The serotonin transporter length polymorphism, neuroticism, and depression: a comprehensive assessment of association.

BACKGROUND: A promoter-based length polymorphism (5-HTTLPR) of the human serotonin gene (SLC6A4) has exhibited inconsistent association with emotionality phenotypes, such as major depression (MD) and the personality trait neuroticism (N). Several explanations have been posited to account for this discrepancy, including underpowered experimental design and variation in gender ratio, age, and ethnicity. METHODS: Here, we describe three independent tests of association between the 5-HTTLPR locus and both N and MD in samples selected for extremeness of N-score from two homogenous populations (n = 88,142, and 20,921). Calculations of statistical power indicated that at a 5% alpha level, these samples retain 100% power to detect a genetic effect accounting for just .5% of phenotypic variance. Effects of age were regressed out of the phenotypic measure, and gender was included as a covariate. RESULTS: No statistically significant effects of genotype could be identified on either N or MD phenotypes (in all cases, p > or = .26), independently of the genetic mode of action applied. CONCLUSIONS: Our data do not support the hypothesis that the 5-HTTLPR variant contributes significantly toward human emotionality as indexed by either the Eysenck Personality Questionnaire N scale or the DSM-IV for MD.     

Anti-GABA antibodies label a subpopulation of chemical synapses which modulate an electrical synapse in crayfish

Summary Antibodies raised against gamma-aminobutyric acid (GABA) were used to stain sections from the crayfish abdominal nervous system, and the sections were examined under the electron microscope using a protein-A/gold conjugate secondary label. Sections were taken through the third ganglionic root, and through the interganglionic connective at the base of the third root posterior to the ganglia. The third root contains two very large motor axons, a non-GABAergic excitor (Motor Giant; MoG), and a GABAergic inhibitor (Flexor Inhibitor; FI). Only one of the two large axons stained positively for GABA, confirming that the antibody has high specificity for GABAergic neurones.The MoG is driven by powerful electrical synapses from the giant fibres, but also receives inhibitory chemical synaptic input which can gate the excitatory input. There is no physiological evidence for any other form of chemical input. However, at the ultrastructural level, the MoG is postsynaptic to three types of chemical profiles; SE-type containing round agranular vesicles, SI-type containing pleomorphic vesicles, and SM-type containing a mixture of round agranular and dense-cored vesicles. There is a highly differentiated staining pattern of these three synaptic types. Only the SI-type profiles stain positively with the GABA antibody, while the SE- and SM-type do not show significant staining. This suggests that the MoG can under some circumstances receive chemical input other than GABAergic inhibitory input. These other types of input have yet to be physiologically identified.     

Is accurate self-monitoring necessary for people with acquired neurological problems to benefit from the use of differential reinforcement methods?

Challenging behaviour exhibited by people with acquired neurological problems must be managed if their maximum rehabilitation potential is to be achieved. Differential reinforcement of low rates of responding (DRL) appears to be an effective method for this. The effectiveness of DRL in the presence of severe cognitive deficits, including disorders of attention and memory, is nevertheless surprising. Indeed, such difficulties may prevent individuals with brain injury benefiting from operant conditioning procedures because of impairment of the central executive component of working memory. Consequently, use of other behavioural techniques such as response cost and self-monitoring training (SMT) have been adopted, as it has been argued they circumvent neuropsychological constraints to learning by directing attention to aspects of behaviour not being monitored. DRL, however, may be more desirable as it involves minimal intrusion; is concerned with establishment of pro-social behaviour; and treatment gains can occur rapidly and be maintained for long periods following withdrawal. Whether DRL is dependent upon accurate self-monitoring is addressed through the study of three people participating in rehabilitation. This shows DRL can be effective, despite severe cognitive impairments, but SMT facilitates greater improvements in selective attention. How DRL may circumvent cognitive impairment is discussed.     

Evidence that the median raphé nucleus – dorsal hippocampal pathway mediates diazepam withdrawal-induced anxiety

On the basis of our previous series of experiments we had postulated that the increased anxiety that occurred during diazepam withdrawal was mediated by increased 5-HT release in the hippocampus. The present series of experiments provide evidence for a major role of the median raphé nucleus (MRN) dorsal hippocampal pathway. Rats were treated once daily for 21 days with diazepam (2 mg/kg IP) and then tested after 24 h withdrawal in the social interaction test of anxiety. Relative to chronically vehicle treated animals, those withdrawn from diazepam were significantly more anxious and had significantly greater K⁺-evoked release of [³H]-5-hydroxytryptamine (5-HT) from slices of dorsal and of ventral regions of the hippocampus. Estimation of extracellular concentrations of 5-HT within the dorsal hippocampus, using in-vivo microdialysis, showed doubling in the levels of 5-HT in the rats withdrawn from chronic diazepam treatment. This just failed to reach significance, but 33% of the rats showed dramatic increases (650%). It was not possible to test these animals in the social interaction test, but it is proposed that only the diazepam-withdrawn rats with raised extracellular levels of 5-HT would have displayed increased anxiety. 5-HT_1A receptor agonists injected into the MRN decrease the MRN firing rate, and hence the release of 5-HT in the dorsal hippocampus. As a further test of our hypothesis, we examined the effects of MRN injection of the 5-HT_1A receptor agonist, 8-OH DPAT, on animals withdrawn from diazepam and tested in the low light familiar condition of the social interaction test. 8-OH DPAT (50–200 ng) dose-dependently reversed the anxiogenic effect of diazepam withdrawal, while having no effects in chronic vehicle-treated animals. These results provide clear evidence that the MRN-dorsal hippocampal 5-HT pathway is at least one of the pathways playing an important role in mediating diazepam withdrawal-induced anxiety. Received: 10 May 1996 / Final version: 15 October 1996     

Increased 5-HT release mediates the anxiogenic response during benzodiazepine withdrawal: a review of supporting neurochemical and behavioural evidence

This paper reviews the biochemical and behavioural evidence that the increased anxiety that occurs during benzodiazepine withdrawal is caused by increased 5-HT activity. In hippocampal slices taken from rats withdrawn for 24 h from chronic diazepam treatment (2 mg/kg/day for 21 days) there was a significant increase in K⁺-evoked release of [³H]5-HT and in⁴⁵Ca²⁺ uptake and both of these changes were reversed by the GABA_B agonist, baclofen. Baclofen also reversed the anxiogenic response that is detected on withdrawal from chronic diazepam treatment. Other drugs that reduce 5-HT function (tianeptine which increases 5-HT uptake; buspirone, a 5-HT_1A receptor agonist/partial agonist; zacopride, a 5-HT₃ receptor antagonist) also reversed this anxiogenic response. Finally, we present data from a group of rats that did not develop tolerance to the anxiolytic effects of diazepam (2 mg/kg), even after 5 weeks treatment. This group failed to show an anxiogenic response on withdrawal from diazepam, nor was there an increase in hippocampal 5-HT release. We discuss the extent to which increased hippocampal 5-HT release can be causally linked to the increased anxiety during benzodiazepine withdrawal.