Improved short-term spatial memory but impaired reversal learning following the dopamine D(2) agonist bromocriptine in human volunteers.

RATIONALE: Studies in humans of cognitive effects of dopaminergic drugs have largely focused on tasks of working memory, with a few studies also examining executive function. OBJECTIVES: This study was designed to investigate the effects of 1.25 mg of the dopamine D(2) agonist bromocriptine on spatial working memory, planning and discrimination reversal learning in young healthy volunteers. METHODS: Twenty volunteers were tested in a double-blind, placebo-controlled, cross-over design. The cognitive assessment included tests taken from the Cambridge Neuropsychological Test Automated Battery (CANTAB) designed to test visuo-spatial recognition memory and spatial working memory. In addition, tests of spatial planning and discrimination reversal learning were used to assess the more general effects of bromocriptine. Tests of subjective feelings and motivation were also incorporated into the battery. RESULTS: Bromocriptine enhanced the spatial memory span of subjects, whilst impairing their ability to reverse a learned probabilistic discrimination. Tests of recognition memory and planning were unaffected by the drug. The findings were not explained by changes in subjective mood or motivational measures. CONCLUSIONS: The pattern of findings observed here mirror medication-dependent observations seen in Parkinson's disease. The results are discussed with reference to the different anatomical networks known to subserve performance of the differentially affected tasks.

Presence of multiple functional polyadenylation signals and a single nucleotide polymorphism in the 3' untranslated region of the human serotonin transporter gene.

The human serotonin transporter (hSERT) gene is a candidate for involvement in the aetiology of affective disorders. In humans, multiple transcripts of the gene have been detected by northern blot analysis of brain and other tissues. We performed 3' rapid amplification of cDNA ends to identify the common sites of polyadenylation in hSERT mRNA from human JAR cells and whole blood. Two major polyadenylation sites were identified: one 567 bp downstream of the stop codon, consistent with the usage of the polyadenylation signal AATGAA, and a second site 690 bp downstream of the stop codon. The putative polyadenylation signal upstream of this site contained a single nucleotide polymorphism (AG/TTAAC). However, allelic variation at this site did not influence polyadenylation site usage, and there were no significant differences in the abundance of the two alleles of this polymorphism between 329 control subjects, 158 individuals with major depression, and 130 individuals with bipolar affective disorder. This single nucleotide polymorphism in the 3' untranslated region of the hSERT gene should provide a useful genetic marker in the evaluation of hSERT as a candidate gene influencing susceptibility to mood disorders.

Altered allelic distributions of the serotonin transporter gene in migraine without aura and migraine with aura.

Allelic variation of the human serotonin transporter gene (HSERT), a highly plausible candidate gene for susceptibility to migraine, was investigated in 266 individuals with migraine, including 173 having migraine without aura (MO), 94 having migraine with aura (MA), 18 with co-occurrence of MO and MA, plus 133 unaffected controls. The distribution of a polymorphism with different forms of a variable tandem number repeat (VNTR) in intron 2 were compared. The MO group had an over-representation of genotypes with two twelve repeat alleles (STin2.12) and a reduction of genotypes containing one ten repeat (STin2.10) compared to controls. The MA group showed a similar pattern, but also a trend towards an increase in genotypes containing the nine repeat allele of the VNTR (STin2.9). Genotypes containing this allele were found in 6.4% of the MA group compared to 2.3% of controls. The group with co-occurrence of MO and MA had a significantly different pattern of overall allele frequency distribution from controls, reflecting a reduction in genotypes containing the STin2.10 allele and a shift both to STin2.9 carriers and to STin2.12 homozygosity. These results support the view that susceptibility to MO and MA has a genetic component, that these disorders are distinct, and that genetic susceptibility may in some cases be associated with a locus at or near the serotonin transporter gene.

Clinical and psychometric correlates of dopamine D2 binding in depression.

BACKGROUND: Single photon emission tomography (SPET) with the dopamine D2/3 ligand 123I-IBZM gives a semi-quantitative estimate of dopamine binding. In depressed patients, we predicted evidence of reduced function, i.e. increased binding, particularly in more retarded patients. METHODS: Fifteen depressed patients with major depressive illness and 15 healthy, age- and sex- matched volunteerS were examined with a clinical and neuropsychological test battery and high resolution IBZM-SPET. Estimates for specific binding were computed by averaging striatum to whole slice or frontal uptake ratios over 8-10 scans acquired from 70 min after tracer injection. RESULTS: Using whole slice as reference, left striatal uptake ratios did not significantly differ for patients from controls. Right ratios were significantly higher in patients than controls (P = 0.03). There were significant correlations between IBZM binding in left and right striatum and measures of reaction time and verbal fluency. CONCLUSIONS: Increased IBZM binding in striatum probably reflects reduced dopamine function, whether due to reduced release of dopamine, or secondary up-regulation of receptors. The observed abnormalities may be trait or state related, an issue that needs to be addressed with longitudinal study designs. The possible role of medication as a confounding variable requires further exploration.

