Biochemical and pharmacological properties of a peripherally acting catechol-O-methyltransferase inhibitor entacapone

Summary Entacapone, OR-611, was found to be a potent peripherally acting inhibitor of catechol-O-methyl-transferase (COMT). IC₅₀ values of 10 nmol/1 and 160 nmol/1 were obtained for rat duodenum and liver-soluble COMT, respectively. There were no effects on other catecholamine metabolizing enzymes. Entacapone showed reversible, tight-binding type of inhibition of soluble rat liver COMT with a K; value of 14 nmol/1 and it also caused 50% inhibition of rat duodenal, erythrocyte, liver and striatal COMT activity 1 h after oral dosing with 1.1, 5.4, 6.7 and 24.2 mg/kg, respectively. However, penetration of entacapone into the brain was poor, since the formation of homovanillic acid (HVA), the O-methyl metabolite of dopamine in the striatum, was not reduced, even after the highest dose of 30 mg/kg.In rat blood serum, the concentration of 3-0-methyldopa (3OMD), the O-methylated product of l-dopa, was reduced in a dose-dependent manner, and the concentration of l-dopa was increased after the administration of entacapone (3 - 30 mg/kg p. o.) together with l-dopa + carbidopa. These changes were reflected, in the striatum, by a significant rise in the dopamine concentration and a reduction in the 30MD concentration.Consequently, when entacapone was added to the treatment with l-dopa + carbidopa, the dose of l-dopa could be lowered from 50 mg/kg to 15 mg/kg in order to produce the same striatal dopamine concentrations as with 50 + 50 mg/kg of l-dopa + carbidopa alone.Correspondence to E. Nissinen at the above address     

Pavlovian conditioning ofl-dopa induced movement

Using the unilateral 6-hydroxydopamine (6-OHDA) substantia nigra pars compacta (SNC) lesion rat model and a Pavlovian conditioning protocol, the present investigation determined that the contralateral rotation response induced by the antiparkinsonian dopaminergic drugl-dopa can become conditioned to exteroceptive test environment stimuli. Two non-drug conditioning tests indicated that contralateral rotation was elicited by the test environment without the presence ofl-dopa. This conditioned response had a rotation diameter profile that was qualitatively the same as thel-dopa induced contralateral rotation response. Additionally, drug tests with the combined dopaminergic receptor antagonists, SCH 23390 (0.1 mg/kg) and haloperidol (0.5 mg/kg), at doses sufficient to block spontaneous behavior andl-dopa (20 mg/kg)-induced rotation, revealed that the conditioned contralateral rotation response, unlikel-dopa-induced contralateral rotation, is not affected by D₁/D₂ receptor blockade. Thus, the conditoned stimuli of the test environment can elicit the contralateral rotation response even in animals rendered akinetic by D₁/D₂ antagonists. This activation of a conditioned dopaminergic drug response by the situational stimuli, independent of dopaminergic mechanisms, may, therefore, contribute to the untoward overstimulation clinical effects ofl-dopa through summation of conditioned and drug-induced effects. Furthermore, the use of conditioning procedures to elicit movement in akinetic animals may provide a new research methodology to investigate the phenomenon of paradoxical kinesia.     

Pharmacologic manipulations of brain catecholamines and the behavior of Callithrix jacchus (marmoset)

In experiment 1, groups of marmosets were injected with 50–200 mg/kg l-dopa, 0.5–2.0 mg/kg apomorphine (AP), or 0.5–5.0 mg/kg methamphetamine. The number of head movements, number of body movements, number of times the tongue was extended, and the time the animals remained in an upright posture were scored during a 90-min period after the injections. l-Dopa and AP induced large dose-dependent increases in body movements and time in upright posture. Furthermore, the smallest dose of AP induced somnolence in all animals and the largest dose of l-dopa induced self-destructive behavior. The main effect produced by methamphetamine was a constant turning of the head with the body remaining still. In experiment 2, the marmosets were treated with -methyl-p-tyrosine (AMPT) or haloperidol prior to challenge with AP or methamphetamine. Haloperidol blocked most of the effects of both drugs, while AMPT blocked only methamphetamine effects. In experiment 3, marmosets were injected with increasing doses of haloperidol for 22 days. Upon withdrawal of the neuroleptic, methamphetamine and AP effects were not increased, suggesting absence of supersensitivity of dopaminergic receptors.     

