Neurosci Lett. 2006 Mar
21; [Epub ahead of print] The VNTR polymorphism
in the human dopamine transporter gene: improved detection and absence of association
of VNTR alleles with attention-deficit hyperactivity disorder. Pharmacol Biochem Behav. 2006 Feb 24; [Epub
ahead of print] Biol Psychiatry. 2006 Feb 21; [Epub ahead of print] Neuropsychopharmacol Hung. 2005 Sep;7(3):125-31. Neurosci Lett. 2006 Feb
18; [Epub ahead of print]
Association of attention-deficit/hyperactivity disorder with serotonin 4 receptor gene polymorphisms in Han Chinese subjects.
Li J, Wang Y, Zhou R, Wang B, Zhang H, Yang L, Faraone SV.
Attention-deficit/hyperactivity disorder (ADHD) is an important public health problem. Although serotonin is believed to be an important neurotransmitter in the etiology of this disorder, it remains unclear which specific 5-HT receptors are involved in regulating the symptoms of ADHD. Previous studies have provided favorable evidence for the association of ADHD with both the serotonin transporter gene and serotonin 1B receptor gene. To further investigate the role of other genes of the serotonergic pathway in ADHD, the current study examined variants of the serotonin 4 receptor gene in a relatively large sample of ADHD nuclear families. The T allele of the 83097 C>T polymorphism of HTR4 showed a tendency of preferential transmission to probands with ADHD (chi(2)=2.699, P=0.100). When haplotype TDT analysis of HTR4 was performed, we further found that the C/G haplotype of the 83097 C>T and 83198 A>G polymorphisms (chi(2)=8.783, P=0.003) and the C/G/C haplotype of these and the -36 C>T polymorphism (chi(2)=5.762, P=0.016) were under-transmitted to probands with ADHD. These results suggest that the HTR4 gene may play a role in the genetic predisposition to ADHD.
PMID: 16563621 [PubMed - as supplied by publisher]
Simsek M, Al-Sharbati M, Al-Adawi S, Lawatia K.
Department of Biochemistry,
The human dopamine transporter (DAT1) gene contains a variable number tandem repeat (VNTR) in its 3'-untranslated region because of repetition of a 40-bp core sequence. Methods available for the diagnosis of this polymorphism are limited in number. We have developed a new polymerase chain reaction (PCR) test, which is similar to that described originally by Vandenbergh's group, but provides a better detection of the VNTR alleles in the human DAT1 gene. Using two independent PCR methods, we have determined the distribution of VNTR alleles in 110 healthy Omani subjects, and in 92 children with attention-deficit hyperactivity disorder (ADHD). The frequency of the risk allele (DAT1*10) was similar in the healthy subjects and ADHD cases, indicating absence of association of this allele with ADHD in
PMID: 16545000 [PubMed - in process]
Orally active vasopressin V1a receptor antagonist, SRX251, selectively blocks aggressive behavior.
Ferris CF, Lu SF, Messenger T, Guillon CD, Heindel N, Miller M, Koppel G, Robert Bruns F, Simon NG.
Center for Comparative Neuroimaging, University of Massachusetts Medical School, Worcester, MA, USA; Azevan Pharmaceuticals, Inc., Bethlehem, PA, USA.
Arginine vasopressin functions as a neurochemical signal in the brain to affect social behavior. There is an expanding literature from animal and human studies showing that vasopressin, through the vasopressin 1A receptor (V1A), can stimulate aggressive behavior. Using a novel monocylic beta lactam platform, a series of orally active vasopressin V1a antagonists was developed with high affinity for the human receptor. SRX251 was chosen from this series of V1a antagonists to screen for effects on serenic activity in a resident-intruder model of offensive aggression. Resident, male Syrian golden hamsters were given oral doses of SRX251 or intraperitoneal Manning compound, a selective V1a receptor antagonist with reduced brain penetrance, at doses of 0.2 mug, 20 mug, 2 mg/kg or vehicle. When tested 90-120 min later, SRX251, but not Manning compound, caused a significant dose-dependent reduction in offensive aggression toward intruders as measured by latency to bite and number of bites. The reduction in aggression persisted for over 6 h and was no longer present 12 h post treatment. SRX251 did not alter the amount of time the resident investigated the intruder, olfactory communication, general motor activity, or sexual motivation. These data corroborate previous studies showing a role for vasopressin neurotransmission in aggression and suggest that V1a receptor antagonists may be used to treat interpersonal violence co-occurring with such illness as ADHD, autism, bipolar disorder, and substance abuse.
ABT-089, A Neuronal Nicotinic Receptor Partial Agonist, for the Treatment of Attention-Deficit/Hyperactivity Disorder in Adults: Results of a Pilot Study.
Wilens TE, Verlinden MH, Adler LA, Wozniak PJ, West SA.
