The effects of low dose ketamine on sensory gating, neuroendocrine secretion and behavior in healthy human subjects

Abstract

Recently, much interest has been given to the role of glutamatergic N-methyl-D-aspartate receptors (NMDA) in sensory gating, such as prepulse inhibition (PPI) and reduction of the P50 evoked response potential (ERP). Currently, mainly animal data are available describing the role of NMDA receptors in these stimulus evaluation processes. Human data are virtually lacking and are potentially important, for instance for the understanding of sensory gating deficits observed in schizophrenia. Therefore, the effects of the NMDA antagonist ketamine, in a dose of 0.3 mg/kg i.v., on concurrent assessment of PPI and P50 reduction was studied in 18 healthy male volunteers. Ketamine was administered in a pseudo-steady state model with a subacute loading dose. In addition, the effects of ketamine on behavior, vital signs, homovanillic acid (HVA) plasma levels and secretion of cortisol and luteinizing hormone (LH) were also determined. Ketamine did not significantly alter PPI or the reduction of the P50 ERP. A small but significant increase in Brief Psychiatric Rating Scale (BPRS) total scores and BPRS composite scores "thinking disorder" and "withdrawal/retardation" was observed. Several subjects experienced visual perceptional alterations, but complex hallucinations did not occur. Ketamine induced mild analgesia and coordination problems. In addition, ketamine induced a marked rise in cortisol secretion, while LH secretion was not affected. Finally, systolic and diastolic, blood pressure and heart rate increased during ketamine infusion. Although in humans NMDA receptors may not be involved in the regulation of PPI and P50 reduction, the most likely explanation for the lack of effect of ketamine on these sensory gating paradigms is the dose used in this experiment. However, using a higher dose is hampered by the aspecificity of racemic ketamine. Future studies should use the enantiomer S-ketamine, which is more specific to NMDA receptors, to evaluate the involvement of NMDA receptors in these neurophysiological processes further.

Early Auditory Sensory Processing Deficits in Mouse Mutants with Reduced NMDA Receptor Function

“…However, it has to be taken into account that these results contrast with most human studies, in which NMDAR antagonists either had no influence or even increased PPI van Berckel et al, 1998;Abel et al, 2003). Furthermore, we found group differences in the prepulse intensity dependence of the PPI.…”

“…However, no effect of NMDAR antagonists on auditory gating was observed in a study in mice (Connolly et al, 2004). Furthermore, two studies in healthy human subjects showed no effect of ketamine on auditory gating (Oranje et al, 2002;van Berckel et al, 1998). The prominent auditory gating deficit in the NR1 mutants contrasts with the unaltered gating in several studies using acute pharmacological NMDAR blockade and possibly indicates that chronic deficient NMDAR-mediated signalling, perhaps even through development, has to be present to cause the auditory gating deficits.…”

Oxytocin as a natural antipsychotic: a study using oxytocin knockout mice

“…41 With regard to PPI, specifically, the findings in healthy patients are mixed, with one study reporting disruption of 'PPI-like' auditory gating following treatment with ketamine, 42 some studies reporting no effects of ketamine on PPI, 43,44 and others reporting enhancement of PPI. [45][46][47] However, it is clear that patients with schizophrenia do have altered PPI 1,5,[48][49][50] and that in nonhuman primates 51,52 and rodents, [53][54][55][56] treatment with NMDA antagonists disrupts PPI.…”

D-Cycloserine Increases Positive Symptoms in Chronic Schizophrenic Patients When Administered in Addition to Antipsychotics A Double-Blind, Parallel, Placebo-Controlled Study

“…Indeed, other NMDA antagonists, like PCP and ketamine, have been shown to induce an exacerbation of disease related psychotic symptoms in schizophrenic patients (Luby et al 1959(Luby et al , 1962Lahti et al 1995;Malhotra et al 1997aMalhotra et al , 1997b. The notion that D-cycloserine may be devoid of agonistic activity at NMDA receptors in this dose and design is supported by the lack of effect of D-cycloserine on LH secretion, as LH secretion in humans has been suggested to be sensitive to the agonistic effects of D-cycloserine (van Berckel et al 1998b) while it is not influenced by NMDA antagonists (van Berckel et al 1998a). Although D-cycloserine did not ameliorate schizophrenic symptoms in this study, the fact that they actually worsened suggests that NMDA systems may be involved in the pathogenesis of schizophrenia.…”