Potentiation of d-amphetamine and l-dopa-induced acoustic startle activity after long-term exposure to amphetamine

The startle response to an auditory atimulus was potentiated by treatment with d-amphetamine sulfate. Administration of l-dopa after pretreatment with the extracerebral decarboxylase inhibitor MK-486 also increased startle activity. After long-term exposure to amphetamine the startle response to l-dopa and d-amphetamine was enhanced. These findings are consistent with the consequences of longterm amphetamine administration on other amphetamine-induced behaviors (e.g. stereotypy), and are discussed in terms of the effects of long-term amphetamine treatment on pre-and postsynaptic dopamine receptors and serotonin.     

Investigation of the effects of lamotrigine and clozapine in improving reversal-learning impairments induced by acute phencyclidine and <Emphasis Type="SmallCaps">d</Emphasis>-amphetamine in the rat

Rationale Phencyclidine (PCP), a glutamate/N-methyl-d-aspartate (NMDA) receptor antagonist, has been shown to induce a range of symptoms similar to those of patients with schizophrenia, while d-amphetamine induces predominantly positive symptoms. Previous studies in our laboratory have shown that PCP can selectively impair the performance of an operant reversal-learning task in the rat. Furthermore, we found that the novel antipsychotic ziprasidone, but not the classical antipsychotic haloperidol, could prevent the PCP-induced deficit.Objectives The aim of the present study was to validate the model further using the atypical antipsychotic clozapine and then to investigate the effects of lamotrigine, a broad-spectrum anticonvulsant that is known to reduce glutamate release in vitro and is able to prevent ketamine-induced psychotic symptoms in healthy human volunteers. A further aim was to compare effects of PCP and d-amphetamine in the test and investigate the effects of the typical antipsychotic haloperidol against the latter.Methods Female hooded-Lister rats were food deprived and trained to respond for food in a reversal-learning paradigm.Results PCP at 1.5 mg/kg and 2.0 mg/kg and d-amphetamine at 0.5 mg/kg significantly and selectively impaired performance in the reversal phase of the task. The cognitive deficit induced by 1.5 mg/kg PCP was attenuated by prior administration of lamotrigine (20 mg/kg and 30 mg/kg) or clozapine (5 mg/kg), but not haloperidol (0.05 mg/kg). In direct contrast, haloperidol (0.05 mg/kg), but not lamotrigine (25 mg/kg) or clozapine (5 mg/kg), prevented a similar cognitive impairment produced by d-amphetamine (0.5 mg/kg).Conclusions Our findings provide further data to support the use of PCP-induced disruption of reversal learning in rodents to investigate novel antipsychotic drugs. The results also provide evidence for different mechanisms of PCP and d-amphetamine-induced disruption of performance in the test, and their different sensitivities to typical and atypical antipsychotic drugs.     

Habituation of acoustic startle is disrupted by psychotomimetic drugs: differential dependence on dopaminergic and nitric oxide modulatory mechanisms

Rationale A deficit in attention and information processing has been considered a central feature in schizophrenia, which might lead to stimulus overload and cognitive fragmentation. It has been shown that patients with schizophrenia display a relative inability to gate incoming stimuli. Thus, patients repeatedly subjected to acoustic startle-eliciting stimuli habituate less to these stimuli than controls. Furthermore, schizophrenia-like symptoms can be induced by pharmacological manipulations in humans by psychotomimetic drugs, e.g. phencyclidine (PCP) and d-amphetamine (d-AMP). Recent studies show that the behavioural and biochemical effects of PCP in rodents are blocked by nitric oxide synthase (NOS) inhibitors, suggesting that NO plays an important role in at least the pharmacological effects of PCP.Objectives The first aim of the present study was to investigate if PCP, MK-801 and d-AMP impair habituation of acoustic startle in mice. Secondly, we examine the effect of the NOS inhibitor, l-NAME, and the dopamine receptor antagonist, haloperidol, on drug-induced deficit in habituation.Results PCP (4 mg/kg), MK-801 (0.4 mg/kg) and d-AMP (5.0 mg/kg), impaired habituation of the acoustic startle response in mice. This effect was reversed by the NOS inhibitor, l-NAME. The typical antipsychotic, haloperidol, reversed the effects of PCP and d-AMP, but not that of MK-801.Conclusions The finding that PCP, MK-801 and d-AMP impair habituation in mice is consistent with the idea that these treatments model certain filter deficits seen in schizophrenic patients. Furthermore, the present results suggest that NO is critically involved in these effects on habituation, whereas that of dopamine is less clear.     

