Jan Ramaekers

Cognitive function and mood in MDMA/THC users, THC users and non-drug using controls

Repeated ecstasy (MDMA) use is reported to impair cognition and cause increased feelings of depression and anxiety. Yet, many relevant studies have failed to control for use of drugs other than MDMA, especially marijuana (THC). To address these confounding effects we compared behavioural performance of 11 MDMA/THC users, 15 THC users and 15 non-drug users matched for age and intellect. We tested the hypothesis that reported feelings of depression and anxiety and cognitive impairment (memory, executive function and decision making) are more severe in MDMA/THC users than in THC users. MDMA/THC users reported more intense feelings of depression and anxiety than THC users and non-drug users. Memory function was impaired in both groups of drug users. MDMA/THC users showed slower psychomotor speed and less mental .exibility than non-drug users. THC users exhibited less mental .exibility and performed worse on the decision making task compared to non-drug users but these functions were similar to those in MDMA/THC users. It was concluded that MDMA use is associated with increased feelings of depression and anxiety compared to THC users and non-drug users. THC users were impaired in some cognitive abilities to the same degree as MDMA/THC users, suggesting that some cognitive impairment attributed to MDMA is more likely due to concurrent THC use.

Transient memory impairment after acute dose of 75mg 3.4-Methylene-dioxymethamphetamine

A range of studies has indicated that users of 3.4-Methylene-dioxymethamphetamine (MDMA, ‘Ecstasy’) display cognitive deficits, particularly memory impairment, as compared to non-drug using controls. Yet it is difficult to determine whether these deficits are caused by MDMA or some other confounding factor, such as polydrug use. The present study was designed to establish the direct relation between MDMA and memory impairment under placebo-controlled conditions. Eighteen recreational MDMA users participated in a double blind, placebo controlled, 3-way crossover design. They were treated with placebo, MDMA 75mg and methylphenidate 20mg. Memory tests were conducted between 1.5-2h (intoxication phase) and between 25.5-26h (withdrawal phase) post dosing. Results showed that a single dose of MDMA caused impairment of immediate and delayed recall on a verbal learning task during the intoxication phase. However, there was no residual memory impairment during the withdrawal phase. Subjects reported more fatigue and less vigour, but no symptoms of depression during the withdrawal phase of MDMA treatment. Methylphenidate did not affect memory or mood at any time of testing. A single dose of MDMA produces transient memory impairment.

The Effects of Acute Tryptophan Depletion on Brain Activation During Cognition and Emotional Processing in Healthy Volunteers

Acute tryptophan depletion (ATD), a method to temporarily lower central serotonin levels, has been used to study the functioning of the serotonergic system. Relatively recent studies that examined the effects of ATD on brain activation associated with cognitive and emotional processing in healthy volunteers are reviewed. An overview of the findings in healthy volunteers is important for the interpretation of the effect of ATD on brain activation in patients with an affective disorder, such as major depression. These studies show that during response control and negative feedback processing ATD modulates the BOLD response in the inferior/orbitofrontal cortex, the anterior cingulate cortex and the dorsomedial prefrontal cortex. During emotional processing, it is consistently found that ATD modulates the BOLD response in the amygdala. These brain regions also show abnormal activation in depressed patients. However, at the moment it remains unclear if the changes induced by ATD are related to decreased basal serotonin (5-HT) release or the result of other biochemical changes that are mediated by ATD. Future studies should implement methodological improvements, explore the possibilities of new promising imaging techniques and expand investigations into the effects of ATD on basal 5-HT release and other biochemical mechanisms that might be modulated by ATD.

The effects of the phosphodiesterase type 5 inhibitor vardenafil on cognitive performance in healthy adults: a behavioral-electroencephalography study.

Phosphodiesterase type 5 inhibitors (PDE5-Is) improve cognitive performance of rodents, but the few human studies investigating their effects did not systematically investigate cognitive effects and the results have been quite contradictory. Therefore, we examined whether the PDE5-I vardenafil improves memory and executive functioning and affect electroencephalography (EEG) in healthy young adults. Participants were selected out of a group of volunteers, based on their performance on a memory screening and they were orally treated with vardenafil (10–20 mg or placebo). Memory and executive functioning were tested while EEG activity was recorded. Additionally, a simple reaction time task and questionnaires addressing various complaints were presented. No prominent effects of vardenafil on cognition were found: participants only made more mistakes on a reaction time task after 20 mg vardenafil. During encoding of words, the P300 was generally smaller after vardenafil treatment. Furthermore, the N400 was larger after vardenafil 10 mg than placebo treatment in a spatial memory task at Fz. Finally, headache and feeling weak were reported more after vardenafil treatment. Vardenafil did not affect cognitive performance of healthy adults and showed only some incidental effects on ERPs. These findings in humans do not corroborate the cognition-enhancing effects of PDE5-Is in healthy animals.

