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Ethanol exposure differentially alters central monoamine neurotransmission in alcohol-preferring versus -nonpreferring rats

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第3期288卷 1223-1228页

作者： Smith, AD Weiss, F Scripps Res Inst Dept Neuropharmacol La Jolla CA USA

Individual differences in ethanol preference may be linked to differences in the functional activity of forebrain monoamine systems or their sensitivity to modification by ethanol. To test this hypothesis, basal extracellular concentrations of dopamine (DA) and serotonin (5-HT) in the nucleus accumbens as well as the effects of repeated ethanol pretreatment on the basal release of these transmitters were examined in alcohol-preferring (P), alcohol-nonpreferring (NP), and genetically heterogeneous Wistar rats. Ail animals received i,p. injections of ethanol (1.0 g/kg) or saline for 5 consecutive days. Fifteen hours after the final pretreatment, basal extracellular concentrations and "in vivo extraction fraction" Values for DA and 5-HT were determined by no-net-flux in vivo microdialysis. in ethanol-naive rats, significant line differences were observed with high basal 5-HT release in P rats, low 5-HT release in NP rats, and intermediate 5-HT levels in Wistar rats. No differences among groups were noted in basal DA release. Ethanol pretreatment decreased basal extracellular 5-HT levels in P rats whereas increasing 5-HT efflux was seen in the Wistar and NP lines, in addition, ethanol pretreatment increased extracellular DA concentrations in Wistar and P rats, but not in NP rats. The results confirm a relationship between the functional status of forebrain DA and 5-HT systems and ethanol preference or aversion. Moreover, the data suggest that ethanol exposure can alter basal DA and 5-HT in the nucleus accumbens and that vulnerability to ethanol-induced changes in monoamine neurotransmission may be a factor in genetically determined ethanol preference.

关键词：饮酒/血液饮酒/遗传学饮酒/代谢生物源单胺类/代谢多巴胺/代谢乙醇/投药和剂量乙醇/血液乙醇/药理学细胞外隙/代谢伏核/药物作用前脑/药物作用前脑/代谢大鼠 Wistar 血清素/代谢动物男(雄)性大鼠

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Increased mesolimbic GABA concentration blocks heroin self-administration in the rat

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期294卷 613-619页

作者： Xi, ZX Stein, EA Med Coll Wisconsin Dept Cell Biol Neurobiol & Anat Milwaukee WI 53226 USA Med Coll Wisconsin Dept Psychiat & Behav Med Milwaukee WI 53226 USA Med Coll Wisconsin Dept Pharmacol & Toxicol Milwaukee WI 53226 USA Med Coll Wisconsin Biophys Res Inst Milwaukee WI 53226 USA

Opiate reinforcement has been hypothesized to be mediated by an inhibition of mesolimbic gamma-aminobutyric acid (GABA) release that subsequently disinhibits ventral tegmental area (VTA) dopamine neurons. In support of this hypothesis, this study demonstrates that when administered directly into the lateral ventricle, the VTA, or the ventral pallidum, but not the nucleus accumbens, gamma-vinyl-GABA (GVG, an irreversible GABA-transaminase inhibitor, 20-50 mu g) dose dependently blocked heroin (0.06 mg/kg) self-administration (SA), as assessed by an increase in heroin SA at low doses of GVG and an initial increase followed 1 to 2 h later by a blockade of heroin SA at higher GVG doses. This effect lasted 3 to 5 days. In drug-naive rats, intra-VTA GVG pretreatment also prevented or delayed acquisition of heroin SA for 2 days. This GVG effect was prevented or reversed by systemic or intra-VTA pretreatment with the GABA(B) antagonist 2-hydroxysaclofen, but not the GABA(A) antagonist bicuculline. Similarly, coadministration of heroin with aminooxy-acetic acid (1-4 mg/kg) or ethanolamine-O-sulfate (50-100 mg/kg), two reversible GABA transaminase inhibitors, dose dependently reduced heroin reinforcement. Coadministration of (+/-)-nipecotic acid (0.1-5 mg/kg) with heroin, or intra-VTA or -ventral pallidum pretreatment with (+/-)-nipecotic acid (10 mu g) or NO-711 (2 mu g), two GABA uptake inhibitors, significantly increased heroin SA behavior, an effect also blocked by systemic 2-hydroxysaclofen, but not bicuculline. Taken together, these experiments, for the first time, demonstrate that pharmacological elevation of mesolimbic GABA concentration blocks heroin reinforcement by activating GABA(B) receptors, supporting the GABAergic hypothesis of opiate reinforcement and the incorporation of GABA agents in opiate abuse treatment.

