Inhibition of cerebral type 1 cannabinoid receptors is associated with impaired auditory mismatch negativity generation in the ketamine model of schizophrenia

• Published in: Psychopharmacologia Vol. 218; no. 4; pp. 611 - 620
• Main Authors: Roser, Patrik, Haussleiter, Ida S., Chong, Hee-Jeong, Maier, Christoph, Kawohl, Wolfram, Norra, Christine, Juckel, Georg
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.12.2011; Springer; Springer Nature B.V
• Subjects: Adult; Adult and adolescent clinical studies; Analysis; Aspartate; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cannabinoid CB1 receptors; Clinical trials; Cognitive ability; Cross-Over Studies; Double-Blind Method; EEG; Electrodes; Evoked Potentials, Auditory; Excitatory Amino Acid Antagonists - pharmacology; Glutamatergic transmission; Glutamic acid receptors; Glutamic acid receptors (ionotropic); Humans; Intravenous administration; Inventories; Ketamine; Ketamine - pharmacology; Male; Medical sciences; Memory; Mental disorders; Methyl aspartate; Mismatch negativity; N-Methyl-D-aspartic acid receptors; Neurons; Neurosciences; Neurotransmission; Original Investigation; Pharmacology/Toxicology; Piperidines - pharmacology; Prospective Studies; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology; Psychopathology. Psychiatry; Psychopharmacology; Psychoses; Pyrazoles - pharmacology; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Schizophrenia; Schizophrenia - chemically induced; Schizophrenia - physiopathology; Young Adult; Germany; Mismatch negativity; Ketamine; receptor; Rimonabant; NMDA; Schizophrenia; CB; CB1 cannabinoid receptor; Central nervous system; Stimulus disparity; Electrophysiology; Male; Glutamate receptor; Prokinetic agent; Encephalon; Psychosis; Acoustic stimulus; Cannabinoid receptor; Drug of abuse; Antagonist; Inhibition; Human; Healthy subject; Hearing; General anesthetic; Auditory evoked potential; Models; Anorectic; Glutamatergic transmission; NMDA receptor
• ISSN: 0033-3158; 1432-2072; 1432-2072
• DOI: 10.1007/s00213-011-2352-y

Rationale Preclinical and clinical research suggests that the endogenous cannabinoid system is involved in cognitive impairments related to schizophrenia. In particular, the deficient generation of mismatch negativity (MMN) indicating auditory sensory memory is a characteristic finding in schizophrenic patients. Experimental studies implicate deficient N -methyl- d -aspartate (NMDA) receptor functioning in such abnormalities. Objectives The primary aim of this study was to investigate the effects of the cannabinoid CB 1 receptor antagonist rimonabant on MMN deficits in the NMDA receptor antagonist model of schizophrenia by using ketamine. Methods Twenty-four healthy male subjects participated in a randomized, double-blind, placebo-controlled cross-over study with subanesthetic doses of intravenous ketamine. The MMNs to frequency and duration deviants were elicited within an auditory oddball paradigm and recorded by a 32-channel EEG. Psychopathology was assessed using the Psychotomimetic States Inventory. Results Twenty subjects completed both experimental sessions. Ketamine infusion had no significant effect on MMN amplitudes in both deviance conditions. In contrast to placebo, co-administration of rimonabant produced significant deficits in MMN amplitudes to duration deviants at electrode position Fz. Conclusions The results point to the involvement of the endogenous cannabinoid system in auditory sensory memory as a cognitive key feature in schizophrenia. They particularly suggest that CB 1 receptor antagonism may impair cognitive performance by a disturbed interaction between endocannabinergic activity and glutamatergic neurotransmission implied in schizophrenia.