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The median raphe nucleus (MR) has been shown to exert a powerful influence on behavioral arousal and marked locomotor hyperactivity can be produced by intra-MR injections of a variety of drugs including GABAA and GABAB agonists, excitatory amino acid antagonists, and μ- and δ-opioid agonists. Other studies have indicated that the MR exerts an inhibitory influence on ascending dopamine systems, suggesting that MR induced alterations in activity may be mediated through changes in dopaminergic transmission. In the present study, we explored this possibility by examining whether systemic administration of the preferential D2 dopamine antagonist haloperidol is able to antagonize the hyperactivity produced by intra-MR injections of various drugs. We found that haloperidol completely blocked the locomotor response to intra-MR injections of the μ-opioid receptor agonist DAMGO and the δ-opioid receptor agonist DPDPE. In marked contrast, at doses which abolished the locomotor response to systemic amphetamine, haloperidol had no effect on the hyperactivity induced by intra-MR injections of GABAA agonist muscimol, the GABAB agonist baclofen, or the kainate/quisqualate antagonist pBB-PZDA, even though it suppressed baseline activity in these same animals. These results indicate that there must be at least two mechanisms capable of influencing behavioral arousal within the MR region, one of which is dependent on D2 dopamine receptors and the other is not., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Protein kinase G (PKG) has been implicated in a variety of physiological functions including synaptic plasticity in the brain. This study investigated the involvement of dopamine D3 (D3) receptors in PKG-regulated dopamine release, long-term changes in gene expression and behavioral sensitization after repeated cocaine administration. Repeated systemic injections of cocaine (20mg/kg), once a day for seven consecutive days, increased extracellular dopamine concentrations in the dorsal striatum. Inhibition of neuronal nitric oxide synthase, cGMP or PKG, stimulation of D3 receptors, and simultaneous inhibition of each of them with D3 receptor stimulation decreased the repeated cocaine-induced increase in dopamine concentrations and locomotor activity. Similarly, inhibition of PKG and simultaneous inhibition of PKG with D3 receptor stimulation decreased ΔFosB immunoreactivity elevated by repeated cocaine administration, however stimulation of D3 receptors alone did not. These findings suggest that activation of PKG after repeated cocaine administration is more sensitive to interact with D3 receptors in the dopamine terminals than those in medium spiny neurons. This interaction may result in the development of behavioral sensitization by the upregulation of dopamine releases in the dorsal striatum., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Parkinson's disease (PD) is caused by the selective loss of dopaminergic neurons in the substantia nigra (SN) and the depletion of striatal dopamine (DA). Acupuncture, as an alternative therapy for PD, has beneficial effects in both PD patients and PD animal models, although the underlying mechanisms therein remain uncertain. The present study investigated whether acupuncture treatment affected dopamine neurotransmission in a PD mouse model using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We found that acupuncture treatment at acupoint GB34 improved motor function with accompanying dopaminergic neuron protection against MPTP but did not restore striatal dopamine depletion. Instead, acupuncture treatment increased dopamine release that in turn, may lead to the enhancement of dopamine availability in the synaptic cleft. Moreover, acupuncture treatment mitigated MPTP-induced abnormal postsynaptic changes, suggesting that acupuncture treatment may increase postsynaptic dopamine neurotransmission and facilitate the normalization of basal ganglia activity. These results suggest that the acupuncture-induced enhancement of synaptic dopamine availability may play a critical role in motor function improvement against MPTP.

