Insop Shim

GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease

In Alzheimers disease (AD), memory impairment is the most prominent feature that afflicts patients and their families. Although reactive astrocytes have been observed around amyloid plaques since the disease was first described, their role in memory impairment has been poorly understood. Here, we show that reactive astrocytes aberrantly and abundantly produce the inhibitory gliotransmitter GABA by monoamine oxidase-B (Maob) and abnormally release GABA through the bestrophin 1 channel. In the dentate gyrus of mouse models of AD, the released GABA reduces spike probability of granule cells by acting on presynaptic GABA receptors. Suppressing GABA production or release from reactive astrocytes fully restores the impaired spike probability, synaptic plasticity, and learning and memory in the mice. In the postmortem brain of individuals with AD, astrocytic GABA and MAOB are significantly upregulated. We propose that selective inhibition of astrocytic GABA synthesis or release may serve as an effective therapeutic strategy for treating memory impairment in AD.

Nicotine-induced behavioral sensitization is associated with extracellular dopamine release and expression of c-Fos in the striatum and nucleus accumbens of the rat

It is well known that repeated injections of nicotine produce progressively larger increases in locomotor activity, an effect referred to as behavioral sensitization. This study was carried out to investigate the neural mechanisms underlying nicotine-induced behavioral sensitization using in vivo microdialysis and Fos-like immunohistochemistry (FLI). Rats were given repeated injections of saline or nicotine (0.4 mg/kg s.c., twice daily for 7 days) followed by one challenge injection on the 4th day after the last daily injection. Systemic challenge with nicotine produced a much larger increase in locomotor activity in nicotine-pretreated rats (659.1+/-94.9 counts/2 h) than in saline-pretreated rats (218.1+/-61 counts/2 h). A direct local challenge of nicotine (1 or 5 mM) via a microdialysis probe in the nucleus accumbens or striatum induced a much greater dose-dependent increase of dopamine (DA) output in nicotine-pretreated rats than in saline-pretreated rats. Furthermore, in parallel with the behavioral and biochemical data, systemic challenge with nicotine produced marked Fos-like immunohistochemistry in the nucleus accumbens and the striatum in the nicotine-pretreated rats. Taken together, this study demonstrates that behavioral sensitization is clearly associated with an increase in DA release and activation of Fos-like immunoreactive cells in the striatum and the nucleus accumbens produced by repeated nicotine treatment. Our results strongly suggest that the striatum and the nucleus accumbens may play a major role in nicotine-induced behavioral sensitization. The present results are discussed in terms of the development and expression of nicotine-induced behavioral sensitization.

Effects of acupuncture on chronic corticosterone-induced depression-like behavior and expression of neuropeptide Y in the rats

Repeated injection of corticosterone (CORT) induces dysregulation in the HPA axis, resulting in depression and anxiety. Many studies have shown that acupuncture, which is widely used for the treatment of stress and mental illness, in East Asian countries, is an effective therapeutic intervention for psychosomatic disorders. We investigated the influence of acupuncture therapy on chronic CORT-induced behavioral responses to the forced swimming test (FST) and elevated plus maze (EPM) and expression of neuropeptide Y (NPY) in the rat brain using immunohistochemistry. Male Sprague-Dawley rats were injected with CORT (40 mg/kg, i.p.) once daily for 19 consecutive days. The dysregulation of HPA axis by external injection of CORT was confirmed by measuring the CORT concentration in plasma and the expression level of CRF in hypothalamus. Acupuncture was performed at the PC6 acupoint for 5 min before CORT injection. Acupuncture significantly reduced depression- and anxiety-like behavior and increased NPY expression in the hypothalamus. These results demonstrated that stimulation of the PC6 acupoint suppresses the symptopathology of the hypoactivated HPA axis in chronic CORT-induced rat model of depression.

Effect of electroacupuncture on response to immobilization stress.

Forced immobilization is a simple and effective stressor which produces large increases in heart rate (HR), blood pressure (BP), and plasma levels of norepinephrine (NE) and epinephrine (EPI). This study investigated the effects of electroacupuncture on BP, HR, and plasma catecholamine levels in rats challenged with immobilization stress. Male Sprague-Dawley rats received electroacupuncture (3 Hz, 0.2 ms pulses, 20 mA) for 30 min after start of immobilization stress (180 min). Needlepoints corresponded to Shaohai (HT3) and Neiguan (PC6) on the heart and pericardium channel. BP and HR were monitored with an indwelling carotid catheter, and blood samples were taken from the jugular vein. Blood (for HPLC determination of NE and EPI), mean BP, and HR were sampled at rest and during the immobilization stress at 15, 30, 60, 90, 120, 150, and 180 min. Electroacupuncture at HT3 and PC6 points but not at control points (TE5, LI11, and tail) significantly reduced the expected increases in BP, HR, and attenuated plasma levels of NE and EPI in response to 3 h of immobilization stress. Results provide strong evidence that electroacupuncture effectively reduces BP and HR increases and plasma catecholamine increases in rats challenged with immobilization stress.

