Analytical and Physical Investigation on Source Resistance in InxGa1-xAs Quantum-Well High-Electron-Mobility Transistors.

We present a fully analytical model and physical investigation on the source resistance (RS) in InxGa1-xAs quantum-well high-electron mobility transistors based on a three-layer TLM system. The RS model in this work was derived by solving the coupled quadratic differential equations for each current component with appropriate boundary conditions, requiring only six physical and geometrical parameters, including ohmic contact resistivity (ρc), barrier tunneling resistivity (ρbarrier), sheet resistances of the cap and channel regions (Rsh_cap and Rsh_ch), side-recessed length (Lside) and gate-to-source length (Lgs). To extract each model parameter, we fabricated two different TLM structures, such as cap-TLM and recessed-TLM. The developed RS model in this work was in excellent agreement with the RS values measured from the two TLM devices and previously reported short-Lg HEMT devices. The findings in this work revealed that barrier tunneling resistivity already played a critical role in reducing the value of RS in state-of-the-art HEMTs. Unless the barrier tunneling resistivity is reduced considerably, innovative engineering on the ohmic contact characteristics and gate-to-source spacing would only marginally improve the device performance.

Polyethylene-Derived Activated Carbon Materials for Commercially Available Supercapacitor in an Organic Electrolyte System.

High-performance supercapacitors based on activated carbons (AC) derived from polyethylene (PE), which is one of the most abundant plastic materials worldwide, are fabricated. First, PE carbons (PEC) are prepared via sulfonation, which is a reported solution for successful carbonization of innately non-carbonizable PE. Then, the physico-electrical changes of PECs upon a chemical activation process are explored. Interestingly, upon the chemical activation, PECs are converted ACs with a large surface area and high crystallinity at the same time. Subsequently, PE-derived ACs (PEAC) are exploited as electrode materials for supercapacitors. Resultant supercapacitors based on PEACs exhibit impressive performance. When compared to supercapacitors based on YP50f, representative commercial ACs, devices using PEACs presented considerably good capacitance, low resistance, and great rate capability. Specifically, the retention rate of devices using PEACs is significantly higher than that of YP50f-based devices. At the high rate of charge-discharge situation reaching 7 A g-1 , the capacitance of supercapacitors using PEACs is ≈70% higher than that of YP50f-based devices. It is assumed that the carbon structure accompanying both large surface area and high conductivity endows a great electrochemical performance at the high current operating conditions. Therefore, it is envisioned that PE may be a viable candidate electrode material for commercially available supercapacitors.

A critical role of striatal A2A R-mGlu5 R interactions in modulating the psychomotor and drug-seeking effects of methamphetamine.

Addiction to psychostimulants is a major public health problem with no available treatment. Adenosine A2A receptors (A2A R) co-localize with metabotropic glutamate 5 receptors (mGlu5 R) in the striatum and functionally interact to modulate behaviours induced by addictive substances, such as alcohol. Using genetic and pharmacological antagonism of A2A R in mice, we investigated whether A2A R-mGlu5 R interaction can regulate the locomotor, stereotypic and drug-seeking effect of methamphetamine and cocaine, two drugs that exhibit distinct mechanism of action. Genetic deletion of A2A R, as well as combined administration of sub-threshold doses of the selective A2A R antagonist (SCH 58261, 0.01 mg/kg, i.p.) with the mGlu5 R antagonist, 3-((2-methyl-4-thiazolyl)ethynyl)pyridine (0.01 mg/kg, i.p.), prevented methamphetamine- but not cocaine-induced hyperactivity and stereotypic rearing behaviour. This drug combination also prevented methamphetamine-rewarding effects in a conditioned-place preference paradigm. Moreover, mGlu5 R binding was reduced in the nucleus accumbens core of A2A R knockout (KO) mice supporting an interaction between these receptors in a brain region crucial in mediating addiction processes. Chronic methamphetamine, but not cocaine administration, resulted in a significant increase in striatal mGlu5 R binding in wild-type mice, which was absent in the A2A R KO mice. These data are in support of a critical role of striatal A2A R-mGlu5 R functional interaction in mediating the ambulatory, stereotypic and reinforcing effects of methamphetamine but not cocaine-induced hyperlocomotion or stereotypy. The present study highlights a distinct and selective mechanistic role for this receptor interaction in regulating methamphetamine-induced behaviours and suggests that combined antagonism of A2A R and mGlu5 R may represent a novel therapy for methamphetamine addiction.

