Spontaneous and antagonist-precipitated withdrawal from nicotine is characterized by marked deficits in extracellular dopamine (DA) in striatum, especially in nucleus accumbens, that have been thought to underlie the affective state associated with drug discontinuation. Uptake via the dopamine transporter (DAT) is a key mechanism for regulating the concentrations of extracellular DA. Accordingly, we questioned whether DAT expression and function are altered in striatum in nicotine withdrawal. Male mice, 30-35 g, were injected with nicotine free base 2 mg/kg, sc, or saline 4 times daily for 14 days and euthanized 4-72 h after drug discontinuation. DA uptake into striatal synaptosomes was increased 12-24 h into nicotine withdrawal, and accompanied by elevated DAT mRNA in the substantia nigra pars compacta and ventral tegmental area, evaluated by in situ hybridization. The overflow of endogenous DA, measured under basal conditions in striatal slices ex vivo, was decreased during nicotine withdrawal in a time pattern paralleling to that of uptake. Added to striatal slices, the DAT inhibitor nomifensine reduced the observed difference in DA overflow between saline and nicotine withdrawn mice implying a role for the transporter. The presented data suggest that DAT is transiently up-regulated in the striatum early during nicotine withdrawal, and enhanced transporter function contributes to the decreased extracellular DA levels. Synapse, 2010. (c) 2010 Wiley-Liss, Inc.

OBJECTIVE: To describe the current treatment; clinical, biochemical, and molecular findings; and clinical follow-up of patients with aromatic L-amino acid decarboxylase (AADC) deficiency. METHOD: Clinical and biochemical data of 78 patients with AADC deficiency were tabulated in a database of pediatric neurotransmitter disorders (JAKE). A total of 46 patients have been previously reported; 32 patients are described for the first time. RESULTS: In 96% of AADC-deficient patients, symptoms (hypotonia 95%, oculogyric crises 86%, and developmental retardation 63%) became clinically evident during infancy or childhood. Laboratory diagnosis is based on typical CSF markers (low homovanillic acid, 5-hydroxyindoleacidic acid, and 3-methoxy-4-hydroxyphenolglycole, and elevated 3-O-methyl-L-dopa, L-dopa, and 5-hydroxytryptophan), absent plasma AADC activity, or elevated urinary vanillactic acid. A total of 24 mutations in the DDC gene were detected in 49 patients (8 reported for the first time: p.L38P, p.Y79C, p.A110Q, p.G123R, p.I42fs, c.876G>A, p.R412W, p.I433fs) with IVS6+ 4A>T being the most common one (allele frequency 45%). CONCLUSION: Based on clinical symptoms, CSF neurotransmitters profile is highly indicative for the diagnosis of aromatic L-amino acid decarboxylase deficiency. Treatment options are limited, in many cases not beneficial, and prognosis is uncertain. Only 15 patients with a relatively mild form clearly improved on a combined therapy with pyridoxine (B6)/pyridoxal phosphate, dopamine agonists, and monoamine oxidase B inhibitors.

Drug addiction is a complex neuropsychiatric disorder involving the environmental and genetic factors. Genetic and physiological evidences suggest that the dopaminergic system may play an important role in cocaine abuse and dependence. Several association studies have focused on dopaminergic genes. We genotyped the Int8 and 3'UTR variable number of tandem repeats of the dopamine transporter gene (DAT1/SLC6A3), the TaqIA (rs1800497) and TaqIB (rs1079597) SNP polymorphisms within the dopamine receptor D2 gene and the 19-bp insertion/deletion and c.444G>A (rs1108580) polymorphisms of the dopamine beta-hydroxylase gene (DBH) in a Spanish sample of 169 patients with cocaine addiction and 169 sex-matched controls. The case-control study showed a nominal overrepresentation of the 5R/5R genotype of the Int8 variable number of tandem repeats within DAT1 in cocaine abusers (P=0.016). However, no significant associations were detected when DAT1 haplotype frequencies or polymorphisms within the other dopaminergic genes were considered. Sample size is limited and further studies should be performed in a larger cohort.

