Local field potential (LFP) power and phase-amplitude coupling (PAC) changes in the striatum and motor cortex reflect neural mechanisms associated with bradykinesia and rigidity during D2R suppression in an animal model.

Impairments in motor control are the primary feature of Parkinson's disease, which is caused by dopaminergic imbalance in the basal ganglia. Identification of neural biomarkers of dopamine D2 receptor (D2R) suppression would be useful for monitoring the progress of neuropathologies and effects of treatment. Male Swiss albino ICR mice were deeply anesthetized, and electrodes were implanted in the striatum and motor cortex to record local field potential (LFP). Haloperidol (HAL), a D2R antagonist, was administered to induce decreased D2R activity. Following HAL treatment, the mice showed significantly decreased movement velocity in open field test, increased latency to descend in a bar test, and decreased latency to fall in a rotarod test. LFP signals during HAL-induced immobility (open field test) and catalepsy (bar test) were analyzed. Striatal low-gamma (30.3-44.9 Hz) power decreased during immobility periods, but during catalepsy, delta power (1-4 Hz) increased, beta1(13.6-18 Hz) and low-gamma powers decreased, and high-gamma (60.5-95.7 Hz) power increased. Striatal delta-high-gamma phase-amplitude coupling (PAC) was significantly increased during catalepsy but not immobility. In the motor cortex, during HAL-induced immobility, beta1 power significantly increased and low-gamma power decreased, but during HAL-induced catalepsy, low-gamma and beta1 powers decreased and high-gamma power increased. Delta-high-gamma PAC in the motor cortex significantly increased during catalepsy but not during immobility. Altogether, the present study demonstrated changes in delta, beta1 and gamma powers and delta-high-gamma PAC in the striatum and motor cortex in association with D2R suppression. In particular, delta power in the striatum and delta-high-gamma PAC in the striatum and motor cortex appear to represent biomarkers of neural mechanisms associated with bradykinesia and rigidity.

Differential local field potential oscillations in the dorsal striatum and locomotor activity induced by morphine and haloperidol in mice.

Dopamine (DA) depletion in the dorsal striatum underlies symptoms of basal ganglia pathologies, including Parkinson's disease (PD). Various drug compounds are used to enhance DA levels for therapeutic purposes. Understanding neural signaling and movement patterns associated with over­ and under­stimulation of the DA system is essential. This study investigated striatal local field potential (LFP) oscillation and locomotor activity following treatments with morphine, a DA release enhancer, and haloperidol (HAL), a DA D2 receptor (D2R) antagonist in mice. After intracranial electrodes were placed into the dorsal striatum of male Swiss albino ICR mice, intraperitoneal injections of morphine or HAL were administered. LFP signals and spontaneous motor activity were recorded simultaneously. The results showed that morphine significantly increased locomotor speed, both low (30.3-44.9 Hz) and high (60.5-95.7 Hz) LFP gamma powers and delta (1-4 Hz)­gamma (30.3-95.7 Hz) phase­amplitude coupling. In contrast, HAL treatments were found to significantly decrease these parameters. Moreover, regression analyses also revealed significant positive correlations between locomotor speed and high gamma powers. Taken together, these results demonstrate opposite LFP oscillations in the dorsal striatum with low and high gamma activities, and delta­gamma couplings in response to a DA release enhancer and D2R antagonist by morphine and HAL, respectively. These parameters reflect fluctuation of neuronal activity in the dorsal striatum that might be useful for pathological research and drug discovery for PD.

Dopamine Improves Low Gamma Activities in the Dorsal Striatum of Haloperidol-induced Motor Impairment Mice.

BACKGROUND/AIM: The dorsal striatum is a brain area integrating information for movement output. The local field potentials (LFPs) reflect the neuronal activity that can be used for monitoring brain activities and controlling movement. MATERIALS AND METHODS: Rhythmic low gamma power activity (30.1-45 Hz) in the dorsal striatum was monitored according to voluntary motor movement in rotarod and bar tests in 0.5 mg/kg haloperidol-induced mice. RESULTS: Haloperidol can effectively induce movement impairment indicated by decreased low gamma LFP with the lessened rotarod test's latency fall, and the enhanced bar test's descending latency. L-DOPA was used for the induction of a dopamine-dependent signal. The results showed that 25 mg/kg of L-DOPA could reverse the effect of haloperidol by enhancing low gamma oscillation concomitantly with the improvement in behavioral movement as fast as 60 min after administration, suggesting that dopamine signaling increases low gamma frequency of LFP in correlation with the improved mice movement. This work supports quantitative LFP assessment as a monitoring tool to track drug action on the nervous system. CONCLUSION: In animal models of motor impairment, oral dopaminergic treatment can be effective in restoring motor dysfunction by stimulating low gamma power activity in the dorsal striatum.

Adaptive changes in local field potential oscillation associated with morphine conditioned place preference in mice.