Expression of neuropeptide Y and cholecystokinin in the rat brain by chronic mild stress.

Neuropeptide Y (NPY) and cholecystokinin (CCK) are known to play important roles in the response to stress and the control of anxiety. In order to investigate the role of NPY and CCK in chronic mild stress (CMS), an animal model of depression, we examined the effects of CMS on sucrose intake as a measure of anhedonia, and expression of NPY and CCK in the rat brain utilizing immunohistochemistry. Sprague-Dawley rats were exposed to a variety of chronic unpredictable mild stressors for 8 weeks. CMS rats significantly reduced the consumption of sucrose intake and gained body weight more slowly, compared to control rats. CMS dramatically produced a decrease in NPY expression in several diencephalic regions including the parvocellular subregion of the paraventricular hypothalamic nucleus (PVN), the periventricular hypothalamic nucleus (PE), the paraventricular thalamic nucleus (PV) and the arcuate nucleus (ACN). In contrast, CCK-like immunoreactivity throughout these areas was substantially increased in chronic mild stressed rats. These results clearly demonstrated that exposure of chronic mild stress upregulated CCK synthesis and downregulated NPY synthesis within the hypothalamus. The present results demonstrated that there was an inverse relationship between NPY and CCK in mediating stress response in an animal model of depression. These findings suggest that CCK and NPY systems may play important roles in expressing the symptopathology of the chronic stress responses such as depression, abnormality of food intake or anxiety-related disorders.

Acupuncture-mediated inhibition of ethanol-induced dopamine release in the rat nucleus accumbens through the GABAB receptor.

Clinical trials are currently underway to determine the effectiveness of acupuncture in the treatment of drug abuse. However, there are still many unanswered questions about the basic mechanisms of acupuncture. Studies have shown that the GABA(B) receptor system may play a significant modulatory role in the mesolimbic system in drug abuse, including ethanol. The in vivo microdialysis study was designed to investigate the effect of acupuncture on acute ethanol-induced dopamine release in the nucleus accumbens and the potential role of the GABA(B) receptor system in acupuncture. Male Sprague-Dawley rats were administered with the highly selective GABA(B) antagonist SCH 50911 (3 mg/kg, i.p.) 1h prior to an intraperitoneal injection of ethanol (1 g/kg). Immediately after ethanol treatment, acupuncture was given at bilateral Shenmen (HT7) points for 1min. Acupuncture at the specific acupoint HT7, but not at control points (PC6 or tail) significantly decreased dopamine release in the nucleus accumbens. Inhibition of dopamine release by acupuncture was completely prevented by SCH 50911. These results suggest that stimulation of specific acupoints inhibits ethanol-induced dopamine release by modulating GABA(B) activity and imply that acupuncture may be effective in blocking the reinforcing effects of ethanol.

Acupuncture normalizes the release of accumbal dopamine during the withdrawal period and after the ethanol challenge in chronic ethanol-treated rats

Many studies have shown that acupuncture can contribute to the biochemical balance in the central nervous system and maintenance or recovery of homeostasis. It is well known that chronic administration of ethanol may produce depletion or sensitization of extracellular dopamine levels in the nucleus accumbens. The present study was designed to investigate the effects of acupuncture on chronic ethanol-induced changes in extracellular dopamine levels in the nucleus accumbens shell (using in vivo microdialysis in unanesthetized rats). Male Sprague-Dawley rats were treated with 3 g/kg/day of ethanol (20%, w/v) or saline by intraperitoneal injection for 21 days. Following 72 h of ethanol withdrawal, acupuncture was applied at bilateral Shenmen (HT7) points for 1 min. Different group of rats using the same paradigm of ethanol treatment were acupunctured at the same points after the systemic ethanol challenge (3 g/kg, i.p.). Acupuncture at the specific acupoint HT7, but not at control points (PC6 or tail) significantly prevented both a decrease of extracellular dopamine levels in the nucleus accumbens during ethanol withdrawal and an increase in accumbal dopamine levels induced by the ethanol challenge. These results provided strong evidence that stimulation of the specific acupoint HT7 helps to normalize the release of dopamine in the mesolimbic system following chronic ethanol treatment.