关键词： 4-氨基丁酸转氨酶/拮抗剂和抑制剂巴氯芬/类似物和衍生物巴氯芬/药理学行为动物/药物作用荷包牡丹碱/药理学酶抑制剂/药理学 GABA拮抗剂/药理学苍白球/药物作用苍白球/代谢海洛因/投药和剂量注射脑室内侧脑室/药物作用侧脑室/代谢微量注射麻醉品/投药和剂量神经递质摄取抑制药/药理学伏核/药物作用伏核/代谢阿片相关性障碍/药物疗法阿片相关性障碍/代谢阿片相关性障碍/病理生理学大鼠 Sprague-Dawley 受体 GABA-A/拮抗剂和抑制剂受体 GABA-B/拮抗剂和抑制剂自我遵嘱服药端脑/药物作用端脑/代谢腹侧被盖区/药物作用腹侧被盖区/代谢氨己烯酸/药理学 γ氨基丁酸/代谢 γ氨基丁酸/生理学动物男(雄)性大鼠

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Ethanol enhances γ-aminobutyric acid responses in a subpopulation of nucleus accumbens neurons:: Role of metabotropic glutamate receptors

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期293卷 654-661页

作者： Nie, ZG Madamba, SG Siggins, GR Scripps Res Inst Res Inst Dept Neuropharmacol La Jolla CA 92037 USA Alcohol Res Ctr La Jolla CA USA

The nucleus accumbens (NAcc) may be a key area in the rewarding effects of abused drugs. We previously showed that low ethanol concentrations decreased both N-methyl-D-aspartate (NMDA)-induced and kainate-induced currents in NAcc core neurons (Nie et al., 1994). To explore the effects of ethanol on gamma-aminobutyric acid (GABA) responses in NAcc, we used intracellular voltage-clamp recordings and locally applied GABA in a slice preparation containing the NAcc. Ethanol (11-200 mM) had no effect on resting membrane properties, but 11, 22, 44, 100, and 200 mM ethanol increased GABA currents in 17, 33, 45, 50, and 22% of cells, respectively. Superfusion of low glutamate concentrations that had no direct effect on membrane properties enhanced ethanol potentiation of GABA currents in more than half the NAcc cells. Neither alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate receptor nor NMDA receptor antagonists affected the percentage of cells showing ethanol enhancement of GABA responses or the degree of ethanol enhancement of GABA currents in NAcc neurons. However, in ethanol-sensitive cells, the metabotropic receptor antagonist alpha-methyl-4-carboxyphenylglycine (MCPG) blocked the ethanol enhancement of GABA currents. In addition, the metabotropic receptor agonist trans-1-aminocyclopentane-1,3-dicarboxylic acid enhanced GABA responses in 50% of cells tested, an effect blocked by MCPG. These data suggest that NAcc core neurons possess both ethanol-sensitive and -insensitive GABA receptors and that glutamate can mimic and enhance the ethanol potentiation of GABA currents in many of these neurons. Furthermore, the ethanol potentiation of GABA currents may involve metabotropic glutamate receptors, perhaps via a phosphorylation mechanism that regulates ethanol sensitivity of GABA receptors in some NAcc neurons.

