The emergence test: effects of psychotropic drugs on neophobic disposition in Wistar Kyoto (WKY) and Sprague Dawley rats

1. The Emergence Test (ET), a variation of the open field test in which the rat is not handled, and is purported to measure neophobia, was applied to Wistar Kyoto (WKY) and Sprague Dawley (S-D) rats.

2. While no-stress control WKY rats were less active in the ET, pre-treatment with shock stress exacerbated strain differences. WKY rats, previously exposed to shock, did not emerge from the home cage start box during repeated testing, whereas previously stressed S-D rats vacated the home cage quickly and revealed increasing behavioral agitation.

3. Diazepam reduced emergence latency only in S-D rats, whereas nomifensine significantly increased head poke responses in WKY rats.

4. WKY rats responded to the ET with characteristically depressive behavior, whereas S-D rats responded to the same ET with behavioral agitation and anxiety. The implications of these behavior patterns for discriminating between anxiety and depressive behavior are presented.

Differential time-course profiles of dopamine release and uptake changes induced by three dopamine uptake inhibitors

Using real-time voltammetry, we compared the effects of cocaine (1.0, 3.0, or 10 microM), WIN 35428 (0.1, 0.5, or 2.0 microM), and nomifensine (0.2, 1.0, or 5.0 microM) on electrically evoked dopamine release and uptake in the rat accumbens slice. The time course for onset and offset of the drug effects were determined by perfusing single drug concentration for 30 min, followed by a 60-min washout. Cocaine elicited a rapid, concentration-independent increase in dopamine release and a more gradual, concentration-dependent inhibition of uptake. During washout, uptake inhibition rapidly abated to near baseline values. During the same period, the potentiation of dopamine release exhibited a slower offset for all concentrations and, for 10 microM cocaine, was even greater than that observed during drug perfusion ("rebound" increase). The release rebound was not observed during continuous 90-min perfusion, verifying that cocaine washout per se was a sufficient condition. Selective D1 or D2 antagonists (0.5 microM SCH 39166 or 2 microM sulpiride, respectively) were without effect on cocaine-induced release alterations. WIN 35428 and nomifensine induced similar changes in dopamine kinetics during perfusion. However, in contrast to cocaine, no consistent release rebound was observed during their washout. For 2 microM WIN 38425, washout and continuous perfusion groups exhibited similar changes in dopamine release and uptake. The time-course mismatch between uptake inhibition and DA release potentiation as well as release rebound during washout suggests that altered dopamine release might play a role in behavioral effects of cocaine.     

Halothane potentiates the effect of methamphetamine and nomifensine on extracellular dopamine levels in rat striatum: a microdialysis study

Brain microdialysis was used to study the in vivo release andmetabolism of dopamine (DA) in the rat striatum during halothaneanaesthesia. Concentrations were measured in microdialysatescollected every 20 min and applied directly to an on-linehigh-performance liquid chromatograph. Halothane was administeredat concentrations of 0.5, 1.0, 1.5 and 2.0%. In another seriesof experiments, rats were treated intraperitoneally or locallywith methamphetamine, a drug of abuse, or with nomifensine,a dopamine uptake blocker and antidepressant, in combinationwith 0.5 or 1.5% halothane. Halothane anaesthesia did not affectthe dialysate (extracellular) concentration of DA at 2.0%. Bycontrast, the concentrations of DA metabolites [3-methoxytyramine(3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillicacid (HVA)] increased during inhaled halothane anaesthesia ina dose-dependent manner and recovered after anaesthesia. Halothanepotentiated the ability of methamphetamine to increase the extracellularconcentration of DA when administered systemically, whereasonly a small increase in DA accumulation was seen when methamphetaminewas administered locally via the perfusate. Similarly, the increasein extracellular DA was accentuated by systemic nomifensineduring halothane anaesthesia, but no obvious enhancement wasobserved when it was applied locally. It has been shown thatthe neurotoxic effect of methamphetamine is mediated by thesuboxidation of DA released from the cytoplasm into the extracellularspace and transformed into highly reactive free radicals. Onthe basis of our results, it is suggested that care should beexercised when halothane anaesthesia is used in patients abusingphenylethylamines (amphetamines) or being treated with DA uptakeblockers (nomifensine). Br J Anaesth 2001; 86: 837–45     

Striatal dopamine uptake in the rat: in vivo analysis by fast cyclic voltammetry

Electrical stimulation of the median forebrain bundle of the chloral hydrate anaesthetised rat evoked dopamine release in the ipsilateral striatum, which was monitored with fast cyclic voltammetry. On cessation of stimulation, the extracellular concentration of dopamine fell to sub-detectable levels over a period of about 15 s. This fall appeared to be due to a saturable, low affinity uptake system that could be inhibited by nomifensine (20 mg/kg i.p.). These experiments constitute the first characterisation of a dopamine uptake mechanism obtained in the intact animal.     

Intracerebroventricular administration of 1-methyl-4-phenylpyridinium ion in mice: Effects of simultaneously administered nomifensine,deprenyl, and 1-t-butyl-4,4-diphenylpiperidine

Summary 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) destroys nigrostriatal dopaminergic pathways and thereby produces a syndrome similar to Parkinson's disease. MPTP is oxidized by monoamine oxidase B (MAO B) to the 1-methyl-4-phenylpyridinium ion (MPP⁺), which is taken up in dopaminergic neurons through the dopamine (DA) uptake system, where it develops its toxic effect. Our observations show a new aspect of the MPP⁺ mode of action, in which deprenyl in mice has a partially protective effect against MPP⁺. Furthermore budipine, a therapeutic agent for Parkinsonism, is also able to partially prevent MPP⁺ toxicity. A MAO B-inhibitory component of budipine, as shown in receptor binding studies previously, could contribute to this effect. Comparable experiments with nomifensine do not exclude the possibility of budipine as an effect as a DA uptake inhibitor. An unexplained after effect of budipine leads to a large increase in 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels five weeks after the last administration.     

