Effects of Ketamine in Normal and Schizophrenic Volunteers

Lahti, Adrienne C.; Weiler, Martin; Michaelidis, B.A Tamara; Parwani, Arti; Tamminga, Carol A.

doi:10.1016/s0893-133x(01)00243-3

Cited by 594 publications

(377 citation statements)

References 57 publications

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“…We hypothesized that ketamine would cause greater behavioral and physiological changes in schizophrenic volunteers. Behavioral measures suggest that the two groups have similar ketamine-induced psychosis changes (Lahti et al, 2001b). However, this study with positron emission tomography (PET) suggests that volunteers with schizophrenia have an abnormally large cingulate blood-flow response to NMDAR blockade.…”

Section: Introductionmentioning

confidence: 79%

“…Ketamine (2-chlorphenyl-2-methylamino-cyclohexanone) is a phencyclidine congener that has psychotomimetic properties in adult humans at subanesthetic doses (Malhotra et al, 1996;Vollenweider et al, 1997a;Lahti et al, 2001a;Newcomer et al, 1999;Zukin and Zukin, 1979). Since, ketamine exacerbates psychotic symptoms in schizophrenia and induces both psychotomimetic symptoms and cognitive disturbances characteristic of schizophrenia, it has been used as a model of the illness in both clinical and preclinical paradigms (Lahti et al, 2001b;Duncan et al, 1999;Jentsch et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…Since, ketamine exacerbates psychotic symptoms in schizophrenia and induces both psychotomimetic symptoms and cognitive disturbances characteristic of schizophrenia, it has been used as a model of the illness in both clinical and preclinical paradigms (Lahti et al, 2001b;Duncan et al, 1999;Jentsch et al, 1997). Ketamine is a non-competitive antagonist of the NMDA glutamate receptor.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Effects of Noncompetitive NMDA Receptor Blockade on Anterior Cingulate Cerebral Blood Flow in Volunteers with Schizophrenia

Holcomb

Lahti

Medoff

et al. 2005

Neuropsychopharmacol

101

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Schizophrenia may be related to dysfunctional glutamatergic activity, specifically hypofunction of the N-methyl-D-aspartate receptor (NMDAR). In addition, it has been proposed that NMDAR hypofunction may paradoxically cause an increase in glutamate release and hypermetabolism in corticolimbic regions. If a state of partial, chronic NMDAR blockade underlies schizophrenia, then schizophrenic volunteers (SV) may have greater glutamate release and associated elevations in regional cerebral blood flow (rCBF) than normal volunteers (NV), following drug-induced NMDAR antagonism. Therefore, we have given acute ketamine, a noncompetitive NMDAR antagonist, to NV (n ¼ 13) and medicated volunteers with schizophrenia (n ¼ 10) in conjunction with serial positron emission tomography blood flow studies. Drug administration caused marked rCBF elevations in frontal and cingulate regions in both groups. Contrasts between NV and SV ketamine groups showed that SV had greater relative blood flow increases in the anterior cingulate than NV. Maximum blood flow, and the area under the curve for blood flow in the anterior cingulate cortex, significantly correlated with changes in psychosis ratings in SV and NV (maximum rCBF only). These changes are consistent with a relatively hypoactive thalamic NMDAR and increased cortical glutamate neurotransmission at non-NMDARs in schizophrenia. We hypothesize that ketamine antagonizes an NMDAR-dependent inhibitory system that is partially compromised in subjects with schizophrenia. The ketamine-induced reduction of inhibition leads to a marked increase in glutamate release and hypermetabolism (elevated rCBF) in frontal and cingulate cortical regions. The loss of inhibition and increased glutamate release may cause the distorted thoughts and diminished cognitive abilities elicited by NMDAR blockade.

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Section: Introductionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of Noncompetitive NMDA Receptor Blockade on Anterior Cingulate Cerebral Blood Flow in Volunteers with Schizophrenia

Holcomb

Lahti

Medoff

et al. 2005

Neuropsychopharmacol

101

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“…33,34 Moreover, both dopamine receptor agonists and NMDA receptor antagonists can produce psychosis-like states in healthy human subjects and exacerbate existing psychoses in schizophrenics. [45][46][47][48][49] Interestingly, increased response to acute AMPH treatment has been directly implicated in the positive symptoms of schizophrenia, 47 whereas acute pharmacological treatment with NMDA receptor antagonists may additionally induce memory impairments related to the cognitive symptoms of schizophrenia. 50, 51 Prenatal immune activation by the inflammatory agent PolyI:C in mice thus precipitates a wide spectrum of adult behavioral and pharmacological abnormalities related especially to the symptom profiles in schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