关键词：中枢神经系统抑制药/药理学电生理学乙醇/药理学 GABA拮抗剂/药理学膜电位/药物作用神经元/药物作用伏核/细胞学伏核/药物作用膜片钳术大鼠 Sprague-Dawley 受体 GABA-A/药物作用受体亲代谢性谷氨酸盐/拮抗剂和抑制剂受体亲代谢性谷氨酸盐/药物作用第二信使系统/药物作用 γ氨基丁酸/药理学动物男(雄)性大鼠

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Psychotomimetics moderately affect dopamine receptor binding in the rat brain

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NEUROCHEMISTRY INTERNATIONAL 2000年第2期36卷 137-142页

作者： Tomic, M Joksimovic, J Inst Biol Res Dept Biochem YU-11060 Belgrade Yugoslavia

The hypothesis that psychotomimetics induce a rapid dopamine receptor regulation that could participate in the expression of the brain dopaminergic overactivation and in the early signs of psychotic-like behaviour, was checked by radioligand binding on rat brain cryosections. For this purpose, subchronic 7-day-d-amphetamine pretreatment was combined with acute amphetamine, phencyclidine or LSD challenge. Acute application of psychotomimetics affected only striatal and accumbens but not nigral and olfactory dopamine receptor binding after 40 min, while subchronic amphetamine expressed no effect, as revealed by two-way ANOVA. Post-hoc statistical analysis showed that only striatal and accumbens[H-3]SCH 23390 binding decrease (10-12%) following phencyclidine and striatal [H-3]spiperone binding increase (11%) after acute amphetamine were significant. It is assumed that such moderate dopamine receptor binding changes probably reflect the fast receptor regulation responses without important influence on a proposed drug-induced dopaminergic overactivity. The registered alterations of D-1 receptor binding after phencyclidine are suggested to be capable to modify the activity of some other neural pathways in the basal ganglia and thus participate in a psychotic-like behaviour. (C) 2000 Elsevier Science Ltd. All rights reserved.

关键词：苯丙胺/药理学苯丙氮|艹卓|类/代谢脑/代谢中枢神经系统刺激剂/药理学纹状体/药物作用纹状体/代谢右苯丙胺/药理学致幻药/药理学麦角酸二乙胺/药理学伏核/药物作用伏核/代谢苯环利定/药理学受体多巴胺/药物作用受体多巴胺/代谢螺哌隆/代谢氚动物男(雄)性大鼠

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Systemic nicotine stimulates dopamine release in nucleus accumbens:: re-evaluation of the role of N-methyl-D-aspartate receptors in the ventral tegmental area

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期294卷 458-465页

作者： Fu, YT Matta, SG Gao, WQ Brower, WG Sharp, BM Univ Tennessee Ctr Hlth Sci Dept Pharmacol Memphis TN 38163 USA

Systemic nicotine stimulates dopamine (DA) release in the nucleus accumbens (NAcc), and N-methyl-D-aspartate (NMDA) receptors in the ventral tegmental area (VTA) appear to be involved. However, it is not known whether the secretion of DA elicited by nicotine depends on the tonic and/or phasic activation of NMDA receptors by glutamate (Glu). To clarify this, in vivo microdialysis was conducted in freely moving, alert rats to measure DA and Glu overflows in the NAcc and Glu in the VTA. Nicotine (0.065, 0.09, or 0.135 mg/kg delivered i.v. at 0.09 mg/kg/60 s via a jugular cannula) dose dependently stimulated NAcc DA secretion (P<.05). However, 0.065 mg/kg nicotine failed to stimulate Glu release in the VTA, whereas higher doses of nicotine (greater than or equal to 0.09 mg/kg) were effective (P<.05). Administering the competitive NMDA receptor antagonists, 2-amino-5-phosphonopentanoic acid (AP-5;1 mM) or 0.2 mM cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755) through the VTA probe, abolished NAcc DA release after 0.065 mg/kg nicotine (P<.01) and reduced the response to 0.09 mg/kg nicotine. Therefore, the NAcc DA response to a relatively low dose of nicotine depends on the tonic activation of NMDA receptors in the VTA. In contrast, infusing 1 mM 2-amino-5-phosphonopentanoic acid or 1 mM 6-cyano-7-nitroquinoxaline-2,3- dione (CNQX), an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist, into the NAcc through the microdialysis probe had no effect on NAcc DA secretion in response to 0.09 mg/kg nicotine. These findings, coupled with data showing that Glu secretion in the VTA was stimulated only by higher doses of nicotine, indicate that the phasic release of VTA Glu is involved in the NAcc DA response to higher doses of nicotine (greater than or equal to 0.09 mg/kg).

