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Effects of the long-acting monoamine reuptake inhibitor indatraline on cocaine self-administration in rhesus monkeys

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第1期291卷 60-69页

作者： Negus, SS Brandt, MR Mello, NK Harvard Univ McLean Hosp Sch Med Alcohol & Drug Abuse Res Ctr Belmont MA 02178 USA

Cocaine is a nonselective monoamine reuptake inhibitor that is widely abused. Useful pharmacotherapies for cocaine dependence may include substitution medications that produce cocaine-like effects but have a slower onset and longer duration of action. Accordingly, the present study examined the effects of the long-acting, nonselective monoamine reuptake inhibitor indatraline in assays of cocaine discrimination and cocaine self-administration that have been used to evaluate other candidate treatment medications. In rhesus monkeys trained to discriminate cocaine (0.4 mg/kg) from saline, indatraline (0.1-1.0 mg/kg) produced a dose- and time-dependent substitution for cocaine. The effects of 1.0 mg/kg indatraline peaked after 30 min and lasted up to 24 h. In monkeys trained to self-administer 0.032 mg/kg/injection cocaine and food pellets during alternating daily sessions of cocaine and food availability, indatraline (0.0032-0.032 mg/kg/injection) maintained lower rates of responding than cocaine. Repeated treatments with indatraline (0.1-0.56 mg/kg/day) for 7 days produced dose-dependent and sustained decreases in cocaine self-administration across a broad range of cocaine doses (0.0032-0.1 mg/kg/injection), and the highest dose of indatraline (0.56 mg/kg/day) nearly eliminated cocaine-maintained responding. However, doses of indatraline that decreased cocaine self-administration also usually decreased rates of food-maintained responding and produced behavioral stereotypies and trends toward weight loss and mild anemia. These findings suggest that although indatraline may decrease cocaine-taking behavior in rhesus monkeys, it also produces undesirable side effects that may limit its clinical utility in the treatment of cocaine dependence.

关键词：恒河猴精神运动性行为/药物作用强化(心理学) 自我遵嘱服药

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Role of the cerebellar posterior interpositus nucleus in saccades I. Effect of temporary lesions

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JOURNAL OF NEUROPHYSIOLOGY 2000年第3期84卷 1289-1302页

作者： Robinson, FR Univ Washington Dept Biol Struct Seattle WA 98195 USA Univ Washington Reg Primate Res Ctr Seattle WA 98195 USA

The ventrolateral corner of the cerebellar posterior interpositus nucleus (VPIN) contains many neurons that respond during saccades. To characterize the VPIN contribution to saccades, I located this area in three monkeys with single-unit recording and injected the GABA(A) agonist muscimol among saccade-related neurons there to reduce or eliminate neural activity. I compared the size, direction, velocity, and duration of saccades recorded before and after a unilateral injection in all three monkeys. In two of three monkeys, I also examined saccades after bilateral injection. After unilateral VPIN inactivation, upward saccades were abnormally large (avg. across all 3 monkeys = 112% of normal) and downward saccades were abnormally small (avg. across all 3 monkeys = 94% of normal). In the two monkeys tested, bilateral inactivation increased these abnormalities. Upward saccades went from 111% of normal size in these two monkeys after unilateral inactivation to 120% after bilateral inactivation;downward saccades went from 97 to 86%. VPIN inactivation caused changes in saccade gain and did not add of a constant offset to saccades. (The 1 exception was upward saccades in 1 monkey in which both gain and offset changed.) Neither uni- nor bilateral VPIN inactivation consistently affected the size of horizontal saccades (uni- avg. = 101% normal;bi-avg. = 97% normal). In two of the three monkeys, saccades to horizontal targets angled significantly upward after VPIN inactivation (uni- avg. = 3.6 degrees above normal, bi-avg. = 10.3 degrees above normal). The velocities of horizontal saccades were not strongly affected, but downward saccades exhibited abnormally low peak velocities and long durations. Upward velocities were inconsistently changed. I interpret these results to mean that the activity of some VPIN neurons helps drive the eyes downward and the activity of others helps drive the eyes upward. The downward drive outweighs the upward drive. The net effect of VPIN inactiva