Discriminative stimulus and reinforcing effects of <Emphasis Type="Italic">p</Emphasis>-fluoro-<Emphasis Type="SmallCaps">l</Emphasis>-deprenyl in monkeys

Rationale para-Fluoro-l-deprenyl (Fludepryl), a halogenated derivative of l-deprenyl, shares structural similarities with amphetamine and may have potential as a medication for psychostimulant abuse. Objectives p-Fluoro-l-deprenyl was evaluated for psychomotor stimulant, discriminative stimulus, and reinforcing effects in squirrel monkeys. Methods One group of monkeys was trained under a ten-response fixed-ratio (FR10) schedule of stimulus termination to discriminate between methamphetamine (0.32 mg/kg, i.m.) and saline. Other monkeys were trained to self-administer i.v. cocaine under either a simple FR10 schedule or a second-order fixed-interval 5-min schedule with FR10 components. Results Full generalization to the methamphetamine-training stimulus was produced by an i.m. dose of 10.0 mg/kg p-fluoro-l-deprenyl. l-Deprenyl and the metabolites of p-fluoro-l-deprenyl, p-fluoro-l-amphetamine, and p-fluoro-l-methylamphetamine were more potent, producing full generalization at doses of 1.0–3.2 mg/kg. Under the FR10 schedule of drug injection, persistent self-administration behavior was maintained by i.v. cocaine injections but not by injections of vehicle or injection doses of p-fluoro-l-deprenyl up to 1.0 mg/kg. However, p-fluoro-l-deprenyl did maintain moderate levels of i.v. self-administration responding under the second-order schedule of drug injection. Peak response rates maintained by 0.1-mg/kg injections of p-fluoro-l-deprenyl were significantly greater than those associated with saline substitution, yet significantly lower than those maintained by cocaine or d-amphetamine. Conclusions p-Fluoro-l-deprenyl has methamphetamine-like discriminative-stimulus properties in squirrel monkeys that appear at higher doses than for its parent compound, l-deprenyl. It also appears to function as a relatively limited reinforcer of intravenous self-administration behavior in monkeys trained to self-administer i.v. cocaine.     

Involvement of dopaminergic neurotransmission in the control of goal-directed movements

Changes produced in dopamine (DA) activity, by administration of the DA-antagonists metoclopramide (10 mg/kg IM) and tiapride (16 mg/kg IM) and of the DA agonists apomorphine (0.5 and 1 mg/kg IM) and bromocriptine (8 mg/kg orally), specifically modified predatory behavior in the ferret. Sulpiride (40 mg/kg IP and 90 mg/kg IM) did not change the behavior. The number of bites necessary to kill the prey was reduced by metoclopramide and tiapride. The number of bites after the death of the prey was not changed. The latency from the first bite to the death of the prey was shortened. Apomorphine and bromocriptine increased the number of bites.The DA receptor blockers haloperidol, chlorpromazine, and clozapine had similar effects to metoclopramide and tiapride, and the DA agonist l-dopa had similar effects to apomorphine and bromocriptine. The pattern of results indicated that, considering the two major DA receptor types, D-2 receptors or D-2 in combination with D-1 but not D-1 receptors alone were involved in the control of goal-directed movements. The results also provided some evidence that blockade of these DA receptors caused a narrowing of the range of exhibited behavioral responses. Stimulation of these DA receptors had opposite effects.     

