In vivo neurochemical characterization of clothianidin induced striatal dopamine release.

Clothianidin (CLO) is a neonicotinoid insecticide with selective action on nicotinic acetylcholine receptors. The aim of this study was to determine the neurochemical basis for CLO-induced striatal dopamine release using the microdialysis technique in freely moving and conscious rats. Intrastriatal administration of CLO (3.5mM), produced an increase in both spontaneous (2462 ± 627% with respect to basal values) and KCl-evoked (4672 ± 706% with respect to basal values) dopamine release. This effect was attenuated in Ca(2+)-free medium, and was prevented in reserpine pre-treated animals or in presence of tetrodotoxin (TTX). To investigate the involvement of dopamine transporter (DAT), the effect of CLO was observed in presence of nomifensine. The coadministration of CLO and nomifensine produced an additive effect on striatal dopamine release. The results suggest that the effect of CLO on striatal dopamine release is predominantly mediated by an exocytotic mechanism, Ca(2+), vesicular and TTX-dependent and not by a mechanism mediated by dopamine transporter.

Dyskinesias in normal squirrel monkeys induced by nomifensine and levodopa.

The mechanisms underlying levodopa-induced dyskinesias are unclear. They might involve impairment of the buffering capacity for dopamine, resulting from loss of nigral dopaminergic cells and the subsequent degeneration of their terminals in striatum. This study investigated the role of striatal buffering in the development of dyskinesias. We used nomifensine, a selective dopamine reuptake blocker, to pharmacologically impair presynaptic buffering capacity in normal squirrel monkeys. Dyskinesias were assessed at 30-min intervals for 4 h after twice-daily treatment with drug. As previously reported by our group, animals receiving levodopa alone (15 mg/kg) exhibited dyskinetic behavior. Treatment with nomifensine alone (3 mg/kg) also induced dyskinesias. Furthermore, combining levodopa with nomifensine significantly increased dyskinesias. Over 4 weeks of treatment, the animals developed tolerance to the dyskinesia-inducing effect of nomifensine. The development of tolerance was prevented by concurrent treatment with levodopa. These results show that impairing buffering by preventing dopamine reuptake can induce dyskinesias and can also augment levodopa-induced dyskinesias. Thus, this study suggests that diminished buffering capacity for dopamine could play a role in the development of dyskinesias, and that an endogenous mechanism might exist that ameliorates dyskinesias.

A pharmacological study of cocaine activity in planaria.

Planaria has been proposed as a suitable research model in neurobiology because of its relatively simple organization. Dopaminergic agonists induce in this flatworm typical hyperkinesias that can be antagonized by dopaminergic blocking agents. The neurochemical basis of the effects of cocaine in vertebrates has not been fully elucidated, but the inhibition of catecholamine reuptake at a presynaptic level seems to play an important role. In this study we analyzed the involvement of the dopaminergic system in the mechanism of action of cocaine in planaria. The dose-related effects of cocaine on planaria motility and the response to cocaine treatment associated with the administration of specific D1 or D2 dopamine agonists and antagonists were investigated. The effects of reuptake inhibitors on cocaine activity were also studied. Planaria specimens treated with low doses of cocaine become motionless, whereas high doses induce a typical behavioural response, identical to the response induced by specific D2 agonists. This response is inhibited by a D2 selective blocking agent. Nomifensine, a specific dopamine reuptake inhibitor, induces a mixed D1/D2 response. The results of these experiments are discussed, also in relation with the conservation of dopaminergic receptors during evolution.

Antidepressant therapy: benefits and risks in perspective.

The introduction of second generation antidepressants, such as mianserin and nomifensine, was prompted by the desire to produce drugs which were safer, had fewer side-effects and were faster acting than the tricyclics. A brief review of the data on mianserin and nomifensine is presented in relation to these aims. Some advantages for the new drugs can be claimed and the risks of severe adverse effects relating to blood dyscrasias in the case of mianserin, and fever in the case of nomifensine, appear outweighed by the therapeutic gains.

Epilepsy, antidepressants, and the role of nomifensine.

The clinical and animal literature on the relationship between antidepressant drugs and the precipitation of seizures or lowering of the seizure threshold is reviewed. All tricyclic antidepressants have the potential to provoke seizures, particularly in patients with a preexisting lowered seizure threshold. A pilot investigation and a double-blind trial comparing the nontricyclic nomifensine with amitriptyline and placebo in epileptic patients are described. Results of these and other studies suggest that nomifensine--almost alone among the antidepressant drugs--has minimal seizure-provoking effects and therefore may be valuable in the management of patients with epilepsy or other neurologic diseases associated with lowered seizure threshold.

Relative acute cardiovascular toxicity induced by maprotiline, mianserin and nomifensine in conscious rabbits.

The relative acute cardiovascular toxicity among three novel antidepressants: maprotiline, mianserin and nomifensine, has been assessed in conscious rabbits ip injected at 50 mg/kg, throughout a 150 min observation period. No death was observed in mianserin rabbits (n = 6), but 3 in the maprotiline rabbits (n = 8) and 1 death in the nomifensine group (n = 8), within the 2 hours. Cardiac output and renal blood flow were determined by the radioactive Sephadex microspheres method. Cardiac output values were significantly lowered (-29%) at 120 min only in mianserin rabbits, whereas renal blood flow values were reduced by 46.8% (mianserin, 35.8% (maprotiline) and 28% (nomifensine) at 120 min. In mianserin and maprotiline rabbits left ventricular pressure and mean arterial pressure fell significantly, but remained unchanged in nomifensine group. ECG disturbances consisting of ventricular and supraventricular extrasystoles were seen in all the injected rabbits, but QRS widening and right bundle branch block were solely observed after maprotiline and mianserin. Nomifensine rabbits experienced severe seizures with hypocapnia and metabolic acidosis. The drug myocardial/plasma ratio ranged between 59.3 (maprotiline) 13.25 (mianserin) and 0.92 (nomifensine). A rise in plasma catecholamines (epinephrine) was documented after mianserin but not after nomifensin and maprotiline. Nomifensine exhibited much lesser cardiotoxicity than mianserin and maprotiline at this dose (50 mg/kg), but induced more convulsions.

Pharmacology of nomifensine.

Nomifensine, a representative of a new class of chemical substances, is a compound of low toxicity and of wide therapeutical range. Nomifensine is absorbed very well, has a rapid onset of action, has no sedative effect and does not prolong alcohol-induced anaesthesia. In studies on thymoleptic activity, nomifensine showed a good and persistent activity, particularly after oral treatment. It had a better quantitative effect than the tricyclic reference compounds from which it differs by the lack of distinct anticholinergic activity. The efficacy of nomifensine does not decrease during long-term treatment. The mechanism of action of nomifensine, whose thymoleptic activity resembles that of a tricyclic antidepressant, may be explained by the influence on the catecholamine metabolism, but contrary to tricyclic compounds, nomifensine also influences the dopamine uptake. The increase in motility induced by nomifensine is based on a different mechanism as that induced by phenylalkylamines. Particularly noteworthy are the lack of a systemic effect, the remarkably slight influence on the cardiovascular system, and the slight cardio-toxicity in comparison with reference compounds. Nomifensine showed an interesting activity component in the protective influence on stress-induced ulcers. The results of kinetic studies of nomifensine in animals explain the rapid onset of action and indicate an easy use in therapy.