Aim of the Study: The purpose of the present study was to screen aromatic essential oils that have antidepressant effects to identify the regulatory mechanisms of selected essential oils., Materials and Methods: The antidepressant effects of essential oils of Anthemis nobilis (chamomile), Salvia sclarea (clary sage; clary), Rosmarinus officinalis (rosemary), and Lavandula angustifolia (lavender) were assessed using a forced swim test (FST) in rats. Rats were treated with essential oils by intraperitoneal injection or inhalation. Serum levels of corticosterone were assessed by enzyme-linked immunosorbent assay (ELISA)., Results: Among the essential oils tested, 5% (v/v) clary oil had the strongest anti-stressor effect in the FST. We further investigated the mechanism of clary oil antidepression by pretreatment with agonists or antagonists to serotonin (5-HT), dopamine (DA), adrenaline, and GABA receptors. The anti-stressor effect of clary oil was significantly blocked by pretreatment with buspirone (a 5-HT(1A) agonist), SCH-23390 (a D(1) receptor antagonist) and haloperidol (a D(2), D(3), and D(4) receptor antagonist)., Conclusions: Our findings indicate that clary oil could be developed as a therapeutic agent for patients with depression and that the antidepressant-like effect of clary oil is closely associated with modulation of the DAnergic pathway., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Hydrocephalus is a pathological enlargement of the cerebral ventricle that results from an obstruction of the space containing cerebrospinal fluid (CSF) in the brain. Motor abnormalities, such as abnormal gait and posture, are frequently seen in patients with hydrocephalus. The present study was designed to investigate locomotor activity in the elevated plus maze behaviorally. Hydrocephalus was induced in Sprague-Dawley rats by injection of 0.1 ml of 20% kaolin solution into the cisterna magna (n=14). Control rats received the same volume of saline (n=12). The rats were sacrificed at 3 days and 4 weeks after the elevated plus maze test. Tyrosine hydroxlyase (TH) immunoreactivity in the substantia nigra was evaluated by immunohistological staining. Hydrocephalic rats showed decreased motor activity for entries of arms when compared to control rats (p<0.05). Compared to control rats, the number of TH immunoreactive neurons was significantly decreased in hydrocephalic rats. These results suggest that decreased motor responses due to ventricle enlargement in hydrocephalic rats are associated with the functional impairment of the central dopamine system.

Acupuncture is widely used for the treatment of many functional disorders, such as substance abuse, and has the suppressive effect on the central nervous system. Many studies have suggested that behavioral sensitization by repeated injections of cocaine produce an increase in locomotor activity and an increase in the expression of tyrosine hydroxylase (TH), in the central dopaminergic system. In order to investigate the effects of acupuncture on the repeated cocaine-induced neuronal and behavioral sensitization alternations, we examined the influence of acupuncture on the repeated cocaine-induced locomotor activity and the expression of TH in the brain using immunohistochemistry. Male SD rats were given repeated injections of cocaine hydrochloride (15 mg/kg, i.p. for 10 consecutive days) followed by one challenge injection on the 4th day after the last daily injection. Cocaine challenge produced a large increase in the locomotor activity and the expression of TH in the ventral tegmental area (VTA). Treatment with acupuncture bilaterally at the Shenman (HT7) points for 1 min significantly inhibited the increase of locomotor activity as well as the TH expression in the VTA. Our data demonstrated that the inhibitory effects of acupuncture on cocaine-induced expression of behavioral sensitization were closely associated with the reduction of dopamine (DA) biosynthesis and the postsynaptic neuronal activity. These results provide evidence that acupuncture may be effective for inhibiting the behavioral effects of cocaine by possible modulation of the central dopaminergic system.

Many studies have suggested that the behavioral and reinforcing effects of cocaine can be mediated by the central dopaminergic systems. It has been shown that repeated injections of cocaine produce an increase in locomotor activity, the expression of the immediate-early gene, c-fos, and the release of dopamine (DA) in the nucleus accumbens (NAc), which is one of the main dopaminergic terminal areas. Several studies have shown that behavioral activation and changes in extracellular dopamine levels in the central nervous system induced by psychomotor stimulants are prevented by ginseng total saponins (GTS). In order to investigate the effects of GTS on the repeated cocaine-induced behavioral and neurochemical alterations, we examined the influence of GTS on the cocaine-induced behavioral sensitization and on c-Fos expression in the brain using immunohistochemistry in rats repeatedly treated with cocaine. We also examined the effect of GTS on cocaine-induced dopamine release in the NAc of freely moving rats repeatedly treated with cocaine using an in vivo microdialysis technique. Pretreatment with GTS (100, 200, 400 mg/kg, i.p.) 30 min before the daily injections of cocaine (15 mg/kg, i.p.) significantly inhibited the repeated cocaine-induced increase in locomotor activity as well as the c-Fos expression in the core and shell in a dose-dependent manner. Also, pretreatment with GTS significantly decreased the repeated cocaine-induced increase in dopamine release in the NAc. Our data demonstrate that the inhibitory effects of GTS on the repeated cocaine-induced behavioral sensitization were closely associated with the reduction of dopamine release and the postsynaptic neuronal activity. The results of the present study suggest that GTS may be effective for inhibiting the behavioral effects of cocaine by possibly modulating the central dopaminergic system. These results also suggest that GTS may prove to be a useful therapeutic agent for cocaine addiction.

