Mark J. Hunt

Differential effects produced by ketamine on oscillatory activity recorded in the rat hippocampus, dorsal striatum and nucleus accumbens

Previously, we showed that NMDA antagonists enhance high-frequency oscillations (130–180 Hz) in the nucleus accumbens. However, whether NMDA antagonists can enhance high-frequency oscillations in other brain regions remains unclear. Here, we used monopolar, bipolar and inverse current source density techniques to examine oscillatory activity in the hippocampus, a region known to generate spontaneous ripples (∼200 Hz), its surrounding tissue, and the dorsal striatum, neuroanatomically related to the nucleus accumbens. In monopolar recordings, ketamine-induced increases in the power of high-frequency oscillations were detected in all structures, although the power was always substantially larger in the nucleus accumbens. In bipolar recordings, considered to remove common-mode input, high-frequency oscillations associated with ketamine injection were not present in the regions we investigated outside the nucleus accumbens. In line with this, inverse current source density showed the greatest changes in current to occur in the vicinity of the nucleus accumbens and a monopolar structure of the generator. We found little spatial localisation of ketamine high-frequency oscillations in other areas. In contrast, sharp-wave ripples, which were well localized to the hippocampus, occurred less frequently after ketamine. Notably, we also found ketamine produced small, but significant, changes in the power of 30–90 Hz gamma oscillations (an increase in the hippocampus and a decrease in the nucleus accumbens).

A systematic review of the effects of NMDA receptor antagonists on oscillatory activity recorded in vivo

Distinct frequency bands can be differentiated from neuronal ensemble recordings, such as local field potentials or electrocorticogram recordings. Recent years have witnessed a rapid acceleration of research examining how N-methyl-D-aspartate receptor (NMDAR) antagonists influence fundamental frequency bands in cortical and subcortical brain regions. Herein, we systematically review findings from in vivo studies with a focus on delta, theta, gamma and more recently identified high-frequency oscillations. We also discuss some of the current hypotheses that are considered to account for the actions of NMDAR antagonists on these frequency bands. The data emphasize a close relationship between altered oscillatory activity and NMDAR blockade, with both local and large-scale networks accounting for their effects. These findings may have fundamental implications for the psychotomimetic effects produced by NMDAR antagonists.

Local injection of MK801 modifies oscillatory activity in the nucleus accumbens in awake rats

Pharmacological blockade of NMDA receptors is used to model certain aspects of schizophrenia. It had been shown previously that ketamine dose dependently enhances high-frequency oscillations in the rodent nucleus accumbens, a structure implicated in schizophrenia. Here, the authors examined the effect of intra-accumbal and systemic administration of MK801 on delta, gamma and high-frequency oscillatory activity recorded in the nucleus accumbens of freely moving rats. In this study, rats were implanted with electrodes in the nucleus accumbens for chronic local field potential recording. Rats received either bilateral injections of MK801 (1 and 4 μg) or intraperitoneal injections of the drug (0.1 and 0.5 mg/kg). Saline was used as control in each instance. Both local and systemic injections significantly enhanced the power and frequency of high-frequency oscillations and caused an increase in the occurrence, duration and amplitude of high-frequency oscillatory bursts. In contrast, no effect or a decrease in the power of delta and gamma bands was observed following local or systemic administration of MK801, respectively. These findings suggest that the dominant change in oscillatory activity after administration of NMDA receptor antagonists affect high frequencies. Moreover, direct NMDA blockade in the accumbal circuitry is sufficient to generate increases in high-frequency oscillations. The presence of abnormal oscillatory activity in the accumbens may be associated with the psychomimetic effects of NMDA receptor antagonists.

Antipsychotic compounds differentially modulate high-frequency oscillations in the rat nucleus accumbens: a comparison of first- and second-generation drugs

Improved understanding of the actions of antipsychotic compounds is critical for a better treatment of schizophrenia. Abnormal oscillatory activity has been found in schizophrenia and in rat models of the disease. N-Methyl-D-aspartic acid receptor (NMDAR) antagonists, used to model certain features of schizophrenia, increase the frequency and power of high-frequency oscillations (HFO, 130-180 Hz) in the rat nucleus accumbens, a brain region implicated in schizophrenia pathology. Antipsychotics can be classified as first- and second-generation drugs, the latter often reported to have wider benefit in humans and experimental models. This prompted the authors to examine the pre- and post-treatment effects of clozapine, risperidone (second-generation drugs) and sulpiride and haloperidol (first-generation drugs) on ketamine and MK801-enhanced accumbal HFO. Both NMDAR antagonists increased HFO frequency. In contrast, clozapine and risperidone markedly and dose-dependently reduced the frequency of spontaneous and NMDAR-antagonist-enhanced HFO, whilst a moderate effect was found for sulpiride and a much weaker effect for haloperidol. Unexpectedly, we found reductions in HFO frequency were associated with an increase in its power. These findings indicate that modulation of accumbal HFO frequency may be a fundamental effect produced by antipsychotic compounds. Of the drugs investigated, first- and second-generation compounds could be dissociated by their potency on this measure. This effect may partially explain the differences in the clinical profile of these drugs.