诺米芬新对慢性吗啡处理后小鸡自发活动量的影响

目的 :探求吗啡对刚出生的小鸡自发活动量的影响以及行为敏感化的多巴胺神经机制。方法 :连续 7d每天给予小鸡ip不同剂量的吗啡 (5、10、2 0mg·kg- 1 ) ,观察其行为敏感化效应 ,撤药 3d后观察多巴胺转运体阻断剂诺米芬新 (0 5、1mg·kg- 1 )的干预效果。结果 :反复给药后 ,5mg·kg- 1 吗啡显著增加小鸡的自发活动量 (P <0 0 5 ,P <0 0 1) ,而且其自发活动量随给药次数的增多而不断增高 ;2 0mg·kg- 1 吗啡则明显降低小鸡的自发活动量 (P <0 0 5 )。诺米芬新呈剂量依赖性增加 5mg·kg- 1 组小鸡的自发性活动量 (P <0 0 5 )。结论 :反复小剂量吗啡处理能够导致鸟类行为敏感化效应 ,多巴胺可能在其中起重要作用。     

Interaction of alcohol with maprotiline or nomifensine: Echocardiographic and psychometric effects

Summary Eight healthy volunteers received low doses of maprotiline and nomifensine up to 50 mg b. d. for 15 days in a double-blind, cross-over, placebo controlled study, during which echocardiography and psychomotor testing were carried out before and after the intake of alcohol 1 g/kg.Maprotiline increased heart rate and cardiac output and reduced peripheral resistance compared to placebo and nomifensine. Nomifensine alone was associated with a slight decrease in heart rate. Alcohol alone caused a significant increase in diastolic blood pressure, but did not otherwise modify the cardiovascular measures. The antidepressants did not augment the effects of alcohol.Antidepressants alone had no effect on psychomotor skills, but alcohol always impaired performance. No additional effects of alcohol were produced by the antidepressants.It appears that practically important peripheral or central consequences are unlikely to follow drinking a moderate amount of alcohol during regular therapy with low therapeutic doses of catecholamine reuptake inhibiting antidepressants. Experimental studies of the interaction of antidepressants and alcohol in patients with chronic heart disease seem to be justified.     

Suppression of MPTP-induced dopaminergic neurotoxicity in mice by nomifensine andl-DOPA

To examine effects of various pharmacological manipulations of dopamine (DA) metabolism on DA neurotoxicity of N-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), C57 black mice were injected with MPTP (30 mg/kg s.c., once daily for two days) alone or in combination with apomorphine, bromocriptine, haloperidol,l-DOPA or nomifensine. MPTP markedly decreased neostriatal DA concentrations at 2, 10, 20 and 30 days post-treatment indicating persistent degeneration of nigrostriatal DA neurons. Suppression or acceleration of DA turnover rates by the DA agonists apomorphine and bromocriptine or by the DA antagonist haloperidol, respectively, did not affect MPTP toxicity. MPTP-induced neostriatal DA depletions were markedly suppressed by nomifensine, a DA reuptake inhibitor, and attenuated by exogenousl-DOPA. MPTP may be a substrate for the DA reuptake system and its specific transport into nigrostriatal terminals may be an important factor for its selective neurotoxicity.     

Nomifensine and amitriptyline in the treatment of depression. A multi-centre double-blind comparison

Nomifensine, an antidepressive agent acting like a dopamine agonist, was investigated in a randomized double-blind comparison with amitriptyline in 29 patients fulfilling the RDC criteria for major depression. The dosage was 150 mg daily in both treatment groups. Assessments were made at weekly intervals for 6 weeks with the Comprehensive Psychopathological Rating Scale. No significant difference could be demonstrated between the two drugs in overall therapeutic efficiency, and only one item, Fatiguability, differed significantly in favour of amitriptyline. Physical and laboratory variables showed no statistically significant differences. Neither drug elicited serious unwanted effects.     

Electrophysiological evidence for a reciprocal interaction between amphetamine and cocaine-related drugs on rat midbrain dopaminergic neurons

To determine the functional interactions occurring between amphetamine and cocaine-like drugs on a single neuron, we used intracellular single-electrode voltage-clamp recordings from dopaminergic cells of the rat midbrain maintained in vitro. In the presence of cocaine (3-30 microM), the outward current caused by amphetamine (100 microM) on cells held at about -60 mV was attenuated. The degree of attenuation of the amphetamine-induced response was almost the same for 3 and 30 microM cocaine (44 and 51% of control, respectively). This effect of cocaine was reversible. We also tested other DA-uptake inhibitors (nomifensine and 4-phenyltetrahydroisoquinoline) against the amphetamine-induced outward current. Both drugs enhanced the effects of dopamine (DA) while reducing the outward response caused by amphetamine. Pretreatment of the animals with reserpine (12 mg/kg/i.p.), which irreversibly depletes the vesicular DA stores, neither affected the amplitude of the current caused by amphetamine nor changed the cocaine-induced attenuation of the membrane responses to amphetamine. Interestingly, when amphetamine (3 microM) was superfused on the dopaminergic neurons prior and during the application of cocaine, the DA-uptake blocker was no longer able to potentiate the outward response caused by the superfusion of DA. Taken together, these data suggest that: (i) amphetamine and cocaine interact with the DA transporter to produce distinct actions which under certain circumstances can compete with each other; (ii) the amphetamine-induced release of DA from the somata and dendrites of the dopaminergic cells is, at least in part, related to the reverse operation of the DA transporter and is not dependent on the integrity of the vesicular content of the catecholamine.