关键词：小脑核/细胞学小脑核/药物作用小脑核/生理学注视眼/药物作用注视眼/生理学 GABA激动剂/投药和剂量猕猴蝇蕈醇/投药和剂量神经元/药物作用神经元/生理学光刺激精神运动性行为/药物作用反应时间/药物作用反应时间/生理学眼扫视/药物作用眼扫视/生理学动物男(雄)性

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Temporary inactivation in the primate motor thalamus during visually triggered and internally generated limb movements

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JOURNAL OF NEUROPHYSIOLOGY 2000年第5期83卷 2780-2790页

作者： van Donkelaar, P Stein, JF Passingham, RE Miall, RC Univ Oxford Physiol Lab Oxford OX1 3PT England Univ Oxford Dept Expt Psychol Oxford OX1 3PT England

To better understand the contribution of cerebellar- and basal granglia-receiving areas of the thalamus [ventral posterolateral nucleus, pars oralis (VPLo), area X, ventral lateral nucleus, pars oralis (VLo), or ventral anterior nucleus, pars parvicellularis (VApc)] to movements based on external versus internal cues, we temporarily inactivated these individual nuclei in two monkeys trained to make visually triggered (VT) and internally generated (IG) limb movements. Infusions of lignocaine centered within VPLo caused hemiplegia during which movements of the contralateral arm rarely were performed in either task for a short period of time (similar to 5-30 min). When VT responses were produced, they had prolonged reaction times and movement times and a higher incidence of trajectory abnormalities compared with responses produced during the preinfusion baseline period. In contrast, those IG responses that were produced remained relatively normal. Infusions centered within area X never caused hemiplegia. The only deficits observed were an increase in reaction time and movement amplitude variability and a higher incidence of trajectory abnormalities during VT trials. Every other aspect of both the VT and IG movements remained unchanged. Infusions centered within VLo reduced the number of movements attempted during each block of trials. This did not appear to be due to hemiplegia, however, as voluntary movements easily could be elicited outside of the trained tasks. The other main deficit resulting from inactivation of VLo was an increased reaction time in the VT task. Finally, infusions centered within VApc caused IG movements to become slower and smaller in amplitude, whereas VT movements remained unchanged. Control infusions with saline did not cause any consistent deficits. This pattern of results implies that VPLo and VLo play a role in the production of movements in general regardless of the context under which they are performed. They also suggest that VPLo contri

关键词：方差分析投药途径四肢/生理学偏瘫/化学诱导运动(Kinesis)/药物作用运动(Kinesis)/生理学利多卡因/投药和剂量猕猴微量注射运动(Movement)/药物作用运动(Movement)/生理学光刺激精神运动性行为/药物作用精神运动性行为/生理学丘脑/药物作用丘脑/生理学丘脑腹侧核/药物作用丘脑腹侧核/生理学动物男(雄)性

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Impaired reaching and grasping after focal inactivation of globus pallidus pars interna in the monkey

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JOURNAL OF NEUROPHYSIOLOGY 1999年第5期82卷 2049-2060页

作者： Wenger, KK Musch, KL Mink, JW Washington Univ Sch Med Dept Neurol St Louis MO 63110 USA Washington Univ Sch Med Program Phys Therapy St Louis MO 63110 USA St Louis Childrens Hosp St Louis MO 63110 USA

The purpose of this study was to test the hypothesis that the basal ganglia output from globus pallidus pars interna (GPi) contributes to inhibition of competing motor patterns to prevent them from interfering with a volitional movement. To test this hypothesis, the kinematics of a natural reach, grasp, and retrieval task were measured in the monkey before and after focal inactivation in GPi with the GABA(A) agonist muscimol. Two rhesus monkeys were trained to reach in a parasagittal plane to grasp a l-cm cube of apple and retrieve it. Reflective markers were applied to the shoulder, elbow, wrist, and index finger. Movements were videotaped at 60 fields/s, digitized, and analyzed off-line. In each session the monkey performed 12-15 reaches before and 12-15 reaches after injection of 0.5 mu l of 8.8 mM muscimol. Muscimol was injected into 22 separate locations in the "arm" area of GPi. Inactivation of the GPi with muscimol produced movement deficits in a reach-grasp-retrieve task that can be summarized as follows: I) decreased peak wrist velocity during the reach to target;2) decreased elbow and shoulder angular velocities, with elbow angular velocity relatively more impaired than shoulder angular velocity;resulting in 3) higher maximum vertical wrist and index finger positions at the apex of the reach;4) prolonged latency from the end of the reach to the completion of grasp;and 5) less impairment of retrieval than reach, with inactivation at the majority of sites causing no impairment and some actually speeding up retrieval despite slow reaching. The results of this study show that reaching movements are impaired in a specific way after focal inactivation of GPi in previously normal monkeys. The slowing of the reach with normal (or fast) retrieval suggests that there is difficulty inhibiting the posture holding mechanisms that were active before the reach, but that assist the retrieval. The nature of the impairment supports the hypothesis that GPi lesions disrupt th

