Ketamine at behaviorally active doses induces a robust increase in EEG power spectra and coherence in rats. The drug rapidly penetrates the brain, reaching peak concentrations within 15 minutes after administration. Ketamine also produces marked hyperlocomotion and deficits in prepulse inhibition of the acoustic startle reaction, a measure of sensorimotor gating. The maximum levels of EEG change correlate with the kinetics of ketamine, and the effects are most pronounced at 10-15 minutes after administration of 30 mg/kg.
Mescaline, a nonselective serotonin receptor agonist, produced significant inhibitory effects on locomotion in rats at low doses and a biphasic effect at the highest dose. In tests of sensorimotor gating (prepulse inhibition of acoustic startle), all doses disrupted gating only when tested 60 minutes after administration. Approximately 50% of animals receiving 100 mg/kg died within 12 hours. Serum mescaline levels rose rapidly within 30 minutes and then quickly declined, while brain concentrations peaked 1 hour after administration and remained elevated for another 60 minutes. The delayed onset of behavioral changes correlated with the drug's pharmacokinetics.
A single dose of ketamine (0.54 mg/kg infused over 30 minutes) rapidly alters brain electrical activity in healthy volunteers, producing a decrease in prefrontal theta cordance—a QEEG measure linked to cerebral blood flow—and an increase in central region theta cordance within 10 to 30 minutes. These changes resemble those seen after one week of treatment with standard antidepressants in people who respond to them, but occur much faster. The prefrontal theta cordance reduction correlated with ketamine and norketamine blood levels at 10 minutes. The findings suggest that theta cordance reduction could serve as a marker and predictor of ketamine's rapid antidepressant effect, a hypothesis warranting testing in depressed patients.