Object: The purpose of this study was to determine whether subthalamic nucleus (STN) ablation caused by kainic acid can restore dopaminergic neurotransmission and improve motor deficits in a 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian model., Methods: The authors investigated behavioral changes in rats displaying parkinsonian symptoms (6-OHDA-lesioned rats) after an STN lesion was created using kainic acid. They also measured levels of dopamine and its metabolites following tissue dissection. The results of this study showed that STN ablation led to behavioral improvement in parkinsonian motor deficits. Increased levels of dopamine were also observed in the striatum and globus pallidus externus (GPE)., Conclusions: The results indicate that creation of an STN lesion in this hemiparkinsonian rat model may counteract some of the neurochemical changes within the striatum and GPE caused by the 6-OHDA, and influence striatal dopaminergic metabolism.

Several studies have shown that behavioral hyperactivity induced by psychomotor stimulants is prevented by ginseng saponins. In an attempt to investigate whether the effect of ginseng saponins is through their inhibitory action on the enhanced dopaminergic transmission by psychomotor stimulants, we examined the effects of ginseng total saponin (GTS) presynaptically on nicotine-induced dopamine (DA) release in the striatum of freely moving rats using in vivo microdialysis technique and postsynaptically on the in vitro and in vivo binding of [3H]raclopride to DA D2 receptors. Also, we examined the effects of GTS on nicotine-induced locomotor hyperactivity and on nicotine-induced Fos protein expression in the nucleus accumbens and striatum. Systemic pretreatment with GTS (100 and 400 mg/kg, intraperitoneally (i.p.)) resulted in a dose-dependent inhibition of locomotor hyperactivity induced by nicotine. GTS decreased nicotine-induced DA release in the striatum in a dose-dependent manner. However, GTS had no effects on resting levels of locomotor activity and extracellular DA in the striatum. GTS inhibited the in vitro binding of [3H]raclopride to rat striatal membranes with an IC50 of 5.14+/-1.09 microM. High doses of GTS (400 and 800 mg/kg, i.p.) resulted in decreases in the in vivo binding of [3H]raclopride in the striatum. GTS decreased nicotine-induced Fos protein expression in the nucleus accumbens and striatum, reflecting the inhibition by GTS of nicotine-induced enhancement of dopaminergic transmission. The results of the present study suggest that GTS acts not only on dopaminergic neurons directly or indirectly to prevent nicotine-induced DA release but also postsynaptically by binding to DA D2 receptors. This may explain the blocking effect of GTS on behavioral activation induced by nicotine and conceivably by other psychostimulants. Our data raise the possibility that GTS, by attenuating nicotine-induced enhancement of dopaminergic transmission, may prove to be a useful therapeutic agent for nicotine addiction and warrant further investigation on its effect on nicotine's rewarding property.

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.

Acupuncture as a therapeutic intervention has been used for the treatment of many functional disorders including substance abuse. However, there are still many unanswered question about the basic mechanism underlying acupuncture's effectiveness in the treatment of drug addiction. Repeated injection of psycostimulants or morphine can produce behavioral and neurochemical sensitization and have been used as a model for studying drug addiction. The present study was designed to investigate the effect of acupuncture on repeated morphine-induced changes in extracellular dopamine levels using in vivo microdialysis and repeated morphine-induced behavioral changes. Male Sprague-Dawley rats were treated with saline or increasing doses of morphine (10, 20 and 40 mg/kg, s.c., twice daily for 3 days). Following 15 days of withdrawal, acupuncture was applied at bilateral Shenmen (HT7) points for 1 min after the systemic challenge with morphine HCl (5 mg/kg, s.c.). Results showed that acupuncture at the specific acupoint HT7, but not at control points (TE8 and tail) significantly decreased both dopamine release in the nucleus accumbens and behavioral hyperactivity induced by a systemic morphine challenge. These results suggest that the therapeutic effect of acupuncture on morphine addiction occurs through inhibition of neurochemical and behavioral sensitization to morphine.