NMDA receptor antagonist-enhanced high frequency oscillations: Are they generated broadly or regionally specific?

Systemic administration of NMDA receptor antagonists, used to model schizophrenia, increase the power of high-frequency oscillations (130-180Hz, HFO) in a variety of neuroanatomical and functionally distinct brain regions. However, it is unclear whether HFO are independently and locally generated or instead spread from a distant source. To address this issue, we used local infusion of tetrodotoxin (TTX) to distinct brain areas to determine how accurately HFO recorded after injection of NMDAR antagonists reflect the activity actually generated at the electrode tip. Changes in power were evaluated in local field potentials (LFPs) recorded from the nucleus accumbens (NAc), prefrontal cortex and caudate and in electrocorticograms (ECoGs) from visual and frontal areas. HFO recorded in frontal and visual cortices (ECoGs) or in the prefrontal cortex, caudate (LFPs) co-varied in power and frequency with observed changes in the NAc. TTX infusion to the NAc immediately and profoundly reduced the power of accumbal HFO which correlated with changes in HFO recorded in distant cortical sites. In contrast, TTX infusion to the prefrontal cortex did not change HFO power recorded locally, although gamma power was reduced. A very similar result was found after TTX infusion to the caudate. These findings raise the possibility that the NAc is an important neural generator. Our data also support existing studies challenging the idea that high frequencies recorded in LFPs are necessarily generated at the recording site.

The effect of dopamine receptor blockade in the rodent nucleus accumbens on local field potential oscillations and motor activity in response to ketamine.

Altered functioning of the nucleus accumbens (NAc) has been implicated in the psychotomimetic actions of NMDA receptor (NMDAR) antagonists and the pathophysiology of schizophrenia. We have shown previously that NMDAR antagonists enhance the power of high-frequency oscillations (HFO) in the NAc in a dose-dependent manner, as well as increase locomotor activity. Systemic administration of NMDAR antagonists is known to increase the release of dopamine in the NAc and dopamine antagonists can reduce ketamine-induced hyperactivity. In this study, we examined the effect of 0.5 μl intra-NAc infusion of 3.2 μg SCH23390 (D1 antagonist), 10 μg raclopride (D2 antagonist) and saline on ketamine-induced changes in motor and oscillatory activity. We found that local blockade of D1 receptors attenuated ketamine-induced increases in motor activity and blockade of D2 receptors produced a much weaker effect, with respect to saline-infused control groups. In contrast, none of the antagonists, infused separately or together, significantly modified the power or dominant frequency of ketamine-induced increases in HFO, but changes in delta and theta frequency bands were observed. Together, these findings suggest, that, in contrast to delta and theta frequency bands, the generation of ketamine enhanced-HFO in the NAc is not causally related to locomotor activation and occurs largely independently of local changes in dopamine receptor activation.

State-dependent changes in high-frequency oscillations recorded in the rat nucleus accumbens.

Among the local field potentials recorded in the rat nucleus accumbens (NAc) spontaneous high frequency oscillations (HFO) are typically represented by a small peak in the power spectra in the range of 140-180 Hz. These HFO are known to occur in the awake state, but their distribution over the sleep-wake cycle has not been investigated. To address this issue we firstly examined the power of HFO during periods of quiet waking, slow-wave sleep (SWS) and rapid eye movement (REM) sleep. Since general anesthesia resembles certain features of naturally occurring SWS we went on to examine the effect of pentobarbital, isoflurane or urethane anesthesia on spontaneous and ketamine-induced increases in HFO. With respect to waking, the power of spontaneous HFO decreased significantly during periods of SWS but did not differ during bouts of REM sleep. General anesthetics also reduced the power of spontaneous HFO recorded in the NAc and prevented the ketamine-induced increase. These findings suggest that behavioural states where the generation of mental activity is most intense are associated with the presence of HFO in the NAc. In line with this, states which lead to decreased mentation, such as naturally occurring SWS and general anesthesia are associated with reductions in the power of HFO. Our results also suggest that the awake state is necessary for NMDA antagonists to produce enhancement of HFO.

Hippocampal theta rhythm after serotonergic activation of the pedunculopontine tegmental nucleus in anesthetized rats.

The pedunculopontine tegmental nucleus (PPN), as a part of reticular formation activating system, is thought to be involved in the sleep/wake cycle regulation, and plays an important role in the generation and regulation of hippocampal rhythmical slow activity. The activity of PPN can be modulated by serotonergic system, mainly through multiple projections from raphe nuclei, which can influence PPN neurons through different classes of 5-HT receptors. In the present study, the effect of intra-PPN injection of two serotonin agonists: 8-OH-DPAT and 5-CT, on hippocampal formation EEG activity was examined in urethane-anesthetized rats. The study found that the microinjections induced prolonged spontaneous theta rhythm in both hippocampi with a short latency. The results obtained suggest that local inhibition of presumably cholinergic neurons in the PPN acts as a trigger for hippocampal theta activity.