Effects of (S)-ketamine on striatal dopamine: a [11C]raclopride PET study of a model psychosis in humans

876

664

Recent advances in the understanding of brain cannabinoid receptor function have renewed interest in the association between cannabinoid compounds and psychosis. In a 3-day, double-blind, randomized, and counterbalanced study, the behavioral, cognitive, and endocrine effects of 0, 2.5, and 5 mg intravenous delta-9-tetrahydrocannabinol (D-9-THC) were characterized in 22 healthy individuals, who had been exposed to cannabis but had never been diagnosed with a cannabis abuse disorder. Prospective safety data at 1, 3, and 6 months poststudy was also collected. D-9-THC (1) produced schizophrenia-like positive and negative symptoms; (2) altered perception; (3) increased anxiety; (4) produced euphoria; (5) disrupted immediate and delayed word recall, sparing recognition recall; (6) impaired performance on tests of distractibility, verbal fluency, and working memory (7) did not impair orientation; (8) increased plasma cortisol. These data indicate that D-9-THC produces a broad range of transient symptoms, behaviors, and cognitive deficits in healthy individuals that resemble some aspects of endogenous psychoses. These data warrant further study of whether brain cannabinoid receptor function contributes to the pathophysiology of psychotic disorders.

Section: Discussionsupporting

confidence: 55%

The Psychotomimetic Effects of Intravenous Delta-9-Tetrahydrocannabinol in Healthy Individuals: Implications for Psychosis

D’Souza

Perry

MacDougall

et al. 2004

876

664

“…While three studies reported that ketamine induced decrease in [ 11 C]raclopride V 3 00 in humans (Breier et al, 1998;Smith et al, 1998;Vollenweider et al, 2000), three other studies (Kegeles et al, 2000(Kegeles et al, , 2002Aalto et al, 2002) did not detect any effect of ketamine on [ 123 I]IBZM or [ 11 C]raclopride V 3 00 in humans. These latter results are consistent with a microdialysis study that failed to detect any effect of PCP or ketamine on extracellular striatal DA levels in awake rhesus monkeys, even under condition of DAT blockade (Adams et al, 2002).…”

Section: Discussionmentioning

confidence: 96%

Modulation of Amphetamine-Induced Dopamine Release by Group II Metabotropic Glutamate Receptor Agonist LY354740 in Non-Human Primates Studied with Positron Emission Tomography

Berckel

Kegeles

Waterhouse

et al. 2005

Pharmacological evidence suggests that schizophrenia is associated with increased stimulation of dopamine (DA) D 2 receptors. Recently, several groups have demonstrated that amphetamine-induced DA release is increased in schizophrenia, providing direct evidence for dysregulation of DA systems in this condition. In healthy volunteers, pretreatment with the noncompetitive N-methyl-D-aspartate (NMDA) antagonist ketamine increases amphetamine-induced DA release to levels similar to those observed in patients with schizophrenia. Therefore, the dysregulation of DA function observed in schizophrenia might be secondary to NMDA hypofunction. In this study, the regulation of this response by glutamate (GLU) transmission was further characterized by using a metabotropic glutamate (mGlu) receptor group II agonist to inhibit GLU transmission. The amphetamine-(0.5 mg/kg intravenously (i.v.)) induced decrease in [ 11 C]raclopride equilibrium-specific binding (V 3 00 ) was measured under control conditions and following pretreatment with the mGlu2/3 receptor agonist LY354740 (20 mg/kg i.v.) in four baboons. Amphetamine reduced [ 11 C]raclopride V 3 00 by 2877% under control conditions. Following LY354740 pretreatment, amphetamine-induced reduction in [ 11 C]raclopride V 3 00 was significantly enhanced (3577%, p ¼ 0.002). The enhancement of the amphetamine-induced reduction in [ 11 C]raclopride V 3 00 by LY354740 was not a simple additive effect, as LY354740 alone did not reduce [ 11 C]raclopride V 3 00 . In conclusion, the results of this study further document the involvement of GLU transmission in regulating the effect of amphetamine-induced DA release, and provide additional support to the hypothesis that the dysregulation of DA function revealed by the amphetamine challenge in schizophrenia might stem from a deficit in GLU transmission. Neuropsychopharmacology (2006) 31, 967-977.

“…Both activation and blockade of 5-HT 2A receptors have been demonstrated to exert strong modulatory effects on dopaminergic neurotransmission Yan, 2000). In humans, ketamine administration increases spontaneous and amphetamineinduced dopamine release (Breier et al, 1998;Kegeles et al, 2000;Vollenweider et al, 2000). Similarly, administration of psilocybin in healthy volunteers is associated with increased dopamine release (Vollenweider et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Effects of the 5-HT2A Agonist Psilocybin on Mismatch Negativity Generation and AX-Continuous Performance Task: Implications for the Neuropharmacology of Cognitive Deficits in Schizophrenia

Umbricht

Vollenweider

Schmid

et al. 2003

Self Cite

155

Previously the NMDA (N-methyl-D-aspartate) receptor (NMDAR) antagonist ketamine was shown to disrupt generation of the auditory event-related potential (ERP) mismatch negativity (MMN) and the performance of an 'AX'-type continuous performance test (AX-CPT)Fmeasures of auditory and visual context-dependent information processingFin a similar manner as observed in schizophrenia. This placebo-controlled study investigated effects of the 5-HT 2A receptor agonist psilocybin on the same measures in 18 healthy volunteers. Psilocybin administration induced significant performance deficits in the AX-CPT, but failed to reduce MMN generation significantly. These results indirectly support evidence that deficient MMN generation in schizophrenia may be a relatively distinct manifestation of deficient NMDAR functioning. In contrast, secondary pharmacological effects shared by NMDAR antagonists and the 5-HT 2A agonist (ie disruption of glutamatergic neurotransmission) may be the mechanism underlying impairments in AX-CPT performance observed during both psilocybin and ketamine administration. Comparable deficits in schizophrenia may result from independent dysfunctions of 5-HT 2A and NMDAR-related neurotransmission.