关键词： 2-氨基-5-膦酰基戊酸盐/药理学 6-氰-7-硝基喹喔啉-2 3-二酮/药理学多巴胺/分泌剂量效应关系药物兴奋性氨基酸拮抗剂/药理学谷氨酸/生理学谷氨酸/分泌微透析尼古丁/药理学烟碱激动剂/药理学伏核/药物作用伏核/分泌哌可酸/药理学大鼠 Sprague-Dawley 受体 AMPA/拮抗剂和抑制剂受体 N-甲基-D-天冬氨酸/拮抗剂和抑制剂受体 N-甲基-D-天冬氨酸/生理学刺激化学性腹侧被盖区/药物作用腹侧被盖区/生理学动物男(雄)性大鼠

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INTERACTION BETWEEN ENDOGENOUS OPIOIDS AND DOPAMINE WITHIN THE NUCLEUS-ACCUMBENS

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ANNALS OF THE NEW YORK ACADEMY OF SCIENCES 1992年第1期654卷 254-273页

作者： STINUS, L CADOR, M LEMOAL, M Laboratoire de Psychobiologie des Comportements Adaptatifs INSERM U. 259 Universit&eacute de Bordeaux II Domaine de Carreire-Rue Camille Saint-Sa&euml ns 33077 Bordeaux Cedex France

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Behavioral and neurochemical effects of the dopamine transporter ligand 4-chlorobenztropine alone and in combination with cocaine in vivo

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第1期289卷 110-122页

作者： Tolliver, BK Newman, AH Katz, JL Ho, LB Fox, LM Hsu, K Berger, SP Univ Calif San Francisco Vet Affairs Med Ctr Dept Psychiat San Francisco CA 94121 USA NIDA Psychobiol Sect Intramural Res Program NIH Baltimore MD USA

The current studies evaluated the novel diphenylmethoxytropane analog 4-chlorobenztropine (4-Cl-BZT), cocaine, and combinations of the two drugs for their abilities to stimulate locomotor activity, produce cocaine-like discriminative stimulus effects, and elevate extracellular dopamine (DA) in the nucleus accumbens (NAc) as measured by in vivo microdialysis. Peripherally administered cocaine was approximately twice as efficacious as 4-Cl-BZT as a locomotor stimulant and was behaviorally active at a lower dose than was 4-Cl-BZT. Cocaine also was more efficacious than 4-Cl-BZT in producing discriminative-stimulus effects in rats trained to discriminate i.p. injections of 10 mg/kg cocaine from saline. The time course of behavioral activation differed markedly between the two drugs, with much shorter onset and duration of locomotor stimulant effects for cocaine relative to 4-Cl-BZT. Similarly, i.p. cocaine (10 and 40 mg/kg) induced a pronounced, rapid, and short-lived increase in DA in the NAc, whereas i.p, 4-Cl-BZT was effective only at the higher dose and produced a more gradual, modest, and sustained (greater than or equal to 2 h) elevation in accumbens DA. In contrast to i.p. administration, local infusion of 4-Cl-BZT (1-100 mu M) into the NAc through the microdialysis probe elevated extracellular DA to a much greater extent than did local cocaine (nearly 2000% of baseline maximally for 4-Cl-BZT versus 400% of baseline for cocaine) and displayed a much longer duration of action than cocaine. However, when microinjected bilaterally into the NAc at 30 or 300 nmol/side, cocaine remained a more efficacious locomotor stimulant than 4-Cl-BZT. Finally, pretreatment with i.p. 4-Cl-BZT dose dependently enhanced the locomotor stimulant, discriminative stimulus effects, and NAc DA response to a subsequent low-dose i.p. cocaine challenge. The diphenylmethoxytropane analog also facilitated the emergence of stereotyped behavior and convulsions induced by high-dose cocaine. The cu