INTRODUCTION: A different genetic background is postulated for alcoholics with early onset and with antisocial personality disorder (type 2 alcoholics) compared with those with late onset and without antisocial personality disorder (type 1 alcoholics). The dopamine transporter (DAT) and the serotonin transporter (SERT) are involved in endophenotypes that are associated with these subtypes. Our study was aimed at investigating whether distinct haplotypes, defined by polymorphisms associated with the expressions of DAT and SERT, were associated with subgroups of alcohol dependence. METHODS: Intron 8 variable number of tandem repeats (VNTR), exon 15 rs27072 and VNTR (DAT), promoter VNTR and rs25531, and intron 2 VNTR (SERT) were genotyped in a case-control sample comprising 360 alcoholics and 368 controls, and in a family-based sample of 65 trios, all of German origin. RESULTS: DAT: The haplogenotypes 6-A-10/6-G-10 and 5-G-9/5-G-9 were more often present in type 2 alcoholics as compared with type 1 alcoholics [odds ratio (OR): 2.8], and controls (OR: 5.8), respectively. The daily ethanol consumption was associated with haplogenotypes. SERT: haplotypes SA-10 (OR: 2.3) and LG-12 (OR: 2.5) were more often present in type 2 alcoholics compared with controls. Haplotype LA-10 was less often present in type 2 alcoholics (OR: 0.5), and was more often transmitted, in families, to the affected offspring (transmission disequilibrium test: OR: 5.2; family-based association test: Z: 1.9). The haplotype LA-12 was significantly undertransmitted to affected offspring in the whole group (transmission disequilibrium test: OR: 0.216; family-based association test: Z: -2.2). A gene by environment interaction was observed with respect to the time course of the depression score after alcohol withdrawal and with respect to the positive family history of alcohol dependence. CONCLUSION: Haplotype analysis, sub-grouping with respect to more homogeneous endophenotypes, and inclusion of quantifiable characteristics are sensible strategies to untangle the genetic background of such a complex disorder like alcohol dependence.

ABSTRACT This study was designed to follow the long-term efficacy, safety, and tolerability of rasagiline for Parkinson's disease (PD) with data collected from all patients who had ever taken rasagiline during the 12-month TEMPO monotherapy trial (N = 398) and subsequent open-label extension. Patients were followed for up to 6.5 years with a mean of 3.5 +/- 2.1 years. After 12 months, additional PD medications were added as required. Of patients remaining in the trial at 2 years, 46% were maintained on rasagiline monotherapy. The majority of patients received a dopamine agonist prior to levodopa as the first additional dopaminergic agent. Analysis using a Kaplan-Meier method indicated that by 5.4 years only 25% of patients progressed to Hoehn & Yahr stage III. Rasagiline was well tolerated, with 11.3% of patients (45/398) withdrawing because of an adverse event. Rasagiline therapy for PD was effective, well tolerated, and safe in this long-term trial.

Similar to dopamine (DA), cannabinoids strongly influence prefrontal cortical functions, such as working memory, emotional learning, and sensory perception. Although endogenous cannabinoid receptors (CB(1)Rs) are abundantly expressed in the prefrontal cortex (PFC), very little is known about endocannabinoid (eCB) signaling in this brain region. Recent behavioral and electrophysiological evidence has suggested a functional interplay between the dopamine and cannabinoid receptor systems, although the cellular mechanisms underlying this interaction remain to be elucidated. We examined this issue by combining neuroanatomical and electrophysiological techniques in PFC of rats and mice (both genders). Using immunoelectron microscopy, we show that CB(1)Rs and dopamine type 2 receptors (D(2)Rs) colocalize at terminals of symmetrical, presumably GABAergic, synapses in the PFC. Indeed, activation of either receptor can suppress GABA release onto layer 5 pyramidal cells. Furthermore, coactivation of both receptors via repetitive afferent stimulation triggers eCB-mediated long-term depression of inhibitory transmission (I-LTD). This I-LTD is heterosynaptic in nature, requiring glutamate release to activate group I metabotropic glutamate receptors. D(2)Rs most likely facilitate eCB signaling at the presynaptic site as disrupting postsynaptic D(2)R signaling does not diminish I-LTD. Facilitation of eCB-LTD may be one mechanism by which DA modulates neuronal activity in the PFC and regulates PFC-mediated behavior in vivo.

