RESUMEN

Ketamine is an NMDA receptor antagonist that has antidepressant and anesthetic properties. At subanesthetic doses, ketamine induces transient psychosis in humans, and is used to model psychosis in experimental animals. In rodents, subanesthetic doses of ketamine increase the power of high-frequency oscillations (HFO, > 100 Hz) in the electroencephalogram (EEG), a frequency band linked to cognitive functions. However, to date, the effects of ketamine in carnivores and primates have been poorly investigated. Here, we examined in the cat, cortical HFO during wakefulness, sleep, and after administering a sub-anesthetic dose of ketamine. Four cats were prepared with cortical electrodes for chronic polysomnographic recordings in head-restrained conditions. The cortical HFO power, connectivity, direction of the information flow using Granger Causality (GC) analysis, their relationships with respiratory activity, and the effect of auditory stimulation were analyzed. During wakefulness, but not during sleep, we found that HFO were coupled with the inspiratory phase of the respiration. After ketamine administration, HFO power was enhanced and remained associated with the inspiratory phase. GC analysis suggests that ketamine-enhanced HFO originate from the olfactory bulb (OB) and stream towards the prefrontal cortex (Pf). Accordingly, occluding the nostrils significantly reduced the power of the ketamine-enhanced HFO in both the OB and Pf. Finally, auditory stimulation did not affect HFO. In conclusion, the HFO are associated with respiration during wakefulness, but not during sleep. The enhancement of this rhythm by ketamine may disrupt cortical information processing, which could contribute to some of the neuropsychiatric effects associated with ketamine.

RESUMEN

Wake-related ketamine-dependent high frequency oscillations (HFO) can be recorded in local field potentials (LFP) from cortical and subcortical regions in rodents. The mechanisms underlying their generation and occurrence in higher mammals are unclear. Unfortunately, anesthetic doses of pure ketamine attenuate HFO, which has precluded their investigation under anesthesia. Here, we show ketamine-xylazine (KX) anesthesia is associated with a prominent 80-130 Hz rhythm in the olfactory bulb (OB) of rats, whereas 30-65 Hz gamma power is diminished. Simultaneous LFP and thermocouple recordings revealed the 80-130 Hz rhythm was dependent on nasal respiration. This rhythm persisted despite surgical excision of the piriform cortex. Silicon probes spanning the dorsoventral aspect of the OB revealed this rhythm was strongest in ventral areas and associated with microcurrent sources about the mitral layer. Pharmacological microinfusion studies revealed dependency on excitatory-inhibitory synaptic activity, but not gap junctions. Finally, a similar rhythm occurred in the OB of KX-anesthetized cats, which shared key features with our rodent studies. We conclude that the activity we report here is driven by nasal airflow, local excitatory-inhibitory interactions, and conserved in higher mammals. Additionally, KX anesthesia is a convenient model to investigate further the mechanisms underlying wake-related ketamine-dependent HFO.

Asunto(s)

RESUMEN

Changes in oscillatory activity are widely reported after subanesthetic ketamine, however their mechanisms of generation are unclear. Here, we tested the hypothesis that nasal respiration underlies the emergence of high-frequency oscillations (130-180 Hz, HFO) and behavioral activation after ketamine in freely moving rats. We found ketamine 20 mg/kg provoked "fast" theta sniffing in rodents which correlated with increased locomotor activity and HFO power in the OB. Bursts of ketamine-dependent HFO were coupled to "fast" theta frequency sniffing. Theta coupling of HFO bursts were also found in the prefrontal cortex and ventral striatum which, although of smaller amplitude, were coherent with OB activity. Haloperidol 1 mg/kg pretreatment prevented ketamine-dependent increases in fast sniffing and instead HFO coupling to slower basal respiration. Consistent with ketamine-dependent HFO being driven by nasal respiration, unilateral naris blockade led to an ipsilateral reduction in ketamine-dependent HFO power compared to the control side. Bilateral nares blockade reduced ketamine-induced hyperactivity and HFO power and frequency. These findings suggest that nasal airflow entrains ketamine-dependent HFO in diverse brain regions, and that the OB plays an important role in the broadcast of this rhythm.

Asunto(s)

RESUMEN

High-frequency neuronal population oscillations (HFO, 130-180 Hz) are robustly potentiated by subanesthetic doses of ketamine. This frequency band has been recorded in functionally and neuroanatomically diverse cortical and subcortical regions, notably ventral striatal areas. However, the locus of generation remains largely unknown. There is compelling evidence that olfactory regions can drive oscillations in distant areas. Here we tested the hypothesis that the olfactory bulb (OB) is a locus for the generation of HFO following a subanesthetic dose of ketamine. The effect of ketamine on the electrophysiological activity of the OB and ventral striatum of male Wistar rats was examined using field potential and unit recordings, local inhibition, naris blockade, current source density and causality estimates. Ketamine-HFO was of larger magnitude and was phase-advanced in the OB relative to ventral striatum. Granger causality analysis was consistent with the OB as the source of HFO. Unilateral local inhibition of the OB and naris blockade both attenuated HFO recorded locally and in the ventral striatum. Within the OB, current source density analysis revealed HFO current dipoles close to the mitral layer and unit firing of mitral/tufted cells was phase locked to HFO. Our results reveal the OB as a source of ketamine-HFO which can contribute to HFO in the ventral striatum, known to project diffusely to many other brain regions. These findings provide a new conceptual understanding on how changes in olfactory system function may have implications for neurological disorders involving NMDA receptor dysfunction such as schizophrenia and depression.

Asunto(s)

RESUMEN

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.

Asunto(s)

RESUMEN

BACKGROUND: In humans, subanesthetic doses of ketamine and recovery from ketamine anesthesia are associated with psychotic-like behavior. In rodents, ketamine produces hyperactivity, stereotypies, and abnormal social interaction used to model certain features of schizophrenia. Increasing evidence has implicated aberrant activity in the nucleus accumbens (NAc) with the pathophysiology of schizophrenia. METHODS: Here, we examined the effect of an IP injection of ketamine (10, 25, 50, and 200 mg/kg) and d-amphetamine (3 mg/kg) on local field potentials in the rodent NAc. Locomotor activity was recorded simultaneously. RESULTS: Spontaneous high-frequency oscillations (HFO) (140-180 Hz) were present in local field potentials recorded from the NAc. Ketamine dose-dependently induced rapid and substantial increases in HFO that correlated with behavioral hyperactivity. Similarly, large increases in HFO occurred during recovery from ketamine anesthesia. In contrast, d-amphetamine, which induced locomotor activity, produced only small increases in HFO. CONCLUSIONS: We propose that ketamine-induced abnormal increases in HFO form part of the complex neurological changes in this model of schizophrenia. Ketamine-induced increases in HFO, although sharing similar temporal dynamics to hyperactivity, may not be functionally related to increased movement.

Asunto(s)