关键词：基底神经节/生理学 GABA激动剂/药理学苍白球/药物作用苍白球/生理学握力/生理学猕猴运动活动/药物作用运动活动/生理学蝇蕈醇/药理学精神运动性行为/药物作用精神运动性行为/生理学反应时间/药物作用受体 GABA-A/生理学动物男(雄)性

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Reversal of antipsychotic-induced working memory deficits by short-term doper D1 receptor stimulation

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SCIENCE 2000年第5460期287卷 2020-2022页

作者： Castner, SA Williams, GV Goldman-Rakic, PS Yale Univ Sch Med Neurobiol Sect New Haven CT 06510 USA

Chronic blockade of dopamine D2 receptors, a common mechanism of action for antipsychotic drugs, down-regulates D1 receptors in the prefrontal cortex and, as shown here, produces severe impairments in working memory. These deficits were reversed in monkeys by short-term coadministration of a D1 agonist, ABT 431, and this improvement was sustained for more than a year after cessation of D1 treatment. These findings indicate that pharmacological modulation of the D1 signaling pathway can produce long-lasting changes in functional circuits underlying working memory. Resetting this pathway by brief exposure to the agonist may provide a valuable strategy for therapeutic intervention in schizophrenia and other dopamine dysfunctional states.

关键词：抗精神病药/药理学环AMP/代谢多巴胺/代谢多巴胺激动剂/药理学多巴胺拮抗剂/药理学减量调节氟哌啶醇/药理学直鼻猴亚目记忆/药物作用额叶前皮质/药物作用额叶前皮质/代谢精神运动性行为/药物作用吡啶类/药理学受体多巴胺D1/激动剂受体多巴胺D1/代谢信号传导四氢萘类/药理学时间因素动物女(雌)性

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Comparative kinetics and response to the benzodiazepine agonists triazolam and zolpidem: Evaluation of sex-dependent differences

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期293卷 435-443页

作者： Greenblatt, DJ Harmatz, JS von Moltke, LL Wright, CE Durol, ALB Harrel-Joseph, LM Shader, RI Tufts Univ Sch Med Dept Pharmacol & Expt Therapeut Boston MA 02111 USA New England Med Ctr Boston MA 02111 USA Pharmacia & Upjohn Inc Kalamazoo MI 49001 USA

Eighteen healthy volunteers (10 men and 8 women) participated in a single-dose, double-blind, three-way crossover pharmacokinetic and pharmacodynamic study. Treatment conditions were 0.25 mg of triazolam, a full-agonist benzodiazepine ligand;10 mg of zolpidem, an imidazopyridine having relative selectivity for the type 1 benzodiazepine receptor subtype;and placebo. Weight-normalized clearance of triazolam was higher in women than in men (8.7 versus 5.5 ml/min/kg), but the difference was not significant. In contrast, zolpidem clearance was lower in women than in men (3.5 versus 6.7 ml/min/kg, P<.06). Compared to placebo, both active medications produced significant benzodiazepine agonist-like pharmacodynamic effects: sedation, impaired psychomotor performance, impaired information recall, and increased electroencephalographic beta-amplitude. Effects of triazolam and zolpidem in general were comparable and less than 8 h induration. There was no evidence of a substantial or consistent sex difference in pharmacodynamic effects or in the kinetic-dynamic relationship, although subtle differences could not be ruled out due to low statistical power. The complete dependence of triazolam clearance on CYP3A activity, as opposed to the mixed CYP participation in zolpidem clearance, may explain the differing sex effects on clearance of the two compounds.

