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.     

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     

Nicotine-conditioned single-trial place preference: selective role of nucleus accumbens shell dopamine D1 receptors in acquisition

Rationale Experimental evidence indicates that the mesolimbic dopamine (DA) pathway innervating the ventral striatum is critically involved in the motivational effects of drug abuse. However, the role of DA transmission of the two main subdivisions of the nucleus accumbens (NAc), the shell and the core, in the motivational properties of nicotine is unknown. Objectives The aim of this study was to investigate the role of DA D₁ and D₂ receptors of the rat NAc shell and core in the motivational effects of nicotine using a conditioned place preference (CPP) paradigm. Methods The effect of the intracerebral infusion of DA antagonists specific for DA D₁ (SCH 39166) and D₂ receptors (l-sulpiride) was studied in a single-trial place-conditioning paradigm with fixed assignment of the drug to the unpreferred compartment. Results Nicotine induced significant CPP at the dose of 0.4 and 0.6 mg/kg subcutaneously (s.c.). Intra-NAc shell infusion of SCH 39166 (6.25, 12.5, 25 and 50 ng bilaterally, 10 min before nicotine administration), impaired in a dose-dependent manner the acquisition of CPP by nicotine (0.4 mg/kg s.c.). SCH 39166 failed to affect nicotine CPP when infused into the NAc core. l-Sulpiride (25 and 50 ng bilaterally) had no effect on acquisition after intra-Nac shell infusion. SCH 39166 and l-sulpiride were ineffective after infusion in the NAc shell and core 10 min before the test session. Conclusions The results indicate that dopamine D₁ but not D₂ receptors of the NAc shell are specifically involved in the acquisition of nicotine-induced CPP.     

Effects of d-amphetamine,maprotiline, l-dopa,and haloperidol on the components of the predatory behavior of the ferret,Putorius furo l.

Ferret predation on rats was examined in an arena. One hour before the test one of the following drugs was administered: d-Amphetamine (0.8 and 1.4 mg/kg IM), maprotiline (10 and 40 mg/kg orally), l-dopa (30 and 60 mg/kg orally), or haloperidol (0.14 and 0.6 mg/kg IM). Provided that capture was successful, the sequence of the behavioral components was not changed by these drugs. With the exceptions of paw movements and rolling over, which were not affected by the drugs, the components of predatory behavior were influenced differently. This leads to the assumption that a drug affects different mechanisms which control behavior. It is assumed that dopamine is involved in the control of capture elicitation as well as in the control of pursuit and biting. Capture elicitation was inhibited by d-amphetamine and l-dopa, but not by maprotiline, and was even facilitated by haloperidol. The orientation of pursuit movements and biting was impaired by l-dopa and improved by haloperidol, whereas maprotiline did not influence these components.     

Failure of MIF-I to affect behavioral responses in patients with parkinson's disease under l-dopa therapy

In eight subjects with Parkinson's disease under an optimal daily dose of l-dopa, acute administration of MIF-I (200 mg i.v.) did not ameliorate either the total disability score or the intellectual test PM 38 when evaluated in comparison with the effect induced by acute administration of a placebo. Also concomitant evaluation of the effect of MIF-I on the secretion of anterior pituitary hormones which are under dopaminergic control i.e., growth hormone and prolactin, did not reveal any potentiation of the l-dopa-induced stimulus.     

Dizocilpine (MK-801), ketamine and phencyclidine: low doses affect brain field potentials in the freely moving rat in the same way as activation of dopaminergic transmission