Neural adaptation associated with formation of morphine conditioned place preference remained largely unexplored. This study monitored longitudinal changes in neural signaling during pre-conditioning, conditioning and post-conditioning periods of morphine conditioned place preference (CPP) paradigm for investigation of adaptive mechanisms of opiate addiction. Male Swiss albino mice implanted with intracranial electrodes into the nucleus accumbens (NAc), striatum (STr) and hippocampus (HC) were used for recording of local field potentials (LFPs). Animals received a 10-day schedule for associative learning to pair the specific compartment of the chamber with morphine effects. Exploratory behavior and LFP signals were recorded during pre-conditioning (baseline level), conditioning (day 1, 5 and 10) and post-conditioning (day 1, 4 and 7) periods. Repeated measures one-way ANOVA followed by Tukey test revealed significant increases in number of visit and time spent in morphine compartment during post-conditioning days. Frequency analysis of LFP highlighted the increases in alpha activity (12 - 18 Hz) in the NAc from post-conditioning day 1 until day 7. Moreover, significantly increased coherent activities between the pair of NAc-HC were developed within gamma frequency range (35 - 42 Hz) on morphine conditioning day 10 and disappeared during post-conditioning days. Taken together, these findings emphasized NAc LFP signaling and neural connectivities between the NAc and HC associated with morphine CPP. These adaptive changes might underlie the formation of morphine conditioned place preference and behavioral consequences such as craving and relapse.

Local field potential power spectra and locomotor activity following treatment with pseudoephedrine in mice.

The efficacy of pseudoephedrine (PSE) as a nasal decongestant has been well­demonstrated; however, PSE is strictly prescribed as a control substance due to its controversial psychostimulant effects. Although standard stimulatory drugs increase exploratory behavior and stimulate the dopamine system, the exact effects of PSE on locomotion and electrical activity in the striatum have not been determined. This study aimed to examine and compare the locomotor activities, local field potential (LFP) and sleep­wake patterns produced by PSE and morphine, which is a standard drug used to promote psychomotor activity. Male Swiss albino mice were anesthetized and implanted with an intracranial electrode into the striatum. Animals were divided into four groups, which received either saline, PSE or morphine. Locomotor activity and LFP signals were continuously monitored following pseudoephedrine or morphine treatment. One­way ANOVA revealed that locomotor count was significantly increased by morphine, but not PSE. Frequency analyses of LFP signals using fast Fourier transform also revealed significant increases in spectral powers of low­ and high­gamma waves following treatment with morphine, but not PSE. Sleep­wake analysis also confirmed significant increases in waking and decreases in both non­rapid eye movement and rapid eye movement sleep following morphine treatment. Sleep­wakefulness did not appear to be disturbed by PSE treatment. These findings indicate that acute PSE administration, even at high doses, does not have psychostimulatory effects and may be relatively safe for the treatment of non­chronic nasal congestion.

Dexamethasone induces alterations of slow wave oscillation, rapid eye movement sleep and high-voltage spindle in rats.

Glucocorticoids arising from chronic stress and long-term inflammatory treatment with corticosteroids are both associated with neuropathology and cognitive impairments. Many previous studies have focused on changes in brain morphology and deficits in learning behavior. However, effects of long-term exposure to stress hormones on electrical brain signaling and sleep-wake patterns have remained largely unexplored. This study aimed to monitor electroencephalographic (EEG) patterns induced by prolonged dexamethasone exposure. Adult male Wistar rats implanted with electrodes on the skull over the frontal and parietal cortices were intraperitoneally injected with either saline or dexamethasone (0.5 mg/kg) once daily for 21 consecutive days. Longitudinal EEG recording was performed on day 6, 11, 16 and 21. Fast Fourier transform was used for frequency power analysis. One-way ANOVA revealed significant increases in parietal EEG power of slow frequencies (delta, theta and alpha) particularly, with the dominant theta activity seen as early as day 11 of dexamethasone treatment. Sleep-wake analysis on day 21 confirmed a significant reduction of rapid-eye movement (REM) sleep and increased slow frequency oscillations mainly in the parietal cortex during the awake period. The number of high-voltage spindles (HVSs) (6-10 Hz EEG oscillation) was significantly increased during awake and slow wave sleep (SWS) periods following dexamethasone treatment. These findings demonstrated that distinct frequency oscillations, sleep-wakefulness and sleep spindles may be parameters of neuropathology produced by long-term dexamethasone exposure. Early detection of these parameters might be predictive of neuropathology in long-term corticosteroid users.

Nucleus accumbens local field potential power spectrums, phase-amplitude couplings and coherences following morphine treatment.