关键词：情感/药物作用曲线下面积色谱法气相交叉研究双盲法脑电描记术/药物作用 GABA激动剂/药代动力学 GABA激动剂/药理学 GABA调节剂/药代动力学 GABA调节剂/药理学半衰期催眠药和镇静药/药理学精神运动性行为/药物作用吡啶类/药代动力学吡啶类/药理学受体 GABA-A/激动剂性征三唑仑/药代动力学三唑仑/药理学成年人女(雌)性人类男(雄)性中年人

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Flumazenil discrimination by humans under a two-response and a novel-response procedure

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第3期291卷 1257-1268页

作者： Smith, BJ Bickel, WK Univ Vermont Dept Psychiat Burlington VT USA Univ Vermont Dept Psychol Burlington VT 05405 USA

In this study we assessed the discriminative stimulus, self-reported, and performance effects of flumazenil in humans. The first group (n = 6) was trained to discriminate flumazenil (0.56 mg/70 kg i.v.) from saline and tested with flumazenil (0.10, 0.32, 0.56, and 1.0 mg/70 kg) under a two-response drug discrimination procedure. The second group (n = 8) was trained to discriminate flumazenil (0.56 mg/70 kg i.v.) from saline and tested with flumazenil (0.32, 0.56, and 1.0 mg/70 kg), midazolam (0.10, 0.56, and 1.0 mg/70 kg), and caffeine (75 mg/70 kg) under a novel-response drug discrimination procedure. In both groups, flumazenil was acquired and maintained as a discriminative stimulus. Flumazenil dose-dependently increased flumazenil-appropriate responding and ratings of strength of drug effect and sedation, and decreased ratings of stimulant effects and psychomotor performance. Under the novel-response procedure, midazolam produced dose-dependent increases in flumazenil-appropriate responding. However, midazolam produced 43 and 25% novel responding at the intermediate and highest test doses, respectively. Midazolam dose-dependently increased ratings of strength of drug effect and sedation, and decreased ratings of stimulant effects and psychomotor performance. The magnitude of effects on ratings of strength of drug effect and sedation were comparable after flumazenil and midazolam, but psychomotor performance effects were greater after midazolam than after flumazenil. Caffeine produced mostly saline-appropriate responding. The results indicate that flumazenil has agonist effects similar to those of midazolam;however, novel responding after midazolam, and the greater performance decrement after midazolam, suggest that flumazenil does not act as a traditional benzodiazepine agonist.

关键词：咖啡因/药理学中枢神经系统刺激剂/药理学辨别(心理学)/药物作用剂量效应关系药物氟马西尼/药理学 GABA调节剂/药理学咪达唑仑/药理学精神运动性行为/药物作用三唑仑/药理学青少年成年人女(雌)性人类男(雄)性

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Behavioral, toxic, and neurochemical effects of sydnocarb, a novel psychomotor stimulant: Comparisons with methamphetamine

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第3期288卷 1298-1310页

作者： Witkin, JM Savtchenko, N Mashkovsky, M Beekman, M Munzar, P Gasior, M Goldberg, SR Ungard, JT Kim, J Shippenberg, T Chefer, V NIDA Drug Dev Grp Addict Res Ctr NIH Baltimore MD 21224 USA NIDA Integrat Neurosci Unit Addict Res Ctr NIH Baltimore MD 21224 USA Minist Publ Hlth Russia Ctr Chem Drugs Moscow Russia

