In the present study, we investigated the effects of dextromethorphan (DXM), an NMDAR antagonist, on the ability of subjects to discriminate between the amplitude of two simultaneously delivered vibrotactile stimuli with/without pre-exposure to adaptation stimulation. The results show that the DXM drug administration had no effect on the subjects' performance on a standard amplitude discrimination task, but it significantly reduced the impact of adaptation on amplitude discrimination, and this reduction began to recover two hours after the ingestion of DXM.
Under control conditions (placebo instead of DXM), the observed impairment in amplitude discrimination induced by adaptation is consistent with a previously published report, which demonstrated that a subject's ability to accurately discriminate differences in the amplitude of two simultaneously delivered vibrotactile stimuli was significantly degraded with prior exposure to an adapting stimulus at the test stimulus site [6
]. Tommerdahl and colleagues proposed that the effect of adaptation on amplitude discrimination capacity was due to an elevation of the detection threshold, and thus a reduction in the perceived intensity of a subsequent stimulus, induced by the adapting stimulus. This phenomenon has been characterized in a large body of psychophysical studies [7
] that reported that when the adapting stimulus is increased in duration or amplitude, the perceived intensity evoked by subsequent test stimuli is reduced. A number of neurophysiological studies have demonstrated that the effects of reduced intensity due to adapting stimulation are possibly attributable to a reduction in the responsivity of central neurons or in synaptic processes associated with the central neurons after prolonged or repetitive stimulation. More specifically, O'Mara and colleagues [10
] found that extended exposure to a vibratory stimulus produced substantial reductions in the responsivity of neurons in the cuneate nucleus, but not in the peripheral afferents. Lee and Whitsel [11
] reported that repetitive brushing stimuli frequently lead individual SI neurons and neuron groups to modify their response to the repetitive afferent drive. Additionally, Lee and Whitsel [12
] found that the majority (~58%) of the SI neurons sampled showed a decreased response to repetitive stimulation (3–5 Hz) of their receptive fields. In that report, it was proposed that the glutamate-mediated excitatory effects on NMDAR are to a large extent responsible for the appreciable capacities of cortical neurons to modify their physiological properties with repetitive sensory experience.
It is important to note that the spatial and temporal patterns of responses in primary somatosensory cortex (SI) to repetitive vibrotactile stimulation are largely dependent on the complex interplay of GABA-mediated inhibition [13
] and NMDAR activation [14
] in addition to other neural processes [15
]. The specific contribution of NMDARs to the response evoked by non-noxious tactile stimulation has been described by relatively few studies. Duncan et al systemically administered ketamine, a noncompetitive NMDAR antagonist, in nonhuman primates and found that the responsivity, receptive field (RF) size, and mean firing rate (MFR) of SI neurons evoked by tactile stimulation were reduced in a dose- and time-dependent fashion [3
]. Similarly, Whitsel et al [4
] examined cortical (SI) neuron activity evoked by skin brushing stimulation and, using intravenous ketamine or phencyclidine (PCP) for NMDAR block, found the SI response to be NMDAR dependent and that SI neuron mean firing rate did not diminish with repetitive stimulation in the presence of NMDAR block. Based on their results, they proposed that in the presence of NMDAR block, normal pericolumnar interactions within the cerebral cortical networks become disrupted and the predominant excitatory drive of each SI neuron is conveyed by direct thalamocortical connections acting via AMPA receptors. However, at the same time, the response to that direct drive becomes partially suppressed by the lateral inhibitions derived from the co-activated columns that surround it, which are mediated via NMDAR on the local GABAergic interneurons. As a result, the systemic administration of an NMDAR antagonist is expected to reduce lateral inhibition on the pyramidal neurons of the directly activated column, but allow a full expression of the direct thalamocortical excitatory drive during skin stimulation. Observations obtained from 2DG, optical imaging and RF studies in the presence of NMDAR block were also consistent with these findings [13
]. To summarize, the time dependent changes often observed in SI cortical response to repetitive stimulation were not observed with NMDAR block. Longer duration time dependent effects on tactile perception have also been demonstrated to be significantly impacted by NMDAR block [20
Similar observations in reduction of adaptation to vibrotactile stimulation have been observed in autism [21
]. However, in those studies, it was concluded that this reduction in adaptation was due to compromised or below-normal GABA-mediated neurotransmission in subjects with autism, a finding consistent with a number of reports in the autism literature ([22
]; also see, for discussion: [23
]). Both the reduction of the impact of adaptation on amplitude discrimination in the presence of DXM and a similar reduction observed in subjects with compromised GABA levels supports the model of dynamic cortical response to repetitive stimulation put forth by Whitsel and colleagues [15
] and later expanded by Kelly and Folger [30
]. One of the key elements of that model is that cortical responses in somatosensory cortex to repetitive stimulation are shaped by dynamic pericolumnar lateral interactions mediated by both GABA and NMDAR neurotransmission.
In short, without NMDAR mediated activity, the level of excitation required to evoke inhibitory responses becomes diminished, and the GABA-mediated activity required to diminish the cortical responses evoked by repetitive stimuli becomes weaker. Thus, with NMDAR block, although the overall cortical response is weaker, the change of the response caused by conditioning or adapting stimuli is significantly reduced. It should be noted that although DXM does have effects other than that of an NMDAR antagonist, the known effects of DXM as an NMDAR antagonist are consistent with the impact of NMDAR block on centrally mediated neurotransmission. The observation of weakened adaptation response – to repetitive stimulation in populations whose GABA- or NMDAR-mediated neurotransmission has been compromised – appears to strengthen the original proposal by Whitsel and colleagues that the adaptive changes observed in sensory perception at short stimulus durations (less than 5 seconds) are principally centrally mediated.