Glutamatergic neurotransmission mediated by N-methyl-D-aspartate (NMDA) receptors is vital for the cortical computations underlying cognition and might be disrupted in severe neuropsychiatric illnesses such as schizophrenia. Studies on this topic have been limited to processes in local circuits; however, cognition involves large-scale brain systems with multiple interacting regions. A prominent feature of the human brain's global architecture is the anticorrelation of default-mode vs. task-positive systems. Here, we show that administration of an NMDA glutamate receptor antagonist, ketamine, disrupted the reciprocal relationship between these systems in terms of task-dependent activation and connectivity during performance of delayed working memory. Furthermore, the degree of this disruption predicted task performance and transiently evoked symptoms characteristic of schizophrenia. We offer a parsimonious hypothesis for this disruption via biophysically realistic computational modeling, namely cortical disinhibition. Together, the present findings establish links between glutamate's role in the organization of large-scale anticorrelated neural systems, cognition, and symptoms associated with schizophrenia in humans.default-mode network | task-based activation | task-based deactivation | pharmacological manipulation | fMRI D rug treatments for serious mental illnesses and investigations of the neurochemical bases of healthy cognition have, for the most part, targeted the slow neuromodulatory neurotransmitters, dopamine and serotonin (1). However, rapid excitatory glutamatergic and inhibitory γ-aminobutyric acid (GABA) signals mediate local and long-range cortical computations (2) and play a critical role in cognition and severe psychiatric illnesses such as schizophrenia (3-5). We investigated how disrupting the N-methyl-D-aspartate (NMDA) receptor component of fast glutamatergic neurotransmission via the administration of the NMDA receptor antagonist ketamine altered cognitive performance and systemslevel neural activity and connectivity in healthy volunteers. Furthermore, we related these system-level neural changes to behavior and transiently evoked psychotic symptoms associated with schizophrenia.Studies investigating glutamate's role in cognition have largely focused on local circuits (5-7); however, cognition involves largescale brain systems with multiple interacting regions. Recent neuroimaging work highlights the competitive relationships between two large-scale neural systems: a set of brain regions preferentially engaged during tasks that require goal-directed cognition and attention (task-positive) and the regions associated with resting conditions [default-mode network (DMN)] (8-10). The neurotransmitter mechanisms behind this inverse relationship remain unexplored, as does the role of this phenomenon in serious mental illness (11). Thus far, functional neuroimaging (fMRI) investigations of these large-scale neural systems have mostly been correlational (12), and the synaptic mechanisms for these eff...

https://clinicaltrials.gov/ct2/show/NCT00588731.

Background The widespread use of cannabis, the increasing legalization of “medical” cannabis, the increasing potency of cannabis and the growing recreational use of synthetic cannabinoid 1 receptor (CB1R) full agonists underscores the importance of elucidating the effects of cannabinoids on the CB1R system. Exposure to cannabinoids is known to result in CB1R downregulation. However, the precise time course of changes in CB1R availability in cannabis dependent subjects (CDs) following short and intermediate term abstinence has not been determined. Methods Using High Resolution Research Tomography (HRRT) and [11C]OMAR, CB1R availability as indexed by the volume of distribution (VT) [11C]OMAR was measured in male CDs (n=11) and matched healthy controls (HCs) (n=19). CDs were scanned at baseline (while they were neither intoxicated nor in withdrawal), and after 2 days and 28 days of monitored abstinence. HCs were scanned at baseline and a subset (n=4) was rescanned 28 days later. Results Compared to HCs, [11C]OMAR VT was 15% lower in CDs (effect size Cohen’s d=−1.11) at baseline in almost all brain regions. However, these group differences in CB1R availability were no longer evident after just 2 days of monitored abstinence from cannabis. There was a robust negative correlation between CB1R availability and withdrawal symptoms after 2 days of abstinence. Finally, there were no significant group differences in CB1R availability in CDs after 28 days of abstinence. Conclusions Cannabis dependence is associated with CB1R downregulation, which begins to reverse surprisingly rapidly upon termination of cannabis use and may continue to increase over time.