Sydnocarb (3-(beta-phenylisopropyl)-N-phenylcarbamoylsydnonimine) is a psychostimulant in clinical practice in Russia as a primary and adjunct therapy for a host of psychiatric disorders, including schizophrenia and depression. It has been described as a stimulant with an addiction liability and toxicity less than that of amphetamines. The present study undertook to evaluate the psychomotor stimulant effects of sydnocarb in comparison to those of methamphetamine. Sydnocarb increased locomotor activity of mice with reduced potency (similar to 10-fold) and efficacy compared with methamphetamine. Sydnocarb blocked the locomotor depressant effects of haloperidol at doses that were inactive when given alone. The locomotor stimulant effects of both methamphetamine and sydnocarb were dose-dependently blocked by the dopamine D1 and D2 antagonists SCH 39166 and spiperone, respectively;blockade generally occurred at doses of the antagonists that did not depress locomotor activity when given alone. In mice trained to discriminate methamphetamine from saline, sydnocarb fully substituted for methamphetamine with a 9-fold lower potency. When substituted for methamphetamine under self-administration experiments in rats, 10-fold higher concentrations of sydnocarb maintained responding by its i.v, presentation. Sydnocarb engendered stereotypy in high doses with approximately a 2-fold lower potency than methamphetamine. However, sydnocarb was much less efficacious than methamphetamine in inducing stereotyped behavior. Both sydnocarb and methamphetamine increased dialysate levels of dopamine in mouse striatum;however, the potency and efficacy of sydnocarb was less than methamphetamine. The convulsive effects of cocaine were significantly enhanced by the coadministration of nontoxic doses of methamphetamine but not of sydnocarb. Taken together, the present findings indicate that sydnocarb has psychomotor stimulant effects that are shared by methamphetamine while demonstrating a reduced

关键词：苯丙氮|艹卓|类/药理学脑/代谢中枢神经系统刺激剂/药理学辨别学习/药物作用多巴胺/代谢多巴胺拮抗剂/药理学剂量效应关系药物氟哌啶醇/药理学迷宫学习/药物作用甲基苯丙胺/投药和剂量甲基苯丙胺/药理学甲基苯丙胺/毒性运动活动/药物作用精神运动性行为/药物作用自我遵嘱服药刻板行为/药物作用斯德酮类/投药和剂量斯德酮类/药理学斯德酮类/毒性动物男(雄)性小鼠

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Subjective, psychomotor, and physiological effects of cumulative doses of opioid μ agonists in healthy volunteers

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第3期289卷 1454-1464页

作者： Walker, DJ Zacny, JP Univ Chicago Dept Anesthesia & Crit Care Chicago IL 60637 USA

The subjective, psychomotor, and physiological effects of three opioid mu-receptor agonists were studied in healthy volunteers using a cumulative-dosing procedure. Sixteen volunteers with no history of drug abuse received i.v. injections of saline (SAL), morphine (MOR), hydromorphone (HM), or meperidine (MEP) in a randomized double-blind crossover design. Subjects received 1 injection/h for the first 4 h, and a 3-h recovery period followed. SAL was injected first during each session, then SAL or increasing doses of each drug were administered every hour for the next 3 h. The absolute doses per injection were MOR: 2.5, 5, and 10 mg/70 kg;HM: 0.33, 0.65, and 1.3 mg/70 kg;and MEP: 17.5, 35, and 70 mg/70 kg. These injections resulted in cumulative doses of MOR: 2.5, 7.5, and 17.5;HM: 0.33, 0.98, and 2.28;and MEP: 17.5, 52.5, and 122.5 mg/70 kg. Subjects completed mood forms and psychomotor tests, and physiological measures were recorded at various times after each injection and during recovery, MEP tended to produce the most intense effects immediately after drug injection, which dissipated rapidly. MOR produced the mildest effects but was associated with unpleasant side effects during recovery and after the session. HM's effects were stronger than MOR's, and the recovery from HM was slower than with MEP. None of the opioids produced consistent effects that are typically associated with abuse liability. Orderly dose-response functions suggested that our cumulative-dosing procedure is an efficient way of determining dose-response functions for multiple opioids within the same subjects within the same study.

关键词：情感/药物作用方差分析态度交叉研究剂量效应关系药物双盲法氢吗啡酮/药理学注射静脉内哌替啶/药理学吗啡/药理学麻醉品安慰剂精神运动性行为/药物作用问卷调查受体阿片样 μ/激动剂参考值呼吸/药物作用时间因素成年人女(雌)性人类男(雄)性

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The effects of typical antipsychotics, clozapine, and risperidone on neuropsychological test performance in schizophrenia

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SCHIZOPHRENIA RESEARCH 1999年第3期40卷 255-256页

作者： Earnst, KS Taylor, SF Smet, IC Goldman, RS Tandon, R Berent, S Ann Arbor Vet Adm Med Ctr Psychol Serv Ann Arbor MI USA Univ Michigan Med Ctr Dept Psychiat Ann Arbor MI 48109 USA Hillside Hosp Long Isl Jewish Med Ctr New York NY USA

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