Characterisation of dyskinesias induced byl-dopa in MPTP-treated squirrel monkeys

Intermittent treatment withl-dopa over a 2-year period induced abnormal involuntary movements in MPTP-treated squirrel monkeys. Dyskinesias included a choreic and dystonic component. Dose-response curves for chorea and dystonia revealed that the same dose ofl-dopa (30 mg/kg) induced the highest score for both dyskinesias; however, the severity was much greater for chorea. Choreic movements were always most prevalent at the time of peak effect, whereas dystonia was apparent at the time of peak effect and at end-of-dose, and was occasionally observed spontaneously. Our findings indicate that squirrel monkeys treated with MPTP developl-dopa-induced dyskinesias which closely resemble those observed in Parkinson's disease. This species provides a valuable animal model to develop improved therapeutic agents.     

Decarboxylation of orally administered l-dopa in the human digestive tract

Summary Carboxyl labelled l-dopa was administered orally and intravenously to Parkinsonian patients and control subjects. Total radioactivity was measured in the expired air, urine and plasma. The activity in plasma was also measured before and after removal of carbon dioxide-dicarbonate. After intravenous administration about four times more radioactivity was recovered in the urine than after oral administration with a roughly corresponding decrease in the recovery from expired air, whereas a considerably smaller proportion of the total radioactivity in plasma was derived from carbon dioxide-bicarbonate. It is concluded that the major fraction of the orally administered l-dopa undergoes decarboxylation in the digestive tract before reaching the general circulation. No difference was observed between the Parkinsonian and the non-Parkinsonian group.     

Subacute l-DOPA in mice: Biochemical and behavioural effects

Mice, pretreated orally with l-DOPA (200 mg/kg) plus benserazide (50 mg/kg) (l-DOPA-B) responded when challenged 24h later with the same drug combination, with significantly greater locomotor stimulation than animals pretreated with the vehicle. The enhanced response was not due to an intrinsic effect of benserazide. Nor was it dependent on a change in central dopamine (DA) receptor sensitivity, because the two pretreatment groups (l-DOPA-B and vehicle) did not differ in their locomotor response to a range of apomorphine doses (300–3,000 g/kg, IP). The enhanced response was, however, due to DA receptor stimulation because it was antagonised by premedication of the mice with haloperidol or pimozide. Moreover, the enhanced response to l-DOPA-B challenge was also produced when mice were pretreated (24h earlier) with a high dose of l-DOPA alone (without benserazide) (1,200 mg/kg, orally). Animals which had been pretreated with l-DOPA-B had significantly higher brain levels of l-DOPA and DA after a subsequent challenge dose of l-DOPA-B administered 24h later. Thus the enhanced response to l-DOPA-B observed in the present experiment appears to be dependent on some mechanism which produces higher concentrations of l-DOPA (and consequently DA) in the brain.     

Discriminative stimulus effects of a centrally administered,delta-opioid peptide (d-Pen2-d-Pen5-enkephalin) in pigeons

The present study assessed the discriminative stimulus effects of the delta-opioid agonist [d-Pen²-d-Pen⁵]enkephalin (DPDPE) in pigeons. Food-restricted pigeons were trained to discriminate between ICV injections of 100 μg [d-Pen²-d-Pen⁵]enkephalin (DPDPE) and saline in a two-key operant procedure; acquisition of discriminative control was rapid (14–28 daily sessions). [d-Ser², Leu⁵, Thr⁶]enkephalin (DSLET) and [d-Ala²]deltorphin II, peptides selective for delta-opioid receptors, produced discriminative stimulus effects similar to DPDPE, and were approximately equipotent to DPDPE. The non-peptidic, delta-opioid agonist BW373U86 (9.032–100 mg/kg, IM) partially generalized to DPDPE. The kappa-opioid agonist U69,593 (0.01–1 mg/kg, IM), and the mu-opioid agonists, DAMGO (0.1–3.2 μg, ICV) and morphine (1–10 mg/kg, IM), did not produce discriminative stimulus effects similar to DPDPE, up to doses that markedly decreased response rates. Naltrindole (0.1 mg/kg, IM), an antagonist selective for delta-opioid receptors, produced approximately a 30-fold reduction in the potency of DPDPE. DPDPE’s discriminative stimulus effect in pigeons appears to be mediated through a delta-opioid receptor; this effect may provide a procedure for assessing delta-opioid receptor function in vivo.     