Knockout subtraction autoradiography: a novel ex vivo method to detect heteromers finds sparse KOP receptor/DOP receptor heterodimerization in the brain.

Several methodological approaches suggest that receptor heteromers exist in cell systems, but their presence in physiological tissue is widely contentious. We describe a novel method to determine if heterodimers exist in brain tissue sections using autoradiographic binding comparisons from single and double gene knockout mice, where tissues either have a full receptor complement and can form heterodimers, or are incapable of making heterodimers. We have tested this model, which we have named Knockout Subtraction Autoradiography, to determine if heterodimerisation of the kappa (KOP) and delta opioid (DOP) receptors occurs, as evidence from binding studies in cell systems suggest they are present in the brain. Using labeling of putative KOP receptor/DOP receptor heterodimers with either [(3)H]bremazocine or with [(3)H]naltrindole, two ligands which were used to provide evidence suggesting that these opioid receptor subtypes heterodimerize, we have applied a subtraction equation model based on the principle that receptor gene double knockout of either MOP receptor/KOP receptor (DOP receptor expression only) or MOP receptor/DOP receptor (KOP receptor expression only) produces tissue incapable of making the KOP receptor/DOP receptor heterodimer. We have shown in most brain regions that the labeling fits a simple additive model of monomer labeling, but that in a few brain regions opioid receptor heterodimerization does occur. The data does not support the conclusion that KOP receptor/DOP receptor heterodimerisation is widespread in the central nervous system, but does indicate that this novel methodology can detect heterodimerisation, when ligands with distinct binding affinities for monomer and heterodimer forms exist.

Lack of genotype effect on D1, D2 receptors and dopamine transporter binding in triple MOP-, DOP-, and KOP-opioid receptor knockout mice of three different genetic backgrounds.

We investigated D1, D2 receptors and dopamine transporter (DAT) binding levels in mice lacking all three opioid receptors and wild-type (WT) mice on three different genetic backgrounds. Quantitative autoradiography was used to determine the level of radioligand binding to the D1 and D2 receptors and DAT labeled with [(3)H]SCH23390, [(3)H]raclopride, and [(3)H]mazindol, respectively in triple-opioid receptor knockout (KO) and WT maintained on C57BL/6 (B6) and 129/SvEvTac (129) as well as C57BL/6 x 129/SvPas (B6 x 129) strains. No significant genotype effect was observed in D1, D2 receptors and DAT binding in any regions analyzed in any of the strains studied, suggesting that a lack of all three opioid receptors does not influence D1, D2 receptors and DAT expression, irrespective of their genetic strain background. However, strain differences were observed in D1 binding between the three strains of mice studied. Lower levels of D1 binding were observed in the substantia nigra of B6 x 129 WT mice compared with the 129 WT mice and in the olfactory tubercle of B6 x 129 WT compared with B6 WT and 129 WT mice. Lower levels of D1 binding were observed in the caudate putamen of B6 x 129 KO mice compared with 129 KO mice. In contrast, no significant strain differences were observed in D2 and DAT binding between the three strains of mice in any regions analyzed. Overall, these results indicate a lack of modulation of the dopaminergic system by the deletion of all three opioid receptors regardless of different background strains.

GABA(A) receptors mediate the attenuating effects of a 5-HT(3) receptor antagonist on methamphetamine-induced behavioral sensitization in mice.