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.

Background. Sasa quelpaertensis Nakai extract (SQE) or dwarf bamboo has been extensively investigated for its antioxidant and anti-inflammatory effects; however, no previous study assessed its effect as an antidepressant agent. Therefore, this study was designed to examine the effect of oral SQE administration in ameliorating menopausal depressive symptoms and to evaluate its mechanisms in ovariectomized rats with repeated stress. Methods. All experimental groups except normal group underwent ovariectomy and then immobilization for 14 consecutive days. During these 2 weeks, two rat groups received SQE (100 and 300 mg/kg orally) and their cutaneous body temperature was measured. The tail suspension test (TST) and forced swim test (FST) were performed in order to evaluate depression-like behavior. Additionally, enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were carried out to evaluate the central monoaminergic neurotransmitter levels and activity. Results. Oral SQE (100 mg/kg) administration had reduced immobility time in TST and FST. Additionally, the SQE 100 and 300 mg/kg administration had decreased the cutaneous body temperature in the rats compared to those without treatment. In ELISA analysis, the SQE 100 group expressed elevated levels of serotonin and dopamine in the hypothalamus, prefrontal cortex, and hippocampus. Antityrosine hydroxylase (anti-TH) antibodies showed a tremendous increase in the density of TH positive cells in the locus coeruleus (LC) region of the SQE 100 group. Likewise, the SQE 100 elevated the number of tryptophan hydroxylase (TPH) and protein kinase C (PKC) immunoreactive cell counts and density in the hypothalamic region. Conclusion. These results suggested that the oral SQE administration induced the antidepressant-like effect in the ovariectomized rats with repeated stress via upregulating the levels of serotonin and dopamine through enhancing the expression of TH, TPH, and PKC in many brain areas. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) is a stress-related psychiatric/mental condition. Tangeretin (TAN), a major polymethoxylated flavone of citrus plants, exhibits anti-inflammatory and neuroprotective activities. However, whether TAN leads to cognitive improvement in PTSD patients remains unclear. In the present study, we explored whether TAN improved cognitive impairment induced in rats by single prolonged stress (SPS episode mimicking PTSD induction) and determined whether TAN reversed reductions in dopamine (DA) and serotonin (5-HT) levels. Rats were intraperitoneally injected with TAN for 14 consecutive days after the SPS, which had induced cognitive deficits evident in the object recognition task and the Morris water maze test; the impairments were improved by TAN (100 mg/kg). TAN rescued the neurochemical abnormalities and the SPS-induced decreases in DA and 5-HT levels in the hippocampus and amygdala. These effects may be attributable in part to induction of hippocampal genes encoding tyrosine hydroxylase and tryptophan hydroxylase-1. Our results support the idea that rats with PTSD exhibit changes in DAergic and serotonergic transmission and in memory impairment. Thus, TAN mediated reversal of memory-related behavioral dysfunction associated with traumatic stress may be a useful therapeutic intervention in PTSD patients. [ABSTRACT FROM AUTHOR]