关键词：载体蛋白质类/代谢色谱法高压液相可卡因/药代动力学可卡因/药理学辨别学习/药物作用多巴胺/代谢多巴胺质膜转运蛋白质类多巴胺摄取抑制剂/药代动力学多巴胺摄取抑制剂/药理学剂量效应关系药物药物拮抗作用注射腹腔内配体膜糖蛋白类膜转运蛋白质类微透析微量注射运动活动/药物作用神经组织蛋白质类伏核/药物作用伏核/代谢大鼠 Sprague-Dawley 男(雄)性大鼠

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LACK OF TOLERANCE TO ETHANOL-INDUCED STIMULATION OF MESOLIMBIC DOPAMINE SYSTEM

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ALCOHOL AND ALCOHOLISM 1992年第4期27卷 329-333页

作者： DIANA, M GESSA, GL ROSSETTI, ZL ‘B. B. Brodie’ Department of Neuroscience University of Cagliarivia Porcell 4 09124 Cagliari Italy

Rats maintained for 10 days on a 10% ethanol solution as the sole source of fluid developed marked tolerance to ethanol-induced loss of righting reflex, but no tolerance to the stimulatory effects on mesolimbic dopaminergic system. An ethanol challenge stimulated both the electrical activity of A10 dopaminergic cells and dopamine output in the ventral striatum of behaviourally tolerant animals and of controls of the same extent. These results are compatible with the hypothesis that an increased dopamine neurotransmission in the limbic system participates in the reinforcing effect of ethanol.

关键词： 3 4-二羟苯酰乙酸/代谢酒精中毒急性/病理生理学酒精中毒/病理生理学纹状体/药物作用纹状体/病理生理学多巴胺/生理学剂量效应关系药物药物耐受性电刺激脑电描记术/药物作用乙醇/药理学高香草酸/代谢边缘系统/药物作用边缘系统/病理生理学肌肉骨骼平衡/药物作用肌肉骨骼平衡/生理学伏核/药物作用伏核/病理生理学大鼠 Sprague-Dawley 受体多巴胺/药物作用受体多巴胺/生理学突触传递/药物作用突触传递/生理学中脑被盖/药物作用中脑被盖/病理生理学动物男(雄)性大鼠

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Dopamine D₃ receptors modulate evoked dopamine release from slices of rat nucleus accumbens via muscarinic receptors, but not from the striatum

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第3期291卷 994-998页

作者： Yamada, S Harano, M Annoh, N Tanaka, M Kurume Univ Sch Med Inst Brain Dis Kurume Fukuoka 8300011 Japan

It is not clear whether dopamine D-3 receptor contributes to the regional difference in dopamine antagonist-induced increase in the evoked dopamine release from the nucleus accumbens and striatum. We investigated the regional differences in augmentation of electrically evoked dopamine release induced by preferential dopamine D-2 or D-3 receptor antagonists from slices of the rat striatum and nucleus accumbens. Haloperidol, a preferential dopamine D-2 receptor antagonist, enhanced the evoked dopamine release from both the striatum and nucleus accumbens. Preferential dopamine D-3 antagonists, cis-(+)-(1S,2R)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin HCl [(+)-UH232] and 5,6-dimethoxy-2-(di-n-propylamine)indan (U-99194A) resulted in a greater increase in the evoked dopamine released from the nucleus accumbens compared with that from the striatum. Moreover, U-99194A attenuated the quinpirole-induced reduction of evoked dopamine release from the nucleus accumbens but not from the striatum. When slices were superfused with pirenzepine, a muscarinic receptor antagonist, the increase in the evoked dopamine release by (+)-UH232 or U-99194A was reduced in the nucleus accumbens to the same level as that in the striatum. Our results indicate that the preferential D-3 receptor antagonists-induced increase in evoked dopamine release is probably mediated by the cholinergic system in the nucleus accumbens, which contains more postsynaptic dopamine D-3 receptors than the striatum.