We previously showed that 5-HT(3) receptors are involved in the development and expression of methamphetamine (MAP)-induced locomotor sensitization in mice. Here, we examined whether the dopaminergic or the GABAergic systems are involved in the attenuating effects of the 5-HT(3) receptor antagonist MDL72222 on MAP-induced locomotor sensitization. Quantitative autoradiography of D1 ([(3)H]SCH23390), D2 ([(3)H]raclopride) receptor, and GABA(A) receptor benzodiazepine ([(3)H]flunitrazepam) binding was carried out in the brains of mice treated with chronic MAP and pretreatment with MDL72222. No significant differences were found in D(1) and D(2) binding between the two groups, suggesting that the attenuating effects of MDL72222 on MAP-induced locomotor sensitization is not medicated by D1 and D2 receptors. Postsynaptic dopamine (DA) receptor supersensitivity was measured by challenge with apomorphine, a dopamine D(1) and D(2) receptor agonist, after repeated MAP treatment or pretreatment with MDL72222 before MAP. Apomorphine induced an enhanced locomotor activity in both chronic MAP-treated mice and mice pretreated with MDL 72222, with no significant differences between the two groups. The binding of [(3)H]flunitrazepam was significantly decreased in the motor and cingulate cortex, caudate putamen, and nucleus accumbens of mice in the repeated MAP treatment group compared with the control group, and this effect was reversed by pretreatment with MDL72222. This suggested that GABA(A) benzodiazepine binding sites are involved in the attenuating effects of a 5-HT(3) receptor antagonist on MAP-induced locomotor sensitization.

Dopamine neurotransmission is involved in the attenuating effects of 5-HT3 receptor antagonist MDL 72222 on acute methamphetamine-induced locomotor hyperactivity in mice.

We have previously shown that 5-HT3 receptors are involved in the development and expression of methamphetamine (MAP)-induced locomotor sensitization in mice. In the present study, we further examined whether the dopaminergic system is involved in the attenuating effects of MDL 72222, a 5-HT3 receptor antagonist, on acute MAP-induced locomotor hyperactivity. For this, we examined alterations of dopamine (DA) in the form of D1 receptor, D2 receptor, and dopamine transporter (DAT) binding labeled with [3H]SCH23390 for D1, [3H]raclopride for D2, and [3H]mazindol for DAT binding in the mouse brains with acute MAP exposure or pretreatment of MDL 72222 with MAP. No significant differences were detected in the D1 receptor, D2 receptor, or DAT binding between any of the groups studied. Interestingly, we found increased DA levels in the striatum following acute MAP exposure; these increased levels were reversed by pretreatment with MDL 72222, but did not affect 5-HT levels in the dorsal raphe. Overall, our results suggest that dopamine neurotransmission plays an important role in the attenuating effects of 5-HT3 receptor antagonist MDL 72222 on acute MAP-induced locomotor hyperactivity in mice.

Involvement of 5-HT receptors in the development and expression of methamphetamine-induced behavioral sensitization: 5-HT receptor channel and binding study.

Methamphetamine (MAP) is one of the most commonly abused drugs in Asia, and previous studies suggest that serotonin 3 receptors (5-HT(3)) are involved in MAP-induced locomotion and reward. However, little is known about the role of 5-HT(3) receptors in MAP-induced behavioral sensitization. Here, we measured the effects of MDL 72222, a 5-HT(3) antagonist, and SR 57227 A, a 5-HT(3) agonist, on the development and expression of MAP-induced behavioral sensitization, and alternations of 5-HT(3) receptor binding labeled with the 5-HT(3)-selective antagonist, [(3)H]GR65630, in mice. In addition, we investigated the effects of MAP on 5-HT(3A) receptor channel activity in Xenopus laevis oocytes expressing 5-HT(3A) receptors. We found that MDL 72222 attenuated both the development and expression of behavioral sensitization to MAP (1.0 mg/kg, i.p.), and that this attenuating effect of MDL 72222 was reversed by pre-treatment with SR 57227 A. In oocytes expressing 5-HT(3A) receptor, MAP exhibited a dual modulation of 5-HT(3A) receptor channel activity, i.e. pre-treatment with a low dose of MAP (0.1 microm) enhanced 5-HT-induced inward peak current (I(5-HT)) but a high dose of MAP (100 microm) inhibited I(5-HT). The acute administration of MDL 72222 with MAP decreased [(3)H]GR65630 binding versus MAP alone in the mouse striatum. Our results suggest that MDL 72222 attenuates MAP-induced behavioral sensitization via 5-HT(3) receptors in the caudate putamen, and that 5-HT(3) receptor antagonists like MDL 72222 have potential as novel anti-psychotic agents for the treatment of MAP dependence and psychosis.