NMDA receptor antagonists ameliorate the stepping deficits produced by unilateral medial forebrain bundle injections of 6-OHDA in rats

Rationale and objectives To test the hypothesis that excess glutamatergic transmission at NMDA receptors may contribute to the pathogenesis of Parkinsons disease (PD), we examined the effects of various NMDA receptor antagonists on a recently developed rat model of PD.Methods Following unilateral injections of 12 µg 6-OHDA into the medial forebrain bundle of male Long Evans rats, stepping with both front paws was measured separately as the paws were dragged backwards and laterally. The effects of IP injections of varying doses of l-dopa, the non-competitive NMDA receptor antagonist dizocilpine [(+)-MK-801], the competitive NMDA receptor antagonist CPP, and combinations of l-dopa and NMDA receptor antagonists were then examined on stepping in three separate groups of rats.Results The lesioned rats stepped less often with their contralateral paw than with their ipsilateral paw, and the magnitude of this stepping deficit was positively correlated with the amount of DA depletion in the ipsilateral dorsal striatum. l-Dopa (1–25 mg/kg) dose dependently enhanced stepping with the contralateral paw, and 0.15-0.3 mg/kg dizocilpine and 1.5–6.25 mg/kg CPP enhanced stepping with the contralateral paw as much as did 8 mg/kg l-dopa. The combinations of l-dopa and each of the NMDA receptor antagonists did not significantly improve stepping more than either drug alone. Moreover, none of the drugs completely eliminated the stepping deficits, and high doses began to impair stepping with the ipsilateral paw by inducing turning.Conclusions These data indicate that deficits in contralateral stepping are a reliable and sensitive measure of akinesia in unilateral 6-OHDA-lesioned rats, and they support the hypothesis that excess glutamatergic transmission at NMDA receptors may play a role in the expression of PD symptomology.     

Discriminative stimulus effects of a centrally administered,delta-opioid peptide (d-Pen2-d-Pen5-enkephalin) in pigeons

The present study assessed the discriminative stimulus effects of the delta-opioid agonist [d-Pen²-d-Pen⁵]enkephalin (DPDPE) in pigeons. Food-restricted pigeons were trained to discriminate between ICV injections of 100 µg [d-Pen²-d-Pen⁵]enkephalin (DPDPE) and saline in a two-key operant procedure; acquisition of discriminative control was rapid (14–28 daily sessions). [d-Ser², Leu⁵, Thr⁶]enkephalin (DSLET) and [d-Ala²]deltorphin II, peptides selective for delta-opioid receptors, produced discriminative stimulus effects similar to DPDPE, and were approximately equipotent to DPDPE. The non-peptidic, delta-opioid agonist BW373U86 (0.032–100 mg/kg, IM) partially generalized to DPDPE. The kappa-opioid agonist U69,593 (0.01–1 mg/kg, IM), and the mu-opioid agonists, DAMGO (0.1–3.2 µg, ICV) and morphine (1–10 mg/kg, IM), did not produce discriminative stimulus effects similar to DPDPE, up to doses that markedly decreased response rates. Naltrindole (0.1 mg/kg, IM), an antagonist selective for deltaopioid receptors, produced approximately a 30-fold reduction in the potency of DPDPE. DPDPE's discriminative stimulus effect in pigeons appears to be mediated through a delta-opioid receptor; this effect may provide a procedure for assessing delta-opioid receptor function in vivo.     

Sub-chronic administration of the dopamine D1 antagonist SKF 83959 in bilaterally MPTP-treated rhesus monkeys: stable therapeutic effects and wearing-off dyskinesia