Allelic variation in the serotonin 5-HT2C receptor gene and migraine.

The 5-HT2C (serotonin-2C) receptor has been implicated along with other components of the 5-HT system in the pathophysiology and pharmacotherapy of migraine. To investigate whether the 5-HT2C receptor gene contributes to the risk of migraine we performed an association study of allelic variation at codon 23 (Cys or Ser) of the gene in 242 migraineurs, including 73 with aura, and 129 controls. No differences nor trends in allele or genotype frequencies were seen in the migraineurs compared to the controls. Neither did the frequencies vary significantly in migraineurs with and without aura, or if men and women were analysed separately. In conjunction with an earlier negative linkage study, these data indicate that the 5-HT2C receptor gene does not contribute to the genetic predisposition to migraine.

Association of short alleles of a VNTR of the serotonin transporter gene with anxiety symptoms in patients presenting after deliberate self harm.

The polymorphism of a variable number tandem repeat (VNTR) region of the serotonin transporter gene consists of three alleles containing, respectively, 9 (STin2.9), 10 (STin2.10) and 12 (STin2.12) copies of a repetitive element. The frequencies of the three alleles in 384 individuals presenting after deliberate self harm were the same as a group of 346 controls. However, ratings of anxiety (and state anger) were higher in those patients with genotypes including the shorter repetitive elements. The findings support the hypothesis that, in this group of patients with low rates of severe psychiatric disorder, allelic variation in the serotonin transporter gene may contribute to the expression of anxiety symptoms.

Polymorphism in serotonin transporter gene associated with susceptibility to major depression.

UNLABELLED: BACKGROUND; The serotonin transporter of the brain provides the primary target for the action of selective antidepressant drugs. We set out to identify polymorphisms of the serotonin transporter gene and to find out whether there was a relation between any such polymorphisms and the occurrence of affective disorder. METHODS: A comparison of a polymorphic region of the human serotonin transporter gene was carried out between two groups. The study group comprised 83 patients (39 unipolar depressive disorder, 44 bipolar disorder) with major affective disorder. The control group comprised 122 anonymous blood donors, and 71 volunteers who had been screened for psychiatric disorders. FINDINGS: We detected three novel alleles of the variable-number-tandem-repeat (VNTR) region (STin2.9, STin2.10) and Stin2.12) containing nine, ten and 12 copies of the VNTR element, respectively. The frequencies of the different forms of the allele in the control group were compared with those in the affective disorder group. There was a significant difference between the control and affective disorder groups, largely explained by the excess of the STin2.9 allele in the unipolar group (chi2=10.05, p<0.004 [Bonferroni corrected]). The presence of the allele with nine copies of the repeat was significantly associated with risk of unipolar disorder (odds ratio=6.95 [95% CI 1.8-27.2]). INTERPRETATION: This association, for an obvious candidate gene, may provide a critical starting point for an understanding of the likely polygenic contributions towards susceptibility to affective disorder.

Structure of a variable number tandem repeat of the serotonin transporter gene and association with affective disorder.

We have recently reported an association between a polymorphism of a variable number tandem repeat (VNTR) region of the serotonin transporter gene and susceptibility to major depressive disorder. We identified three alleles containing respectively 9 (STin2.9), 10 (STin2.10) and 12 (STin2.12) copies of a repetitive element. We report here the sequences of the three alleles. The repetitive element conformed to the consensus sequence, GGCTGYGACCY(R)GRRTG, where Y = T/C, R = G/A, with loss of the 12th base pair in one of the repeating elements. We have also extended the numbers of cases and controls in the study. The frequencies of the three alleles in 119 individuals with single or recurrent major depressive episodes, 128 individuals with bipolar disorder and a group of 346 controls were compared. There was a significant difference between patients with affective disorder and controls in the proportion of individuals carrying the STin2.9 allele. For the risk of unipolar disorder given a single STin2.9 allele, the odds ratio was 4.44 (95% Cl, 1.65-11.95) and for bipolar disorder 3.22 (95% Cl, 1.15-9.09). The findings support the hypothesis that allelic variation in the serotonin transporter gene may contribute to susceptibility for both major depression and bipolar disorder.

In situ hybridisation.

In situ hybridisation of mRNA in tissues or cell preparations is a powerful technique for studying gene expression. When combined with cell phenotyping with monoclonal antibodies it gives insights into the cellular basis of disease in vivo. The technique has also been used widely to identify foreign nucleic acids--for example, bacterial or viral, in host cells. The major disadvantages of this approach in the past have been that it was technically demanding, time consuming, and provided qualitative rather than quantitative results. Now, with the use of non-radioactive probes and improved imaging systems, the full potential of this form of molecular analysis is increasingly accessible and should generate rapid advances in many fields.