Modulation of high-frequency oscillations associated with NMDA receptor hypofunction in the rodent nucleus accumbens by lamotrigine

Abstract

We reported recently that ketamine can increase the power of high-frequency oscillations (HFO) in the rodent nucleus accumbens (NAc), a region implicated in the pathophysiology of schizophrenia. Lamotrigine is known to reduce several of the abnormal behaviors induced by NMDA receptor antagonists in humans and rodents. This prompted us to examine whether lamotrigine would disrupt ketamine-enhanced HFO. Local field potentials (LFPs) and locomotor activity were recorded from male Wistar rats chronically implanted with electrodes in the NAc. Rats were pretreated with either saline or lamotrigine for 60min followed by injection of ketamine (25mg/kg). A separate group received a unilateral intra-NAc infusion of lamotrigine immediately followed by systemic injection of ketamine. We found systemic injection of a high dose of lamotrigine (20.1mg/kg) reduced the power and frequency of ketamine-enhanced HFO. This dose of lamotrigine was also associated with a decrease in both spontaneous HFO and locomotor activity, but did not significantly reduce locomotor activity induced by ketamine. In contrast, a low dose of lamotrigine (2.0mg/kg) produced a small, but significant increase of both ketamine-enhanced HFO and locomotor activity. Local infusion of lamotrigine into the NAc did not significantly affect ketamine-induced HFO, suggesting lamotrigine produces its effect on structures afferent to the NAc, and effects on HFO most likely result from modulating excitatory transmission to the NAc.