Association of schizophrenia onset age and white matter integrity with treatment effect of D-cycloserine: a randomized placebo-controlled double-blind crossover study.

BACKGROUND: It has been reported that drugs which promote the N-Methyl-D-aspartate-type glutamate receptor function by stimulating the glycine modulatory site in the receptor improve negative symptoms and cognitive dysfunction in schizophrenia patients being treated with antipsychotic drugs. METHODS: We performed a placebo-controlled double-blind crossover study involving 41 schizophrenia patients in which D-cycloserine 50 mg/day was added-on, and the influence of the onset age and association with white matter integrity on MR diffusion tensor imaging were investigated for the first time. The patients were evaluated using the Positive and Negative Syndrome Scale (PANSS), Scale for the Assessment of Negative Symptoms (SANS), Brief Assessment of Cognition in Schizophrenia (BACS), and other scales. RESULTS: D-cycloserine did not improve positive or negative symptoms or cognitive dysfunction in schizophrenia. The investigation in consideration of the onset age suggests that D-cycloserine may aggravate negative symptoms of early-onset schizophrenia. The better treatment effect of D-cycloserine on BACS was observed when the white matter integrity of the sagittal stratum/ cingulum/fornix stria terminalis/genu of corpus callosum/external capsule was higher, and the better treatment effect on PANSS general psychopathology (PANSS-G) was observed when the white matter integrity of the splenium of corpus callosum was higher. In contrast, the better treatment effect of D-cycloserine on PANSS-G and SANS-IV were observed when the white matter integrity of the posterior thalamic radiation (left) was lower. CONCLUSION: It was suggested that response to D-cycloserine is influenced by the onset age and white matter integrity. TRIAL REGISTRATION: UMIN Clinical Trials Registry (number UMIN000000468 ). Registered 18 August 2006.

[Behavioral characteristics of nicotine seeking: a role of the nicotine-conditioned effects and other mechanisms].

Nicotine dependence and its neural mechanisms have been well documented by pharmacological, behavioral and neuroscience studies. In this review, we introduce recent new findings in this theme, particularly on the role of nicotine -associated stimuli as non-pharmacological factors affecting maintaining/reinstating nicotine seeking. By using the techniques of drug self-administration and conditioned place preference, nicotine's specific property of forming seeking/taking behavior is well characterized, and the mechanisms of seeking/taking could be partly explained by discrete and/or contextual conditioned stimuli (dCS and cCS). After having the repeated Pavlovian conditioning in the training/conditioning sessions, CSs begin to play a key role for eliciting nicotine seeking behavior, with the activation of mesolimbic dopaminergic systems. In our study, intracranial self- stimulation (ICSS) was used to assess the mesolimbic dopamine activity. The nicotine-associated cCS also activated this neural system, which resulted in decreasing the ICSS threshold approximately 20% in the testing session under the cCS presentation. This finding would support the evidence of CS-induced incentive motivation for nicotine. According to the incentive salience hypothesis, the mesolimbic dopamine reflects the motivation elicited by incentives (CSs), and induces the drug seeking behavior, which is activated through amygdala--nucleus accumbens--medial prefrontal cortex circuit. Additionally, human brain imaging studies have revealed that tobacco- associated stimuli activate not only these regions, but also right temporo-parietal junction of human cortex, which is relevant to the visual attention. In summary, the above evidence shows that nicotine-conditioned stimuli might have powerful incentive salience and regulate nicotine seeking/taking behavior in animals and humans, though stress and nicotine-withdrawal could also enhance nicotine taking in the same way as other dependence -producing mechanisms.

A distinctive abnormality of diffusion tensor imaging parameters in the fornix of patients with bipolar II disorder.

Diffusion tensor imaging (DTI) studies have revealed a changed integrity in the white matter of bipolar disorder. However, only a few investigations have examined bipolar II disorder (BP-II). A cross-sectional study was conducted to compare thirty-eight patients with BP-II (mean age = 38.26 years, F/M = 19/19) with thirty-eight age- and gender-matched healthy controls (mean age = 34.45 years, F/M = 18/20). Tract Based Spatial Statistics (TBSS) analysis of the fractional anisotropy (FA) was done with age, gender and education years as covariates, then a complementary atlas-based region-of-interest (ROI) analysis including the axial diffusivity (AD) and radial diffusivity (RD) was conducted to obtain further information. The patients with BP-II showed a significant decrease in FA in the corpus callosum (commissure fibers), fornix (association fibers) and right anterior corona radiata (projection fibers) compared to the controls. Moreover, a significant increase in the RD was observed in all of the fibers of the BP-II patients, while the AD significantly increased only in the fornix of the patients. Thus, in addition to the abnormal integrity of the commissure and projection fibers, the present study suggested an involvement of the limbic association fibers in the pathophysiology of BP-II induced by a distinctive neuropathology.

Facilitation of intracranial self-stimulation behavior in rats by environmental stimuli associated with nicotine.

Environmental stimuli associated with nicotine act as a trigger for nicotine-seeking behavior and make it difficult to quit smoking. The trigger action might be related to the activity of the mesolimbic dopamine "reward" system. Thus, in the present study, we investigated the effects of nicotine-associated stimuli on reward seeking, assessed by current intensity thresholds of intracranial self-stimulation (ICSS) in rats. Rats were unilaterally implanted with an electrode into the lateral hypothalamus and trained to press a lever to obtain electrical brain stimulation. After stable responses had been established, the rats underwent six conditioning sessions with subcutaneous nicotine at 0.4 mg/kg in particular visual and tactile contexts. The threshold for electrical stimulation was then tested in either the nicotine-conditioned environment or novel environment under saline or nicotine treatment. Nicotine enhanced the responding for ICSS and significantly lowered the threshold in both environments. Under saline treatment, the responding for ICSS was facilitated and the threshold was significantly lower in the nicotine-conditioned environment than in the novel environment. The present results demonstrate that nicotine-conditioned contextual stimuli may affect the mesolimbic dopamine system through ICSS threshold lowering effect.

Decreases in brain reward function reflect nicotine- and methamphetamine-withdrawal aversion in rats.

The purpose of the present study was to investigate whether brain reward function decreases during withdrawal from nicotine and methamphetamine, and whether decreased reward function is related to aversion during withdrawal from these drugs. For that purpose, male Sprague-Dawley rats were chronically infused subcutaneously with 9 mg/kg per day nicotine, or with 6 mg/kg per day methamphetamine using osmotic minipumps. In an intracranial self-stimulation (ICSS) paradigm, chronic infusion of nicotine and methamphetamine decreased the thresholds for lateral hypothalamic ICSS, whereas their antagonists, mecamylamine and haloperidol increased the ICSS thresholds in the rats treated with nicotine and methamphetamine, respectively. In a conditioned place aversion paradigm, mecamylamine and haloperidol produced place aversion in nicotine- and methamphetamine-infused rats, respectively. Interestingly, elevations in ICSS reward thresholds and place aversion during mecamylamine-precipitated nicotine withdrawal were almost the same in magnitude as those observed during haloperidol-precipitated methamphetamine withdrawal. The present study indicates that 1) brain reward function decreased during nicotine and methamphetamine withdrawal, and 2) a decrease in reward function may reflect the negative affective state (aversion) during withdrawal from nicotine and methamphetamine.