  Rationale: SKF 83959 acts as a D₁ antagonist in vitro but has been claimed to induce anti-parkinsonian effects after acute administration in MPTP-treated marmosets. Objective: The aim of the present study was to evaluate the therapeutic and undesired effects of sub-chronic administration of SKF 83959 in bilaterally MPTP-treated rhesus monkeys and to compare these effects with the effects of l-dopa and the dopamine agonist SKF 82958. Methods: MPTP was given in the left carotid artery (2.5 mg) and 6 weeks later, the right carotid artery (1.25 mg). The monkeys (n=4) had previously been treated chronically with l-dopa (22 days, 10 mg/kg) and SKF 82958 (22 days, 1 mg/kg). Three months after the last administration of SKF 82958, SKF 83959 was given in a dose of 0.5 mg/kg from day 1 to day 15 and in a dose of 1.0 mg/kg from day 16 to day 18. Results:SKF 83959 increased goal-directed limb movements in all animals, including those unresponsive to l-dopa. This therapeutic effect did not diminish during treatment. With respect to body displacement and undesired effects, a large variation in the response to SKF 83959 was found: a large increase in body displacement co-occurred with oro-facial dyskinesia (n=2), whereas a small increase in body displacement co-occurred with dystonia (n=2). In contrast to the undesired effects of l-dopa, the dyskinetic effects of SKF 83959 were primarily limited to the first treatment day. Unlike l-dopa and SKF 82958, SKF 83959 did not induce epileptoid behaviour. Conclusion: Sub-chronic administration of SKF 83959 induced both clear-cut therapeutic effects that remained stable in time, and a limited number of dyskinetic effects that wore off during the treatment. The dopamine D₁ antagonist SKF 83959 may be considered as an alternative treatment in Parkinson’s disease, especially in those patients who do not respond to l-dopa. Received: 4 March 1999 / Final version: 5 May 1999     

Effect of LP-805, a releaser of endothelium-derived nitric oxide,on systemic vasodilatation in vivo

Summary We have investigated relations between hypotensive responses to LP-805, a newly synthesized vasodilator, and the production of nitric oxide (NO), in anesthetized rats. LP-805 (0.1–0.5 mg/kg, i.v.) or acetylcholine (ACh) (0.3 – 3.0 g/kg, i.v.) caused a dose-dependent transient decrease in diastolic blood pressure. The decrease induced by 0.3 mg/kg LP-805 (i.v.) was partially inhibited by pretreatment with N^G-nitro-l-arginine (LNNA), a specific inhibitor of endothelial NO synthase, but the responses to lower or higher doses of LP-805 (0.1 or 0.5 mg/kg, i.v.) were not affected. The dose-dependent decrease in diastolic blood pressure, caused by LP-805, was not affected by pretreatment with l- or d-arginine. The dose-dependent decrease in diastolic blood pressure caused by ACh was not affected by pretreatment with L-NNA or with l- or d-arginine. The hypotensive response to 20-min infusions of LP-805 (100 g/kg per min) wassignificantly inhibited by pretreatment with L-NNA (10 mg/kg, i.v.). The half-recovery times (T_1/2) of LP-805 or ACh-induced depressor responses were shortened by pretreatment with L-NNA. They were prolonged by l-arginine, but not by d-arginine. This shortening, by L-NNA, of the half-recovery time after LP-805 or ACh was reversed by l-arginine, but not by d-arginine. The T_/2 of the LP-805-induced hypotensive response was not affected by pretreatment with indomethacin (1 mg/kg, i.v.). In the presence of L-NNA (10 mg/kg, i.v.), the T_/2 of the LP-805-induced hypotensive response was not affected by pretreatment with indomethacin. The results suggest that the LP-805-induced hypotensive response may be related to direct or indirect activation of NO synthase in vascular endothelial cells, and to release of endothelium-derived NO. Correspondence to M. Inazu at the above address     

Intruder-evoked aggression in isolated and nonisolated mice: Effects of psychomotor stimulants and l-Dopa

Adult male Swiss-Webster mice were housed either singly (isolated) or with a female (nonisolated). Aggressive behavior was evoked by introducing a group-housed male mouse (intruder) into the home cage of the isolated or nonisolated mouse (resident). d-Amphetamine, methamphetamine, methylphenidate, cocaine, and l-dopa decreased attack and threat behavior by resident mice, the isolates requiring 2–4 times higher drug doses for the antiaggressive effects than the nonisolates. d-Amphetamine, methamphetamine, and methylphenidate caused intruder mice to be more frequently attacked by their nontreated resident opponents, to escape more often, to assume the defensive upright posture less, and to move about more often. l-Dopa nonspecifically decreased all elements of agonistic and nonagonistic behavior, while the amphetamines and methylphenidate suppressed attacks, increased escapes, decreased upright postures, and increased nonagonistic locomotion. By contrast, cocaine's antiaggressive effects were remarkably specific, i.e., not accompanied by changes in other behavioral elements.     