Differential effects of morphine- and cocaine-induced nNOS immunoreactivity in the dentate gyrus of hippocampus of mice lacking mu-opioid receptors.

This study investigated the expression of nNOS after repeated morphine or cocaine administration in order to determine if nNOS (neuronal nitric oxide synthase) is involved in the morphine- or cocaine-induced behavioral sensitization in mu-opioid receptor knockout (MOR(-/-)) mice. Higher numbers of nNOS-positive cells were observed in the dentate gyrus of the hippocampus (DG) of the wild-type (MOR(+/+)) mice repeatedly treated with either morphine or cocaine than in the saline treated MOR(+/+) mice (morphine, +122%; cocaine, +82%). Moreover, the MOR(-/-) mice also showed significantly higher morphine- or cocaine-induced nNOS expression levels in the DG than in the saline treated MOR(+/+) mice (morphine, +234%; cocaine, +54%). The MOR(-/-) mice showed a significantly higher morphine-induced nNOS expression level (+103%) or a lower cocaine-induced nNOS expression level (+38%) in the DG than in the morphine- or cocaine-treated MOR(+/+) mice. These results suggest that morphine and cocaine sensitization is differentially regulated by the mu-opioid receptors in MOR(-/-) mice via the nNOS systems in the DG.

A lack of mu-opioid receptors modulates the expressions of neuropeptide Y and substance P mRNA.

The present study was undertaken to investigate changes in the expressions of neuropeptide Y (NPY) and substance P (SP) in mice lacking mu-opioid receptors. In an in situ hybridization study, in which we compared wild type and mu-opioid receptor knockout mice, NPY mRNA levels were found to be lower in the caudate-putamen and nucleus accumbens of mu-opioid receptor knockout mice. In addition, SP mRNA levels were lower in the ventromedial hypothalamic nucleus of mu-opioid receptor knockout mice. Our findings suggest that a lack of mu-opioid receptors modulates basal NPY mRNA levels in striatal regions and SP mRNA levels in the ventromedial hypothalamic nucleus of the mouse, and that these changes are due to compensatory modulation in the brain.

Reduced nNOS expression induced by repeated nicotine treatment in mu-opioid receptor knockout mice.

To determine whether neuronal nitric oxide synthase (nNOS) is involved in nicotine-induced behavioral sensitization in mu-opioid receptor knockout mice we adopted an immunohistochemical approach. Our results confirm that repeated nicotine administration increased locomotor activity in wild-type mice, but failed to increase locomotor activity in mu-opioid receptor knockout mice, thus suggesting that the mu-opioid receptor is involved in behavioral sensitization. Higher numbers of nNOS-positive cells were observed in the striatum of wild-type mice repeatedly treated with nicotine than in saline-treated wild-type mice. However, mu-opioid receptor knockout mice showed significantly lower nicotine-induced nNOS expression in the striatum versus wild-type mice. No differences were found in the hilus of the dentate gyrus between wild-type and mu-opioid receptor knockout mice. These findings demonstrate that the absence of mu-opioid receptors can cause a significant reduction in the expression of nNOS in the striatum, as induced by repeated nicotine treatment.

Altered emotional behaviors and the expression of 5-HT1A and M1 muscarinic receptors in micro-opioid receptor knockout mice.