Long-term dopamine replacement therapy in Parkinson’s disease leads to the development of disabling involuntary movements named dyskinesias that are related to adaptive changes in striatal signaling pathways. The chronic transcription factor DeltaFosB, which is overexpressed in striatal neurons after chronic dopaminergic drug exposure, is suspected to mediate these adaptive changes. Here, we sought to demonstrate the ability of DeltaFosB to lead directly to the abnormal motor responses associated with chronic dopaminergic therapy. Using rAAV (recombinant adenoassociated virus) viral vectors, high levels of DeltaFosB expression were induced in the striatum of dopamine-denervated rats naive of chronic drug administration. Transgenic DeltaFosB overexpression reproduced the entire spectrum of altered motor behaviors in response to acute levodopa tests, including different types of abnormal involuntary movements and hypersensitivity of rotational responses that are typically associated with chronic levodopa treatment. JunD, the usual protein partner of DeltaFosB binding to AP-1 (activator protein-1) sites of genes, remained unchanged in rats with high DeltaFosB expression induced by viral vectors. These findings demonstrate that the increase of striatal DeltaFosB in the evolution of chronically treated Parkinson’s disease may be a trigger for the development of abnormal responsiveness to dopamine and the emergence of involuntary movements.

Objective. To explore the role of cabergoline, a dopamine agonist, in the progression of meningiomas. Design. Case report. Setting. Teaching hospital in Barcelona, Spain (Gynecology, Obstetrics and Neonatology Clinical Institute, Hospital Clínic). Patient(s). Women with a history of meningioma underwent surgery via right pterional craniotomy. During the follow-up, at 18 months after the operation the patient developed a progressive hyperprolactinemia with amenorrhea and galactorrhea. An MR examination revealed a recurrence of the neoplasm. Intervention(s). Cabergoline treatment. Main outcome measure(s). Progression of meningioma. Result(s). Long-standing cabergoline treatment in this patient with meningioma relapse early after surgery and subsequent hyperprolactinemia resulted in absence of progression of the neoplasm many years after the dopamine agonist initiation. Conclusion(s). These data suggest that cabergoline, a dopamine agonist, had an antiproliferative effect on the growth of meningiomas. Thus, one can hypothesise that the proliferation of cerebral meningiomas may be under dopaminergic control and that dopamine agonists such cabergoline may have a potential role in the medical treatment of patients with meningiomas.

SK channels are small conductance calcium-activated potassium channels that are widely expressed in different neurons with distinct subtypes. They play an important role in modulating synaptic plasticity, dopaminergic neurotransmission, and learning and memory. The present review was mainly focused on the recent findings on the contradictory roles of SK channels in modulating dopaminergic neurons in substantia nigra and in the pathogenesis of Parkinson’s disease (PD). Besides, whether modulation of SK channels could be a potential target for PD treatment was also discussed.

Abstract Our previous work suggested a role for oligomerization in regulating dopamine transporter (DAT) internalization, with d-amphetamine dissociating DAT oligomers and monomers being endocytosed. This model was put to detailed testing in the present work with the use of DAT constructs differentially tagged with Myc or Flag, reversal of tags in coimmunoprecipitation and cross-linking assays, and application of antibodies against different tags in biotinylation experiments. Upon pairing wild-type (WT) DAT with W84L mutant, effects of d-amphetamine on oligomerization (decrease) but not surface DAT are observed. Internalization of W84L monomers appears to be slow as inferred from the inability of d-amphetamine to reduce surface Myc upon co-expressing Flag-WT with Myc-W84L but not Myc-WT with Flag-W84L, and from the sluggish Myc-W84L endocytosis rate (both with or without d-amphetamine). Results obtained for D313N, D345N, or D436N mutants can all be accommodated by a model in which d-amphetamine is unable to dissociate mutant protomers from oligomers (tetramers or higher-order assemblies) that contain them; this interpretation is confirmed in experiments with both tag reversal in co-expression and antibody reversal in Western blotting. Upon co-transfecting Myc- and Flag-tagged constructs, resulting tetramers can be calculated to be composed of different species (MycMycMycMyc, MycMycMycFlag, MycMycFlagFlag, MycFlagFlagFlag, and FlagFlagFlagFlag), but it is shown that outcomes predicted by models based on MycMycFlagFlag oligomers are not changed in a major way by the occurrence of the additional species.