Adult behavioral and pharmacological dysfunctions following disruption of the fetal brain balance between pro-inflammatory and IL-10-mediated anti-inflammatory signaling

et al. 2007

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Maternal infections during pregnancy increase the risk for schizophrenia and related disorders of putative neurodevelopmental origin in the offspring. This association has been attributed to enhanced expression of pro-inflammatory cytokines in the fetal environment in response to maternal immunological stimulation. In contrast, the specific roles of anti-inflammatory cytokines are virtually unknown in this context. Here, we demonstrate that genetically enforced expression of the anti-inflammatory cytokine interleukin (IL)-10 by macrophages attenuates the long-term behavioral and pharmacological consequences of prenatal immune activation in a mouse model of prenatal viral-like infection by polyriboinosinic-polyribocytidilic acid (PolyI:C; 2 mg/kg, intravenously). In the absence of a discrete prenatal inflammatory stimulus, however, enhanced levels of IL-10 at the maternal-fetal interface by itself also precipitates specific behavioral abnormalities in the grown offspring. This highlights that in addition to the disruptive effects of excess pro-inflammatory molecules, a shift toward enhanced antiinflammatory signaling in prenatal life can similarly affect cognitive and behavioral development. Hence, shifts of the balance between pro-and anti-inflammatory cytokine classes may be a critical determinant of the final impact on neurodevelopment following early life infection or innate immune imbalances.

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“…When given acutely, SSR180711 improved memory performances in several variants of the object recognition task, using either a long-term episodic memory procedure in nontreated animals or a short-term episodic memory protocol using animals impaired either by an acute dose of MK-801, or by an acute low dose of PCP in rats sensitized by repeated treatment with high doses of PCP. The latter property is particularly interesting, in the light of the observation that schizophrenic patients exhibit more pronounced negative symptoms than normal volunteers following an acute challenge with ketamine (Lahti et al, 2001), indicating that the former are sensitized to the effects of this PCP analog. Moreover, SSR180711 reversed MK-801-induced spatial learning deficit in the Morris water test in rats using a working memory protocol.…”

Section: Profile Of Ssr180711 In Tests Predictive Of Therapeutic Actimentioning

confidence: 99%

SSR180711, a Novel Selective α7 Nicotinic Receptor Partial Agonist: (II) Efficacy in Experimental Models Predictive of Activity Against Cognitive Symptoms of Schizophrenia

Pichat

Bergis

Terranova

et al. 2006

Neuropsychopharmacol

235

155

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SSR180711 (4-bromophenyl 1,4diazabicyclo(3.2.2) nonane-4-carboxylate, monohydrochloride) is a selective a7 nicotinic receptor (n-AChR) partial agonist. Based on the purported implication of this receptor in cognitive deficits associated with schizophrenia, the present study assessed efficacy of SSR180711 (i.p. and p.o.) in different types of learning and memory involved in this pathology. SSR180711 enhanced episodic memory in the object recognition task in rats and mice (MED: 0.3 mg/kg), an effect mediated by the a7 n-AChR, as it was no longer seen in mice lacking this receptor. Efficacy was retained after repeated treatment (eight administrations over 5 days, 1 mg/kg), indicating lack of tachyphylaxia. SSR180711 also reversed (MED: 0.3 mg/kg) MK-801-induced deficits in retention of episodic memory in rats (object recognition). The drug reversed (MED: 0.3 mg/kg) selective attention impaired by neonatal phencyclidine (PCP) treatment and restored MK-801-or PCP-induced memory deficits in the Morris or linear maze (MED: 1-3 mg/kg). In neurochemical and electrophysiological correlates of antipsychotic drug action, SSR180711 increased extracellular levels of dopamine in the prefrontal cortex (MED: 1 mg/kg) and enhanced (3 mg/kg) spontaneous firing of retrosplenial cortex neurons in rats. Selectivity of SSR180711 was confirmed as these effects were abolished by methyllycaconitine (3 mg/kg, i.p. and 1 mg/kg, i.v., respectively), a selective a7 n-AChR antagonist. Additional antidepressant-like properties of SSR180711 were demonstrated in the forced-swimming test in rats (MED: 1 mg/kg), the maternal separation-induced ultrasonic vocalization paradigm in rat pups (MED: 3 mg/kg) and the chronic mild stress procedure in mice (10 mg/kg o.d. for 3 weeks). Taken together, these findings characterize SSR180711 as a promising new agent for the treatment of cognitive symptoms of schizophrenia. The antidepressant-like properties of SSR180711 are of added interest, considering the high prevalence of depressive symptoms in schizophrenic patients.

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Effects of Ketamine in Normal and Schizophrenic Volunteers

Abstract: This study evaluates the effects of ketamine on healthy and schizophrenic volunteers (SVs)

Cited by 594 publications

References 57 publications

Effects of Noncompetitive NMDA Receptor Blockade on Anterior Cingulate Cerebral Blood Flow in Volunteers with Schizophrenia

Effects of Noncompetitive NMDA Receptor Blockade on Anterior Cingulate Cerebral Blood Flow in Volunteers with Schizophrenia

Adult behavioral and pharmacological dysfunctions following disruption of the fetal brain balance between pro-inflammatory and IL-10-mediated anti-inflammatory signaling

SSR180711, a Novel Selective α7 Nicotinic Receptor Partial Agonist: (II) Efficacy in Experimental Models Predictive of Activity Against Cognitive Symptoms of Schizophrenia

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