'-UTR VNTR polymorphism is related with modification of dopamine transmission. The association between with VNTR polymorphism and neuropsychiatric disorders such as alcohol dependence, and low activity ALDH has been studied but their relationship is unclear. We study about association of 3'-UTR VNTR of DAT gene and G2319A and alcohol dependence. METHOD: Group of Korea subjects were studied with alcohol dependence(n=49 male) compared to mentally healthy controls(n=53 male). The peripheral blood sample was acquired. and Polymerase Chain Reaction(PCR) amplification, Mspl procedure was done. RESULT: There was a significant difference between alcohol dependence group and normal control(genotype frequency p<0.05 allele frequency p<0.05) Allele A frequency and genotype(GG,GA) frequency was a significant difference between alcohol dependence group and normal control(p<0.05) CONCLUSION: Our study showed that genetic polymorphism of DAT1 G2319A had relation with alcohol dependence.
Alcoholism* ; Alleles ; Dopamine Plasma Membrane Transport Proteins ; Dopamine* ; Gene Frequency ; Humans ; Korea ; Neurotransmitter Agents ; Polymorphism, Genetic* ; Substrate Specificity

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*

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*

OBJECTIVE: Serotonin is a neurotransmitter which might play an important role in the pathophysiology of schizophrenia. As atypical antipsychotics, which antagonize serotonin receptors, exert effects on negative symptoms of schizophrenia, perturbation of serotonin system has been thought as a good indicator to probe the pathogenesis of schizophrenia. Serotonin transporter is crucial for regulating serotonergic neurotransmission and has a deletion/insertion polymorphism of the gene's transcriptional initiation site. This study was designed to examine the association of schizophrenia and polymorphism of serotonin transporter gene (5-HTTLPR). METHODS: Genomic DNA analysis with polymerase chain reaction (PCR) was used for genetic typing of polymorphism of 5-HTTLPR. It was carried out among a total of 111 patients with schizophrenia and 208 normal controls. The significances of genetic association of the polymorphisms with the disease and with clinical variables were estimated by chi-square test and analysis of variances. RESULTS: The results were as follows: 1) There were no significant differences in allelic or genotype frequencies between the group of patients with schizophrenia and controls. 2) There were no significant differences in positive syndrome scale score of positive and negative syndrome scale (PANSS), duration of illness and number of admission according to 5-HTTLPR genotypes. 3) There was a difference in age at onset according to 5-HTTLPR genotypes. 4) There was a significant difference in negative syndrome scale score and general psychopathology score of PANSS according to 5-HTTLPR genotypes. CONCLUSION: These results suggest that polymorphism of serotonin transporter gene might be related to the pathophysiology of schizophrenia.
Antipsychotic Agents ; DNA ; Genotype ; Humans ; Neurotransmitter Agents ; Polymerase Chain Reaction ; Psychopathology ; Receptors, Serotonin ; Schizophrenia* ; Serotonin Plasma Membrane Transport Proteins* ; Serotonin* ; Synaptic Transmission