In the past decade, neural processing has been extensively studied in cognitive neuroscience. However, neural signaling in the nucleus accumbens (NAc) that might clarify reward process remained to be investigated. Male Swiss albino ICR mice implanted with intracranial electrodes into the NAc and the ventral tegmental area (VTA) were used for morphine administration and local field potential (LFP) recording. One-way ANOVA revealed significant increases in low (30.3-44.9 Hz) and high (60.5-95.7 Hz) gamma powers in the NAc following morphine administration (5 and 15 mg/kg, i.p.). These gamma activities oscillated independently with different time-course responses. Locomotor activity was also significantly increased by morphine administration. Regression analyses revealed that high gamma activity induced by morphine was positively correlated with distance travelled by animals. Low and high gamma powers were completely abolished by injection of naloxone, a non-specific opiate antagonist. Analysis of phase-amplitude coupling confirmed that slow oscillations at 1-4 Hz (delta) and 4-8 Hz (theta) for phase were found to significantly increase modulation index of broad (30.27-80.77 Hz) and narrow (59.48-70.34 Hz) frequency ranges for amplitude, respectively. Moreover, significant increases in coherence values between the NAc and the VTA during 30-40 min following morphine administration were seen for 22.46-44.90 Hz frequency range. Altogether, this study demonstrated changes of LFP oscillations in the NAc with low and high gamma activities, delta- and theta-gamma couplings and interplay with VTA in response to morphine administration. These findings represent neural signaling in the mesolimbic dopamine pathway that might process reward function.

Effects of alkaloid-rich extract from Mitragyna speciosa (Korth.) Havil. on naloxone-precipitated morphine withdrawal symptoms and local field potential in the nucleus accumbens of mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Mitragyna speciosa (Korth.) Havil. (M. speciosa) is among the most well-known plants used in ethnic practice of Southeast Asia. It has gained increasing attention as a plant with potential to substitute morphine in addiction treatment program. However, its action on the central nervous system is controversial. AIM OF THE STUDY: This study investigated the effects of M. speciosa alkaloid extract on naloxone-precipitated morphine withdrawal and neural signaling in the nucleus accumbens (NAc, brain reward center) of mice. MATERIALS AND METHODS: The effects of M. speciosa alkaloid extract and mitragynine, a pure major constituent, on naloxone-precipitated morphine withdrawal were examined. Male Swiss Albino (ICR) mice were rendered dependent on morphine before injection with naloxone, a nonspecific opioid antagonist, to induce morphine withdrawal symptoms. The intensity of naloxone-precipitated morphine withdrawal was assessed from jumping behavior and diarrhea induced during a period of morphine withdrawal. To test possible addictive effect of M. speciosa alkaloid extract, mice were implanted with intracranial electrode into the NAc for local field potential (LFP) recording. Following M. speciosa alkaloid extract (80mg/kg) and morphine (15mg/kg) treatment, LFP power spectra and spontaneous motor activity were analyzed in comparison to control levels. RESULTS: One-way ANOVA and multiple comparisons revealed that M. speciosa alkaloid extract (80 and 100mg/kg) significantly decreased the number of jumping behavior induced by morphine withdrawal whereas mitragynine did not. Additionally, M. speciosa alkaloid extract significantly decreased dry and wet fecal excretions induced by morphine withdrawal. LFP analysis revealed that morphine significantly decreased alpha (9.7-12Hz) and increased low gamma (30.3-44.9Hz) and high gamma (60.5-95.7Hz) powers in the NAc whereas M. speciosa alkaloid extract did not. Spontaneous motor activity was significantly increased by morphine but not M. speciosa alkaloid extract. CONCLUSIONS: Taken together, M. speciosa alkaloid extract, but not mitragynine, attenuated the severity of naloxone-precipitated morphine withdrawal symptoms. Neural signaling in the NAc and spontaneous motor activity were sensitive to morphine but not M. speciosa alkaloid extract. Therefore, treatment with the M. speciosa alkaloid extract may be useful for opiate addiction treatment program.

Low gamma wave oscillations in the striatum of mice following morphine administration.

Functional role of the striatum in motor control has been widely studied. In addition, its involvement in reward function as a brain area in the dopamine system has also been mentioned. However, neural signaling in the striatum in response to consumption of emotional enhancing substances remained to be explored. This study aimed to investigate local field potential (LFP) of the striatum following morphine administration. Male Swiss albino mice implanted with electrode into the striatum were given an intraperitoneal injection of either saline or morphine (5 or 15 mg/kg). LFP and locomotor activity of individual animals were simultaneously recorded in the recording chamber following the administration. The inspection of LFP tracings revealed the increase in fast wave induced by morphine particularly at a high dose. Statistical analyses were performed using a one way ANOVA followed by Tukey post hoc test. Frequency analysis using Fast Fourier transform also confirmed a significant elevation of low gamma (30-44.9 Hz) activity. When analyzed in time domain, significant increase in low gamma power was observed from the 15th to 65th min following 15 mg/kg morphine treatment. Moreover, morphine treatment also exhibited a stimulating effect on locomotor speed. However, regression analyses revealed no significant correlation between low gamma power and locomotor speed. In summary, this study demonstrated the increase in low gamma oscillation in the striatum and this effect was not associated with locomotor activity of animals. Thus, it is possible that low gamma oscillation induced by morphine treatment is related with the reward function.