Dissociable effects of histamine H1 antagonists on reaction-time performance in rats

The most pronounced side effect of antiallergic histaminergic drugs (H1 antagonists) is sedation. These effects have been linked with the effects of histaminergic drugs on central H1 receptors. In the present study, we investigated the dose-response relationship of different antihistamines on the performance in a reaction-time task that has been developed for rats. The dose-response relationship of diphenhydramine, cetirizine and terfenadine were examined for the various behavioural measures in this task (i.e., reaction time, motor time, premature responses and number of trials completed). In addition, the effects of scopolamine were assessed to evaluate the cholinergic profile in this task. Diphenhydramine did not reliably affect the reaction time, but increased the motor time and the proportion of premature responses, and decreased the number of trials completed in a session. A low dose of cetirizine decreased the reaction time, whereas an increase in reaction time was found for the high dose. The motor time was increased after both doses of cetirizine. Terfenadine did not affect the responding of rats in the reaction-time task at the doses tested. The effects of scopolamine were very similar to those of diphenhydramine. The reaction-time task used in this study was able to dissociate different types of antihistamines on aspects of psychomotor function, which were likely to be related to central muscarinic or H1 antagonism. These findings suggest that the reaction-time task may be a sensitive tool for assessing effects of drugs on psychomotor function.

T173. GABA AND GLUTAMATE IN PATIENTS WITH 22Q11.2 DELETION SYNDROME AND HEALTHY VOLUNTEERS AND THE RELATION WITH COGNITION: A RANDOMIZED DOUBLE-BLIND 7TESLA PHARMACOLOGICAL MRS STUDY

Abstract Background 22q11.2 deletion syndrome (22q11DS) is characterized by a microdeletion on the long arm of chromosome 22. The clinical phenotype of this syndrome is highly variable but symptoms include cognitive impairment, heart malformations, auto-immune problems and a high risk of developing a psychotic disorder. One of the genes located in the deleted region is PRODH which encodes proline dehydrogenase (PRODH). This enzyme is involved in converting proline to glutamate (GLU). GLU is involved in the pathophysiology of psychosis, particularly in cognitive symptoms (Lewis and Moghaddam 2006). Gamma-aminobutyric acid (GABA) is involved in cognition and psychosis as well (Vinkers et al. 2010). With this study we aimed to investigate GLUergic and GABAergic reactivity in the anterior cingulate cortex (ACC) and striatum in medication-free patients with 22q11DS with no psychiatric history and healthy controls (HC). Methods This was a randomized double-blind placebo controlled cross-over study. Groups were matched for age and gender. 12 patients with 22q11DS (mean age 35 years) and 20 HCs (mean age 31 years) were enrolled in the study. GABA and GLU, levels in the ACC and striatum were obtained twice with 7Tesla Magnetic Resonance Spectroscopy (MRS, STEAM): once after placebo and once after oral administration of 50 mg. riluzole (agent with anti-glutamate and pro-GABA action). Striatal and ACC GLU/GABA ratios were computed as well as GLUergic and GABAergic reactivity (placebo minus riluzole). In addition, within the 22q11DS group, the relationship between cognitive functions (memory and attention) measured with the CANTAB and GABA, GLU, GLU/GABA ratio, GABAergic reactivity and GLUergic in the ACC and striatum were examined. Results Analyses of Covariance (ANCOVA) showed no baseline group differences in glutamate and GABA levels and GLU/GABA ratios (corrected for fraction of cerebral spinal fluid, CSF) in both brain regions. A repeated measures ANCOVA showed a trend level significant increase in striatal GABA concentrations after (p= 0.065). Riluzole had no significant effect on GLU (p= 0.303) and GLU/GABA ratios (p= 0.150) in the striatum. No medication X group interaction effects were found. Riluzole had no significant effect on GABA (p= 0.101), GLU (p= 0.847) and GLU/GABA ratio (p= 0.108) in the ACC. No group main effects and no medication X group interactions effects were found. However, a significant negative correlation was found between verbal memory (r= -0.650, p= 0.030) and ACC GLU levels, as well as GLUergic reactivity (r= -0.733, p= 0.010). Moreover, in the 22q11DS group, a significant negative correlation was found between attention (target sequence detection) and ACC GLU levels (r= -0.704, p= 0.016) as well as GLU/GABA ratio (r= -0.602, p= 0.050). Furthermore, sustained attention was positively associated with ACC GABA levels (r= 0.700, p= 0.024) and negatively associated with GLU/GABA ratio r= -0.639, p= 0.047) in these patients. Finally, a positive correlation was found between visual memory and striatal GLU levels (r= 0.616, p= 0.043). Discussion The present study did not demonstrate differences in ACC and striatal GLU and GABA levels, nor in GLUergig or GABAergic reactivity in response to riluzole between 22q11DS patients and controls. However, these results suggest a role for GLU and GABA in cognition in the 22q11DS group. Therefore, influencing these neurotransmitter systems might enhance cognitive functioning in these patients. More studies are required to replicate these findings.