Effects of aversive stimuli beyond defensive neural circuits: reduced excitability in an identified neuron critical for feeding in Aplysia.

In Aplysia, repeated trials of aversive stimuli produce long-term sensitization (LTS) of defensive reflexes and suppression of feeding. Whereas the cellular underpinnings of LTS have been characterized, the mechanisms of feeding suppression remained unknown. Here, we report that LTS training induced a long-term decrease in the excitability of B51 (a decision-making neuron in the feeding circuit) that recovered at a time point in which LTS is no longer observed (72 h post-treatment). These findings indicate B51 as a locus of plasticity underlying feeding suppression. Finally, treatment with serotonin to induce LTS failed to alter feeding and B51 excitability, suggesting that serotonin does not mediate the effects of LTS training on the feeding circuit.

Clinical factors associated with non-polypoid colonic adenomas ≥6 mm: a prospective study in an asymptomatic population using a high-definition colonoscope.

OBJECTIVES: To examine the clinical factors associated with adenomas ≥6 mm presenting as non-polypoid polyps. METHODS: We conducted a prospective cross-sectional examination with a target population of consecutive asymptomatic patients presenting to a University endoscopy center for screening colonoscopy. Data, which included demographics, known colorectal cancer risk factors, and medications, were collected. One endoscopist using a high-definition wide-angle colonoscope performed all of the colonoscopies. Polyp morphology was classified according to the JRSC (Japanese Research Society for Cancer of Colon and Rectum) JRSC guidelines. RESULTS: A total of 600 patients were screened and 150 adenomas ≥6 mm were detected. Of these 150 adenomas, 70 adenomas had a non-polypoid morphology while 80 were polypoid. Adenomas were more likely to present as non-polypoid in women as compared with men (adjusted odds ratio (AOR)=2.49; 95% confidence interval (CI)=1.08-5.75, P=0.03). Location of the adenoma in the proximal colon (AOR=4.21; 95% CI=1.83-9.71, P=0.001) and smoking (AOR=2.54; 95% CI=1.01-6.38, P=0.048) were independent predictors of flat morphology. In addition, advanced adenomas were also more likely to be flat in women (AOR=7.99; 95% CI=1.32-48.39, P=0.02) and proximal location was an independent predictor of flat morphology. CONCLUSIONS: Adenomas ≥6 mm and advanced lesions were more likely to present as non-polypoid polyps in women when compared with men. Proximal location and smoking were also observed to be independent predictors of flat morphology.

Temperature regulation in depression: functional 5HT1A receptor adaptation differentiates antidepressant response.

Observations in humans and animals have indicated that chronic, but not acute, antidepressant treatment (ADT) can desensitize 5-HT1A receptor-mediated responses, such as hypothermia. We hypothesized that 5-HT1A desensitization would be necessary for an antidepressant response (ADR) to occur. To test this hypothesis, we examined 5HT1A-agonist ipsapirone (IPS)-induced hypothermia in 28 depressed patients being treated with fixed doses of nortriptyline (75 mg) at 3-day and 3-week treatment points. Decreases in 24-item Hamilton scores (>12) were used to dichotomize the response data into ADR groups of 13 responders (ADR+) and 15 nonresponders (ADR-). A two-way repeated measures analysis of variance indicated significant temperature differences in the area under the curve between response groups across time from 3-day to 3-week intervals (df=1, 26, F=6.6, p<0.02). In comparison to 3 days treatment, at 3 weeks, the ADR+ patients showed blunted hypothermic responses to IPS. ADR- did not show this effect, implicating ADR+ patients to be less responsive to 5HT1A-receptor stimulation after 3 weeks treatment. Similar effects were not found for 5HT1A postsynaptically mediated ACTH and cortisol responses. These results indicate that to achieve ADR, serotonergic neurotransmission needs to be altered as reflected by the change in 5-HT1a receptor responsiveness documented herein.

Serotonin transport kinetics correlated between human platelets and brain synaptosomes.

RATIONALE: Blood platelets have been used extensively as a model system for investigating the role of the serotonin transporter (SERT) in various psychiatric disorders, especially depression. However, to date, it is not known whether platelet serotonin (5-HT) transport would be related to that in brain. OBJECTIVES: We examined 5-HT transport kinetics simultaneously in human blood platelets and human cortical brain synaptosomes to determine whether they were correlated. METHODS: Blood platelets and synaptosomes were obtained from 25 patients undergoing epileptic surgery. Synaptosomes were obtained from normal margins of surgical neuropathology specimens of anterotemporal cortex. RESULTS: Platelet SERT V(max) was significantly correlated with brain SERT V(max) on linear regression (r=0.58, p<0.005), after controlling for the confounding effects of gender (t=-2.4, p=0.025) and time of day (t=2.1, p<0.05). Consistent with previous observations, there was a negative correlation between the maximum velocity (V(max)) of platelet 5-HT transport and pO2 (r=-0.52, p<0.01). Females had a significantly higher pO2 than males (F=4.9, p<0.05). After accounting for gender differences, addition of pO2 did not add further strength to the regression, given the aforementioned gender differences in pO2. The correlation between unadjusted values for platelet vs brain SERT V(max) was r=0.3, p=0.06. CONCLUSIONS: These results suggest that a relationship may exist between 5-HT transport in platelets and cortical synaptosomes, when appropriate controls for confounding factors are employed.

