NMDA Antagonist Ketamine Reduces Task Selectivity in Macaque Dorsolateral Prefrontal Neurons and Impairs Performance of Randomly Interleaved Prosaccades and Antisaccades

Abstract

Ketamine, an NMDA receptor antagonist, has been shown to induce behavioral abnormalities in humans that mimic the positive, negative, and most importantly cognitive deficits observed in schizophrenia. Similar cognitive deficits have been observed in nonhuman primates after a subanesthetic dose of ketamine, including an impairment in their ability to perform the antisaccade task, which requires the suppression of a prosaccade toward a flashed stimulus and the generation of a saccade in the opposite direction. The neural basis underlying these cognitive impairments remains unknown. Here, we recorded single-neuron activity in the lateral prefrontal cortex of macaque monkeys before and after the administration of subanesthetic doses of ketamine during the performance of randomly interleaved prosaccade and antisaccade trials. Ketamine impeded the monkeys' ability to maintain and apply the correct task rule and increased reaction times of prosaccades and antisaccades. These behavioral changes were associated with an overall increase in activity of PFC neurons and a reduction in their task selectivity. Our results suggest that the mechanism underlying ketamine-induced cognitive abnormalities may be the nonspecific increase in PFC activity and the associated reduction of task selectivity.

Computational Psychiatry

“…In a recent experiment with monkeys performing a working memory task , iontophoresis of drugs that blocked the NMDA receptors suppressed delay-period persistent activity of PFC ( Figure 4D), in support of an important role of the NMDA receptors in PFC processes. Another monkey experiment showed that ketamine (an NMDA receptor antagonist) reduces task selectivity of PFC neurons in parallel with behavioral impairment (Skoblenick and Everling 2012). These findings are directly relevant to psychiatry.…”

S-ketamine influences strategic allocation of attention but not exogenous capture of attention

“…It could be that the afferent input from one of these cortical areas into the SC or even a merely cortically generated inhibitory effect is ultimately responsible for the selective influence of s-ketamine on strategic shifting of attention or the eyes (cf. Skoblenick & Everling, 2012). With respect to a cortical origin, because several areas of the cortex have been demonstrated to be involved in inhibiting of attention shifts (Mayer, Seidenberg, Dorflinger, & Rao, 2004), all effects of s-ketamine on early strategic attention shifts could possibly be due to cortical processing alone.…”

Blocking NMDAR Disrupts Spike Timing and Decouples Monkey Prefrontal Circuits: Implications for Activity-Dependent Disconnection in Schizophrenia

“…Blocking NMDAR weakens delay period activity associated with working memory (Wang et al, 2013), reduces the strength and task selectivity of neural signals reflecting executive control in rule-based tasks (Ma et al, 2015; Skoblenick and Everling, 2012), and modifies prefrontal oscillations reflecting trial outcome (Skoblenick et al, 2016). However, prior studies have not investigated how blocking NMDAR alters spike timing in monkey prefrontal circuits or whether such a change in spiking dynamics may persistently decouple prefrontal circuits.…”