关键词： 8-羟-2-(二-n-丙胺)四氢萘/类似物和衍生物 8-羟-2-(二-n-丙胺)四氢萘/药理学多巴胺/代谢多巴胺激动剂/药理学多巴胺拮抗剂/药理学电刺激氟哌啶醇/药理学茚满类/药理学毒蕈碱拮抗剂/药理学新纹状体/药物作用新纹状体/代谢新纹状体/生理学伏核/药物作用伏核/代谢伏核/生理学哌仑西平/药理学喹吡罗/药理学大鼠 Wistar 受体多巴胺D2/药物作用受体多巴胺D3 受体毒蕈碱/药物作用动物男(雄)性大鼠

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Differential effect of local infusion of serotonin reuptake inhibitors in the raphe versus forebrain and the role of depolarization-induced release in increased extracellular serotonin

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期294卷 571-579页

作者： Tao, R Ma, ZY Auerbach, SB Rutgers State Univ Nelson Biol Labs Dept Cell Biol & Neurosci Piscataway NJ 08854 USA

Systemic administration of selective serotonin reuptake inhibitors (SSRIs) elicits larger increases in serotonin (5-HT) in raphe than in forebrain sites. Because serotonergic neuronal activity is suppressed, the mechanism underlying SSRI-induced increases in extracellular 5-HT is unclear. This study determined whether local infusion of SSRIs also elicited regionally selective increases in extracellular 5-HT, and whether changes depended on serotonergic neuronal depolarization. Conventional microdialysis methods were used to measure 5-HT in dorsal raphe (DRN), median raphe, nucleus accumbens (NAcc), and frontal cortex of unanesthetized rats. During infusion of SSRIs into each site, the maximum response was an similar to 6- to 7-fold increase in 5-HT in NAcc and frontal cortex, and an similar to 20-fold increase in DRN and median raphe. The larger increase in 5-HT in raphe was confirmed using zero-net-flux microdialysis. In NAcc, baseline 5-HT was 0.7 nM, and levels increased to a maximum of 3.1 nM during infusion of the SSRI citalopram. Baseline 5-HT in DRN was greater, 1.3 nM, and increased to 12.4 nM in response to citalopram. Consistent with evidence that autoreceptor activation inhibits serotonergic neuronal discharge, SSRI infusion into DRN produced a moderate decrease in 5-HT in NAcc. However, increases in 5-HT in DRN elicited by SSRI infusion were attenuated by 8-hydroxydipropylaminotetralin and tetrodotoxin. These data indicate that depolarization-dependent 5-HT release was not fully inhibited during SSRI infusion into DRN. In summary, SSRIs produce larger increases in extracellular 5-HT in raphe than in forebrain sites. Increases depend in part on depolarization-induced release, which may be greater in raphe than in forebrain.

关键词： 8-羟-2-(二-n-丙胺)四氢萘/药理学西酞普兰/药理学树突细胞/药物作用树突细胞/代谢树突细胞/生理学剂量效应关系药物药物相互作用细胞外隙/代谢微透析伏核/药物作用伏核/代谢伏核/生理学前脑/药物作用前脑/代谢前脑/生理学中缝核/药物作用中缝核/代谢中缝核/生理学大鼠 Sprague-Dawley 受体血清素/生理学受体血清素 5-HT1 血清素/代谢血清素/分泌血清素激动药/药理学血清素摄取抑制药/投药和剂量血清素摄取抑制药/药理学河豚毒素/药理学动物男(雄)性大鼠

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