Stress has been shown to suppress immune function and increase susceptibility to inflammatory disease and psychiatric disease. CD4+CD25+ regulatory T (Treg) cells are prominent in immune regulation. This study was conducted to determine if anti-CD25 antibody (Ab) mediated depletion of Treg cells in mice susceptibility to stress-induced development of depression-like behaviors, as well as immunological and neurochemical activity. To accomplish this, an elevated plus-maze test (EPM), tail suspension test (TST), and forced swim test (FST) were used to examine depression-like behaviors upon chronic immobilization stress. Immune imbalance status was observed based on analysis of serum cytokines using a mouse cytometric bead array in conjunction with flow cytometry and changes in the levels of serotonin (5-HT) and dopamine (DA) in the brain were measured by high performance liquid chromatography (HPLC). The time spent in the open arms of the EPM decreased significantly and the immobility time in the FST increased significantly in the anti-CD25 Ab-treated group when compared with the non stressed wild-type group. In addition, interlukin-6 (IL-6), tumor necrosis factor-á (TNF-á ), interlukin-2 (IL-2), interferon-gamma (IFN-c), interlukin-4 (IL-4) and interlukin-17A (IL-17A) concentrations were significantly upregulated in the stressed anti-CD25 Ab-treated group when compared with the non stressed wild-type group. Furthermore, the non stressed anti-CD25 Ab-treated group displayed decreased 5-HT levels within the hippocampus when compared with the non stressed wild-type group. These results suggest that CD4+CD25+ Treg cell depletion modulated alterations in depressive behavior, cytokine and monoaminergic activity. Therefore, controlling CD4+CD25+ Treg cell function during stress may be a potent therapeutic strategy for the treatment of depression-like symptoms. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is caused by the selective loss of dopaminergic neurons in the substantia nigra (SN) and the depletion of striatal dopamine (DA). Acupuncture, as an alternative therapy for PD, has beneficial effects in both PD patients and PD animal models, although the underlying mechanisms therein remain uncertain. The present study investigated whether acupuncture treatment affected dopamine neurotransmission in a PD mouse model using 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP). We found that acupuncture treatment at acupoint GB34 improved motor function with accompanying dopaminergic neuron protection against MPTP but did not restore striatal dopamine depletion. Instead, acupuncture treatment increased dopamine release that in turn, may lead to the enhancement of dopamine availability in the synaptic cleft. Moreover, acupuncture treatment mitigated MPTP-induced abnormal postsynaptic changes, suggesting that acupuncture treatment may increase postsynaptic dopamine neurotransmission and facilitate the normalization of basal ganglia activity. These results suggest that the acupuncture-induced enhancement of synaptic dopamine availability may play a critical role in motor function improvement against MPTP. [ABSTRACT FROM AUTHOR]

Substantial evidence suggests that the behavioral and reinforcing effects of cocaine can be mediated by the central dopaminergic systems. Repeated injections of cocaine produce an increase in locomotor activity and the expression of tyrosine hydroxylase (TH) in the main dopaminergic areas. Protoberberine alkaloids affect neuronal functions. Coptidis rhizoma (CR) and its main compound, berberine (BER) reduced the dopamine content in the central nervous system. In order to investigate the effects of CR or BER on the repeated cocaine-induced neuronal and behavioral alterations, we examined the influence of CR or BER on the repeated cocaine-induced locomotor activity and the expression of TH in the brain by using immunohistochemistry. Male SD rats were given repeated injections of saline or cocaine hydrochloride (15 mg/kg, i.p. for 10 consecutive days) followed by one challenge injection on the 4th day after the last daily injection. Cocaine challenge (15 mg/kg, i.p) produced a larger increase in locomotor activity and expression of TH in the central dopaminergic areas. Pretreatment with CR (50, 100, 200 and 400 mg/kg, p.o.) and BER (200 mg/kg, p.o.) 30 min before the daily injections of cocaine significantly inhibited the cocaine-induced locomotor activity as well as TH expression in the central dopaminergic areas. Our data demonstrate that the inhibitory effects of CR and BER on the repeated cocaine-induced locomotor activity were closely associated with the reduction of dopamine biosynthesis and post-synaptic neuronal activity. These results suggest that CR and BER may be effective for inhibiting the behavioral effects of cocaine by possibly modulating the central dopaminergic system. [ABSTRACT FROM AUTHOR]