Role of nitric oxide synthase inhibitors and NMDA receptor antagonist in nicotine-induced behavioral sensitization in the rat

Repeated injections of nicotine are well known to produce progressively larger increases in locomotor activity, an effect defined as behavioral sensitization. This study was carried out to investigate the role of nitric oxide (NO) and N-methyl-D-aspartate (NMDA) receptors in nicotine-induced behavioral sensitization. Rats were given repeated injections of nicotine (0.4 mg/kg, s.c., twice daily for 7 days) followed by one challenge injection on the fourth day after the last daily injection. Systemic challenge with nicotine produced a much larger increase in locomotor activity in nicotine-pretreated rats. Rats were pretreated with the nonselective nitric oxide synthase (NOS) inhibitor, N(G)-nitro-arginine-methyl-ester (L-NAME; 75 mg/kg, i.p.), the selective constitutive NOS inhibitor, N-nitro-L-arginine (L-NNA; 15 mg/kg, i.p.), the prototypical selective inducible NOS inhibitor, aminoguanidine (100 mg/kg, i.p.) or NMDA receptor antagonist, MK-801 ((5R,10S)-(+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine; 0.3 mg/kg, i.p.), 30 min before injections of nicotine during a 7-day development or a 3-day withdrawal phase after which challenged with nicotine on day 11. Pretreatment with L-NAME, L-NNA and MK-801, but not aminoguanidine, blocked the development of nicotine-induced sensitization to subsequent nicotine challenge. Injections of MK-801 twice daily during 3-day withdrawal periods after a 7-day induction period of nicotine attenuated nicotine-induced behavioral sensitization, whereas injections of L-NAME, L-NNA or aminoguanidine had no effects on the expression of sensitization produced by repeated nicotine. This study demonstrates that NMDA receptors can play a major role in the expression as well as development of nicotine-induced behavioral sensitization, and that NO is also involved in the development, but not critically involved in the expression of behavioral sensitization to nicotine.

The effects of acupuncture stimulation at PC6 (Neiguan) on chronic mild stress-induced biochemical and behavioral responses

In the present study, the effects of acupuncture on the behavioral and physiological responses induced by chronic mild stress (CMS) were evaluated. Sprague-Dawley rats were exposed to a variety of chronic unpredictable, mild stressors for 8 weeks. The effects of acupuncture on stress-induced anxiety and anhedonia were investigated using the elevated plus maze (EPM) and sucrose intake test. In addition, c-fos expression, as an early neuronal marker in the brain was also examined utilizing Fos-like immunohistochemistry (FLI). CMS rats significantly reduced the consumption of sucrose intake and latency in the open arms of the EPM, and gained body weight more slowly, compared to non-stressed normal rats. Exposure to CMS also significantly increased FLI in the paraventricular nucleus (PVN) of the hypothalamus. Acupuncture stimulation at point PC6 on the pericardium channels (3 min), but not at other point (TE5), restored stress-induced decrease in the latency in the open arms and significantly attenuated FLI in the PVN produced by CMS. Acupuncture stimulation also tended to restore stress-induced decrease in the sucrose intake. The present results demonstrated that acupuncture was effective in restoring CMS-related biochemical and behavioral impairments such as anxiety and anhedonia and that acupuncture point was more effective than non-acupuncture point. These results suggest that acupuncture has a therapeutic effect on chronic stress-related diseases such as depression and anxiety.

The effect of acupuncture on anxiety and neuropeptide Y expression in the basolateral amygdala of maternally separated rats.

Recent studies have suggested that maternally deprived rats exhibit anxiogenic-like behavior when exposed to stress in later life. Neuropeptide Y (NPY) is involved in the regulation of various physiological functions such as the expression of anxiety. Female Wistar rat pups were separated from their mothers for 3h daily from postnatal days 3 (P3) to 14 (P14). Acupuncture groups were treated with acupuncture at Shenmen (HT7) or Zusanli (ST36) on alternate days from P50 to P62. Their anxiety-like behavior was evaluated using an elevated plus-maze at P62, and then NPY immunohistochemistry in the basolateral amygdala (BLA) was performed. Rats exposed to maternal separation (MS) were less likely to explore the open arms of the plus-maze compared to control rats that were not exposed to MS. Among maternally separated groups, the percentage of time spent in the open arms was significantly increased in the HT7 acupuncture group, but not the ST36 acupuncture group, compared to MS group. In accordance with this behavior, the numbers of NPY-immunoreactive cells in the BLA were lower in the MS group compared to the control group. Among maternally separated groups, the numbers of NPY-immunoreactive cells in the BLA were significantly higher in the HT7 acupuncture group, but not higher in the ST36 acupuncture group, compared to MS group. These findings suggest that acupuncture treatment might reduce anxiety-like behavior in adult rats following maternal separation by modulating the NPY system in the amygdala.