Anxiety and depression alterations have been reported in micro-opioid receptor knockout mice after exon 2 disruption. However, emotional behaviors, such as novelty and emergence responses have not been reported in micro-opioid receptor knockout mice due to the disruptions of exon 2 and 3. Here, we report that mu-opioid receptor knockout mice, with deletion of exon 2 and 3, display significant emotional behavior changes; they showed less anxiety in the elevated plus maze and emergence tests, reduced response to novel stimuli in the novelty test, and less depressive-like behavior in the forced-swim test. Analysis of the compensatory mechanism in mu-opioid receptor knockout mice revealed that the M1 mRNA levels were reduced in the cortex, caudate putamen, nucleus accumbens, and hippocampus, and that M1 receptor levels were reduced in the nucleus accumbens, CA1, and the dentate gyrus of the hippocampus, versus the wild-type. However, 5-HT1A receptor levels were significantly elevated in the cerebral cortex and in the hypothalamus of mu-opioid receptor knockout mice versus the wild-type. These aberrant emotional behavioral phenotypes are possibly related to M1 and 5-HT1A receptor alterations in the micro-opioid receptor knockout mice. Overall, our study suggests that micro-opioid receptor may play a role in the modification of emotional responses to novelty, anxiety, and depression.

Loss of nicotine-induced behavioral sensitization in micro-opioid receptor knockout mice.

Repeated administration of nicotine produces behavioral sensitization. However, the possible mechanism of behavioral sensitization to nicotine remains unclear. The present study was undertaken in micro-opioid receptor knockout mice, to examine the hypothesis that micro-opioid receptors play a crucial role in behavioral sensitization to nicotine. All mice received saline or nicotine (0.05 mg/kg, s.c) twice a day for 7 consecutive days. The mice remained drug free for 3 days and on day 11 each group was challenged with saline or nicotine (0.05 mg/kg, s.c.). On day 1, it was observed that the single injection of nicotine (0.05 mg/kg, s.c.) did not influence locomotor activity in either micro-opioid receptor knockout or in wildtype mice. On day 7 (24 h after mice had been treated twice daily for 6 consecutive days with an injection of 0.05 mg/kg of nicotine), the mice were challenged with a single injection of nicotine, which produced behavioral sensitization in the wildtype but not in micro-opioid receptor knockout mice. On day 11, following 3 days of withdrawal after the second injection of nicotine on day 7, nicotine-treated mice were challenged with a single injection of nicotine and showed the behavioral sensitization of wildtype. However, nicotine challenge did not induce behavioral sensitization in micro-opioid receptor knockout mice. Our data indicate that a lack of micro-opioid receptors can inhibit the effects of nicotine-induced behavioral sensitization. This result strongly suggests that the micro-opioid receptor plays an important role in behavioral sensitization to nicotine.

Impaired water maze learning performance in mu-opioid receptor knockout mice.

Previous study has demonstrated that the lack of mu-opioid receptor decreased LTP in the dentate gyrus of the hippocampus, suggesting the possibility that the lack of mu-opioid receptor may accompany a change in learning and memory. However, no behavioral study has been undertaken to correlate LTP deficits with spatial memory impairment in mu-opioid receptor knockout mice. Therefore, the present study investigated the hypothesis that mu-opioid receptors contribute to learning and memory by using the Morris water maze, and comparing responses in wild type and mu-opioid receptor gene knockout mice. Our results indicated that mu-opioid receptor knockout mice showed a significant spatial memory impairment compared to wild type in the Morris water maze. This result suggests that the expression of mu-opioid receptor plays an important role in spatial learning and memory examined by Morris water maze.

Differential effects of morphine and cocaine on locomotor activity and sensitization in mu-opioid receptor knockout mice.

The present study was undertaken to investigate the hypothesis that the mu-opioid receptors play a crucial role in locomotor activity and sensitization to cocaine and morphine in wild-type and mu-opioid receptor knockout mice. Our results show that morphine and cocaine increased locomotor activity in wild-type mice, but failed to increase locomotor activity in mu-opioid receptor knockout mice, suggesting a contribution of mu-opioid receptor. Repeated morphine treatment induced sensitization in wild-type mice, but this was not observed in mu-opioid receptor knockout mice. In contrast repeated cocaine treatment produced sensitization in mu-opioid receptor knockout mice, but not in wild-type mice on day 6. However, the sensitization to cocaine was observed in mu-opioid receptor knockout and wild-type mice on day 12. These results suggest that the expression of mu-opioid receptor may contribute to locomotor sensitization induced by morphine, but that mu-opioid receptor does not play an important role in mediating sensitization to cocaine.