Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [11C]ABP688 and PET imaging study in depression.

The mechanisms of action of the rapid antidepressant effects of ketamine, an N-methyl-D-aspartate glutamate receptor antagonist, have not been fully elucidated. This study examined the effects of ketamine on ligand binding to a metabotropic glutamatergic receptor (mGluR5) in individuals with major depressive disorder (MDD) and healthy controls. Thirteen healthy and 13 MDD nonsmokers participated in two [11C]ABP688 positron emission tomography (PET) scans on the same day-before and during intravenous ketamine administration-and a third scan 1 day later. At baseline, significantly lower [11C]ABP688 binding was detected in the MDD as compared with the control group. We observed a significant ketamine-induced reduction in mGluR5 availability (that is, [11C]ABP688 binding) in both MDD and control subjects (average of 14±9% and 19±22%, respectively; P<0.01 for both), which persisted 24 h later. There were no differences in ketamine-induced changes between MDD and control groups at either time point (P=0.8). A significant reduction in depressive symptoms was observed following ketamine administration in the MDD group (P<0.001), which was associated with the change in binding (P<0.04) immediately after ketamine. We hypothesize that glutamate released after ketamine administration moderates mGluR5 availability; this change appears to be related to antidepressant efficacy. The sustained decrease in binding may reflect prolonged mGluR5 internalization in response to the glutamate surge.

A single-day paradigm of self-regulated human cocaine administration.

UNLABELLED: Prior work by our group has shown the feasibility, safety, and validity of a multi-day, multi-dose paradigm of self-regulated cocaine administration in humans. The current work sought to consolidate these methods in a single-day design focused on reducing logistical complexity, decreasing research burden to human subjects, and increasing suitability for medication development designs. METHODS: Eleven experienced cocaine users participated in a 6-hour, single-day design, consisting of one safety/eligibility and three experimental cocaine periods (during which subjects were allowed to self-administer 8, 16, and 32 mg/70 kg cocaine doses under a fixed-ratio 1:5 minute timeout schedule). Changes in cocaine-induced cardiovascular response, self-administration behavior, and subjective effects were assessed. RESULTS: Procedures were well tolerated by participants, and no significant adverse events were noted. Significant (p < 0.05), changes in measures of cocaine self-administration (e.g., responses, infusions, interinfusion intervals, consumption, and plasma levels), cardiovascular response (HR), and subjective effects ("high") were observed. In contrast, cocaine-induced increases in other vital signs (e.g., SBP, DBP) and subjective effect measures (e.g., paranoia) did not differ between doses. CONCLUSIONS: These data support the safety, tolerability and validity of our single-day design. Depending on the application, such methods may afford advantages for assessing the self-regulation of cocaine administration behavior in humans (e.g., including medication development designs).

A multistudy analysis of the effects of early cocaine abstinence on sleep.

OBJECTIVE: To describe the sleep patterns of early cocaine abstinence in chronic users by polysomnographic and subjective measures. METHODS: 28 cocaine-dependent participants (ages 24-55) underwent polysomnographic sleep (PSG) recording on the 1st, 2nd and 3rd weeks of abstinence on a research dedicated inpatient facility. Objective measures of total sleep time, total REM time, slow wave sleep, sleep efficiency and a subjective measure (sleep quality) along with demographic data were collected from three different long term research studies over a five year period. Data were reanalysed to allow greater statistical power for comparisons. RESULTS: Progressive weeks of abstinence had main effects on all assessed PSG sleep measures showing decreased total sleep time, REM sleep, stages 1 and 2 sleep, and sleep efficiency; increases in sleep onset and REM latencies and a slight increase in slow-wave sleep time were also present. Total sleep time and slow wave sleep were negatively associated with years of cocaine use. Total sleep time was positively associated with the amount of current ethanol use. Sex differences were found with females having more total REM time and an increase at a near significance level in slow wave sleep. Subjective measures were reported as improving with increasing abstinence over the same time period. CONCLUSIONS: Chronic cocaine users show a general deterioration in objective sleep measures over a three-week period despite an increase in subjective overall sleep quality providing further evidence for "occult insomnia" during early cocaine abstinence.