Abstract: Repeated exposure to cocaine upregulates endoplasmic reticulum (ER) stress response and c-Jun N-terminal kinase (JNK) phosphorylation is associated with the ER stress response in neurons. In this study, we investigated the involvement of JNK in the regulation of the ER stress response following repeated cocaine administration in the dorsal striatum in vivo. The results showed that systemic injections of cocaine (20 mg/kg) for seven consecutive days increased the induction of p46 JNK (JNK) phosphorylation, immunoglobulin heavy chain binding protein (BiP), the ER stress-associated protein caspase-12, and behavioral locomotor activity. This enhancement of BiP and caspase-12 expression and locomotor response was reduced by inhibiting JNK. Similar reduction of elevated JNK phosphorylation was induced by blocking dopamine D1 receptors, N-methyl-d-aspartate (NMDA) receptors, and group I metabotropic glutamate receptors (mGluRs). These data suggest that JNK activation following repeated cocaine administration is required for the regulation of the ER stress protein expression and behavioral alteration in the dorsal striatum. Stimulation of dopamine D1 receptors, NMDA receptors or group I mGluRs participates in the regulation of JNK activation. [Copyright &y& Elsevier]

Abstract: In our previous study we demonstrated that acupuncture at Shenmen (HT7) points suppressed a decrease of accumbal dopamine (DA) release in ethanol-withdrawn rats. Furthermore, here we found that it inhibited behavioral withdrawal signs of ethanol. In an effort to better understand the mechanisms underlying this inhibition, the potential role of GABA receptor system in acupuncture was investigated. Male Sprague–Dawley rats were treated with 3g/kg/day of ethanol (20%, w/v) or saline by intraperitoneal injection for 21 days. Following 48 or 72h of ethanol withdrawal, acupuncture was applied at bilateral HT7 for 1min. The selective GABAA antagonist bicuculline and the selective GABAB antagonist SCH 50911 were injected intraperitoneally 20min before acupuncture, respectively. Importantly, suppressive effects of acupuncture on DA deficiency were completely abolished by SCH 50911, but not by bicuculline, whereas ameliorating effects of acupuncture on ethanol withdrawal syndrome were completely blocked either by SCH 50911 or bicuculline. These results suggest that acupuncture at specific acupoint HT7 may normalize the DA release in the mesolimbic system and attenuate withdrawal syndrome through the GABAB receptor system in ethanol-withdrawn rats. [Copyright &y& Elsevier]

Abstract: This study was conducted to determine the phosphorylation state of N-methyl-d-aspartate (NMDA) NR1 subunit on serine residues 896 (Ser896) and 897 (Ser897), the extracellular signal-regulated kinase 1/2 (ERK1/2), and the cyclic AMP response element-binding protein (CREB) after repeated exposure to cocaine (20 mg/kg, once daily for 9 days) in the dorsal striatum of rats. The real-time changes of glutamate concentration evoked by repeated cocaine injections were examined using a glutamate biosensor in order to evaluate the correlation between glutamate concentration and the change in these phosphoproteins. The results of this study showed that the immunoreactivity of phosphorylated (p)NMDA NR1 subunit at Ser896 and Ser897 as well as pERK1/2, but not pCREB, in the dorsal striatum was increased at 30 min and then returned to basal levels 4 h after repeated cocaine injections. Similarly, glutamate responses evoked by repeated cocaine injections were also increased 30 min after repeated cocaine injections for 3 days and were prolonged by the 9th day of treatment. However, the glutamate responses were not detected at 4 h after repeated cocaine injections for 5 days. In addition, the elevated immunoreactivity of the phosphoproteins 2 h after repeated cocaine injections was attenuated by the blockade of dopamine D1 receptors and NMDA receptors with the SCH23390 or MK801 antagonists, respectively. These findings suggest that glutamate release and dopamine D1 and NMDA receptor stimulation after repeated exposure to cocaine are associated with NMDA NR1 subunit, ERK1/2 and CREB phosphorylation in the dorsal striatum. [Copyright &y& Elsevier]

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 GABAB 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 GABAB receptor system in acupuncture. Male Sprague–Dawley rats were administered with the highly selective GABAB antagonist SCH 50911 (3mg/kg, i.p.) 1h prior to an intraperitoneal injection of ethanol (1g/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 GABAB activity and imply that acupuncture may be effective in blocking the reinforcing effects of ethanol. [Copyright &y& Elsevier]