Department of Psychiatry (TEW),
BACKGROUND: This pilot study was designed to evaluate ABT-089, a neuronal nicotinic receptor partial agonist, as treatment for adult attention-deficit/hyperactivity disorder (ADHD). METHODS: Adults with ADHD received placebo, 2 mg, 4 mg, or 20 mg of ABT-089 for 2 weeks each in a randomized, double-blind, placebo-controlled, 4 x 4 Latin square design for a total of 8 weeks. In addition to the primary outcome, the Conner's Adult ADHD Rating Scale (CAARS), secondary rating scales, and neuropsychological and safety assessments were completed. RESULTS: A total of 11 adults with well-characterized ADHD completed this crossover study. ABT-089 b.i.d. was superior to placebo for the CAARS Total Symptom Score, which was the primary endpoint (placebo: 38.0 +/- 1.9; 2 mg b.i.d.: 32.2 +/- 1.9, one-tail p = .021; 4 mg b.i.d.: 33.2 +/- 1.9, p = .047; 20 mg b.i.d.: 33.5 +/- 1.9, p = .056). ABT-089 was also superior to placebo for the CAARS ADHD Index and Hyperactive/Impulsive scores and the Clinical Global Impression-ADHD Severity score. On the clinical efficacy endpoints, CAARS Total Symptom Score and CAARS Hyperactive/Impulsive score, a shallow inverted U-shaped dose-response curve was observed; however, the dose-response curve for attention and memory effects as measured by computerized cognitive testing seemed dose-linear. No clinically meaningful findings in safety assessments or side effect profile were observed. CONCLUSIONS: Data from this pilot study suggest that ABT-089 might be effective in treating adult ADHD and that it is well tolerated. On the basis of these promising results, larger, parallel-group ABT-089 studies of longer duration are warranted.
[Effects of the D4 dopamine receptor gene variation on behavior problems at 6 years of age]
[Article in Hungarian]
Birkas E, Lakatos K, Nemoda Z, Ney K, Toth I, Novak A, Sasvari-Szekely M, Gervai J.
Magyar Tudomanyos Akademia Pszichologiai Kutatointezet,
Association of the 7-repeat allele of the D4 dopamine receptor (DRD4) exon 3 polymorphism with attention deficit/hyperactivity disorder is well-established, and a link with mother-reported aggressiveness was also found in healthy pre-schoolers assessed by the quantitative scale of the Child Behavior Checklist. In the present study, we hypothesized that children carrying the 7-repeat allele would show more attention problems and externalizing (aggressive and delinquent) behavior at 6 years of age. Further, we hypothesized a potential mediating role of early temperament in the relationship of DRD4 gene with behavior problems. Mothers filled in the Achenbach Child Behavior Checklist for 88 six-year-old firstborn children (51 boys, 35 girls) followed from birth. Mother-reported temperament for the same children was assessed by the Rothbart Infant Behavior Questionnaire at 12 months. Genotypes of the DRD4 repeat polymorphism were determined using buccal cells. Significant main effects of gender and DRD4 genotype were observed on 6-year behavioral problems. Boys showed more attention problems and externalizing behavior, and children lacking the 7-repeat variant showed more externalizing and internalizing behavior. These effects remained significant after controlling for 1-year temperament. Our results did not confirm the negative effect of the 7-repeat allele on attention problems and externalizing behavior measured on quantitative scales. On the contrary, we found elevated problem scores in the absence of the 7-repeat allele. Further research including environmental risk factors is needed to clarify the role of the DRD4 gene in the development of externalizing behavior.
PMID: 16493876 [PubMed - indexed for MEDLINE]
Characterization of the neuronal dopamine transporter DAT in human blood platelets.
Frankhauser P, Grimmer Y, Bugert P, Deuschle M, Schmidt M, Schloss P.
Department Psychiatry, Central Institute of Mental Health,
Compelling evidence suggests a monoaminergic dysfunction in the aetiology of various neuro-psychiatric diseases such as depression, attention deficit hyperactivity disorder (ADHD), schizophrenia, addiction and Parkinson's disease. The efficiency of monoaminergic neurotransmission is controlled by rapid and efficient reuptake of dopamine out of the synaptic cleft by specific transporters for dopamine, serotonin and noradrenalin. In case of the serotonin transporter, many investigators have determined its function and expression also on peripheral cells such as blood platelets under the assumption that changes in protein expression in these cells might reflect neuronal changes. No comparable studies have so far been performed with respect to the dopamine transporter due to the lack of information about the existence of this protein in platelets. Here, we present pharmacological, immunological as well as microarray and PCR data that human blood platelets express the dopamine transporter protein (DAT), which is identical to that first identified in neurons. Because DAT expression is modulated also in non-neuronal cells independently of gene transcription, platelets may well serve as an easy accessible peripheral system to study DAT regulation in mental diseases or during drug treatment or drug abuse.
PMID: 16490314 [PubMed - as supplied by publisher]
Neurosci Lett. 2006 Mar 21; [Epub ahead of print]
The VNTR polymorphism
in the human dopamine transporter gene: improved detection and absence of association
of VNTR alleles with attention-deficit hyperactivity disorder.
Pharmacol Biochem Behav. 2006 Feb 24; [Epub ahead of print]
Biol Psychiatry. 2006 Feb 21; [Epub ahead of print]
Neuropsychopharmacol Hung. 2005 Sep;7(3):125-31.
Neurosci Lett. 2006 Feb 18; [Epub ahead of print]