Biotransformation of locally applied l-dopa in the corpus striatum of the hemi-Parkinsonian rat studied with microdialysis

Microdialysis was used to study the biotransformation of l-dopa in intact and denervated striata of rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the substantia nigra. Microdialysis probes were placed in the intact and in the denervated striatum. Observations were then made on freely moving rats. Extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxyphenylacetic acid (homovanillic acid; HVA) were monitored before, during and after the local administration of l-dopa via the microdialysis probe for 20 min.A dose-dependent increase in extracellular dopamine levels was seen in intact striatum after application of l-dopa in concentrations ranging between 100 nmol/l and 10 mol/l. In the denervated striatum, the severity of the lesion influenced dopamine formation, so that no dose-effect relation could be established.The effects of the continuous intra striatal infusion of nomifensine, tetrodotoxin or benserazide on the l-dopa-induced dopamine outflow revealed that in the intact striatum this dopamine release is mainly voltage dependent. It was concluded that in the denervated striatum other cells of non-neuronal origin and containing aromatic l-amino acid decarboxylase make a major contribution to the increase in extracellular dopamine levels. Furthermore, l-dopa itself shows no dopamine-releasing properties, at least under the present experimental conditions. Correspondence to: S. Sarre at the above address     

Evidence for the role of nitric oxide in nicotine-induced locomotor sensitization in mice

Rationale Nitric oxide (NO) is implicated in both acute effects of addictive drugs and development of dependence to them. We investigated the role of NO in nicotine-induced locomotor sensitization.Objectives The effects of N-nitro-l-arginine methyl ester (l-NAME), a NO synthase inhibitor, and a combination of a NO precursor l-arginine and l-NAME on nicotine-induced locomotor sensitization were investigated in Swiss Webster mice.Methods Sensitization to psychomotor stimulating effect of nicotine was rendered by seven injections of nicotine (1 mg/kg) on every other day. To investigate their effect on the development of sensitization to nicotine, l-NAME (15–60 mg/kg) and l-arginine (1 g/kg) were given before nicotine administration during the first seven sessions. To investigate the effect of these compounds on the expression of nicotine sensitization, after a 4-day drug-free period another group of mice received a challenge injection of nicotine on day 18.Results Nicotine (1 mg/kg) produced a robust locomotor sensitization in mice. The doses of 30 mg/kg and 60 mg/kg of l-NAME blocked the development of sensitization to nicotine; and, l-arginine (1 g/kg) pretreatment reversed this effect of l-NAME. Likewise, the doses of 30 mg/kg and 60 mg/kg of l-NAME inhibited the expression of sensitization to nicotine on day 18; and, l-arginine (1 g/kg) pretreatment reversed this inhibitory effect of l-NAME.Conclusions Our results suggest that NO is implicated in the development and expression of nicotine-induced locomotor sensitization in mice.     

Effects of l-dihydroxyphenylalanine (l-Dopa) and d,l,5-hydroxytryptophan (d,l,5-HTP) on reserpine-induced amnesia

In a series of experiments the effects of reserpine, l-Dopa, and d,l,5-hydroxytryptophan (d,l,5-HTP) on retention of a passive avoidance training in mice were investigated. Reserpine (2.5 mg/kg) produced amnesia when given at 120 min before but not at 30 min before or at 0, 10, 30, or 90 min following training. This time-dependent reserpine effect did not appear to be due to either an alteration in footshock sensitivity during training or to the drug producing state-dependent learning. The amnesic effect of reserpine could be blocked when both l-Dopa and d,l,5-HTP were also administered up to 10 min but not at 30 or 90 min following training. The drugs, l-Dopa or d,l,5-HTP, given alone or in higher doses, could not at any time counteract the reserpine effect. The retrograde effects of the combined administration of these biogenic amine precursors on the reserpine-induced amnesia are discussed in terms of the possible role of biogenic amines in memory formation.