Open-label risperidone for Asperger's disorder: negative symptom spectrum response.

OBJECTIVE: Asperger's disorder consists of negative symptoms similar to those seen in schizophrenia, autism, schizoid personality disorder, and schizotypal personality disorder. We investigated whether risperidone, which is effective in treating the negative symptoms of schizophrenia, would improve such symptoms observed in Asperger's disorder in a prospective, open-label trial. METHOD: Thirteen male patients aged 6 to 18 years who were diagnosed with Asperger's disorder by DSM-IV criteria were enrolled in a 12-week, prospective, open-label pilot study from March 13, 2002 to August 11, 2003. All subjects were started on risperidone 0.25 mg twice per day. Doses were increased based on clinical indication and tolerability. The primary efficacy variable was the Scale for the Assessment of Negative Symptoms (SANS). Each subject's baseline score served as his control. Secondary efficacy measures included the Positive and Negative Syndrome Scale, Brief Psychiatric Rating Scale, Montgomery-Asberg Depression Rating Scale, Global Assessment Scale, and a modified Asperger Syndrome Diagnostic Scale. RESULTS: We found a statistically significant improvement from baseline for last-observation-carried-forward (LOCF) analyses as well as for analyses of 12-week completers (N = 9) in our primary outcome measure, SANS scores (F = 13.41, p < .0001 for 12-week completers; F = 9.64, p < .0001 for LOCF). We also found statistically significant improvement in all secondary efficacy measurements (F values range, 8.41 to 15.73, p values range, < .0001 to < .005 for 12-week completers; F values range, 6.53 to 7.75, all p < .0001 for LOCF). CONCLUSIONS: Subjects' symptoms significantly improved after risperidone. The open-label nature of this small pilot study suggests caution in interpreting these data, but the results suggest that placebo-controlled trials should follow.

Initial platelet serotonin (5-HT) transport kinetics predict nortriptyline treatment outcome.

According to the hypothesis of initial conditions, drug response may be determined by different initial states of neurotransmitter protein recognition systems. Platelet serotonin (5-HT) transport kinetics were studied as initial-conditions predictors of antidepressant response in 24 depressed patients before and after 3 weeks of treatment with nortriptyline (75 mg). The initial affinity of the 5-HT transporter (5-HTT) correctly predicted 71% of the outcome. The pretreatment affinity constant ( Km) correlated (r = 0.61; p < 0.002) with that measured after 3 weeks of treatment (Kapp). Responding patients had a significantly higher initial Km before treatment and a significantly higher Kapp after treatment. Nonresponders had an initial Km significantly lower than that of 24 controls. Nortriptyline plasma levels were not statistically different between response groups. These results are consistent with two previously published observations, which indicate that the initial affinity of the 5-HTT predicted response to fluvoxamine or fluoxetine in the same way. Insofar as all three drugs increase the apparent affinity of the 5-HTT, it appears that a better response is related to those cases where the initial affinity is already higher before treatment.

Initial conditions of serotonin transporter kinetics and genotype: influence on SSRI treatment trial outcome.

BACKGROUND: Fifty-one patients with major depression were classified for 5-HTT promoter region polymorphism and platelet 5-HTT kinetics before treatment with fluoxetine, and then examined for treatment outcome. METHODS: Dose was stratified from 1.25 mg to 40 mg per day to allow for the possibility that one genotype could express a lower-dose fluoxetine response. A repeated-measures analysis of variance of 24-item Hamilton depression change through baseline, 1-week placebo lead-in, and 6, 12, and 18 weeks treatment was done to test a genotype effect on outcome. RESULTS: Genotype had a significant effect on outcome (F = 4.7, p <.02), with the initial affinity constant (K(m)) (F = 11.9, p =.001), and dose (F = 6.0, p <.02) being significant covariates on outcome as well. The gene effect, however, was complex in that the 5-HTT promoter region insertion showed two effects: both a placebo response effect (F = 4, p <.025), and a drug dose response effect (r =.40, p <.01). The long allele group was more responsive to placebo, as well as more responsive to drug dose than was the short allele group. CONCLUSIONS: This is the first study to examine the antidepressant dose-response relationship to 5-HTT kinetics and genetics. The findings indicate that both the initial affinity and genotype of 5-HTT may contribute in unique ways to the variation in the outcome of depression treatment trials.