The effects of dizocilpine (MK-801), (±)-5-methyl-10,11-dihydro-5Hdibenzo-[a,d]-cyclohepten-5,10-imine maleate, after IP injection into freely behaving rats, have been compared with the action of ketamine-chloride and phencyclidine (PCP). MK-801 produced strongly dose-dependent effects which could be followed quantitatively over a time of 4 h. During this time spectral analysis of the field potentials continuously recorded from frontal cortex, hippocampus, striatum, and reticular formation revealed a particular pattern of changes which was very stable over time, and, after low doses of 0.05 and 0.1 mg/kg, matched that produced by phencyclidine (2 and 4 mg/kg) or ketamine chloride (10 and 20 mg/kg). With higher doses of MK-801 a continuous change from power decreases to power increases was observed. These increases were accompanied by strong behavioral effects in terms of impaired locomotor control. All three non-competitive NMDA antagonists showed a high degree of similarity with respect to the changes of the frequency content of the field potentials over time. The same pattern of electrical changes could be observed after the application ofl-dopa (50 mg/kg) or amphetamine (0.2 mg/kg). This can be interpreted in the sense that the same population of cells within the recording area which is under dopaminergic control is at the same time under glutamate control. This leads to the hypothesis that it might be possible to bypass the missing dopaminergic control during parkinsonism by noncompetitive NMDA-receptor blocking drugs.     

Nitric oxide synthesis,epileptic seizures and kindling

Nitric oxide (NO) has been implicated in synaptic changes underlying long-term potentiation and some forms of learning. It is unclear, however, whether NO contributes to long-term changes associated with the kindling of epileptic seizures. In the present study rats were treated, on the first 6 days of kindling, withl-arginine (l-Arg), the endogenous donor from which NO derives, or withl-nitro-arginine (l-No-Arg), a competitive inhibitor of NO synthesis, or with vehicle. Drugs were given in doses previously shown to affect learning or other behaviour.l-Arg (750 mg/kg IP) did not affect kindling or seizure severity.l-No-Arg (100 mg/kg) prolonged the duration of afterdischarges and convulsions on treatment days but did not advance kindling or affect seizures on subsequent days. A second experiment examined the possible rôle of NO in the development of resistance to seizures following prior seizures. Six or more stimuli were administered at 10-min intervals to fully-kindled rats after injection ofl-No-Arg or vehicle. Vehicle-treated rats became progressively more resistant to afterdischarges and convulsions with successive stimulations butl-No-Arg-treated rats failed to do so. Rats injected withl-No-Arg also showed an unexpected high mortality in the ensuing 24 h.l-No-Arg appeared to have no direct effect on the course of kindling but impaired the development of postictal resistance, and increased the duration and lethal after-effects of closely repeated seizures. The results do not support suggestions that antagonists of NO might prove clinically useful as anticonvulsants.     

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.     

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     

<Emphasis Type="Italic">d</Emphasis>-Amphetamine responses in catechol-O-methyltransferase (COMT) disrupted mice

Rationale We have earlier found that 1) COMT inhibitors did not enhance amphetamine-induced dopamine efflux into striatal extracellular, that 2) they did not increase dopamine levels in striatal tissue and that 3) they did not potentiate amphetamine-induced turning behavior of hemiparkinsonian rats. Further, when COMT knockout mice were challenged with l-dopa or a dopamine transporter (DAT) inhibitor, an accumulation of dopamine occurred and the neurochemical and locomotor effects of l-dopa and GBR 12909 were modified accordingly.Objective Since DAT inhibitors and amphetamine apparently have different mechanisms of action, we were interested to see how COMT knockout mice would react to d-amphetamine treatment.Methods We measured the effects of d-amphetamine on locomotor activity and on the levels of catecholamines and their metabolites in striatal microdialysis fluid and in striatal, hypothalamic and cortical brain regions of COMT gene disrupted mice. Striatal dopamine receptor binding was also determined.Results After d-amphetamine administration, the DOPAC content in homozygous mice was 3-fold in the striatum, 17- to 18-fold in the cortex and 7- to 8-fold in the hypothalamus higher than in wild-type control mice, and there were no indications of genotype×sex interactions. However, the lack of COMT did not potentiate d-amphetamine-induced dopamine levels in brain tissue or in striatal extracellular fluid. d-Amphetamine-induced (10 mg/kg) hyperlocomotion was less suppressed in male COMT knockout mice than in their wild-type counterparts. Striatal dopamine D₁ and D₂ receptor levels in male mice were not altered by COMT gene disruption.Conclusions Changes in COMT activity modulates dopamine metabolism but the behavioral effects of d-amphetamine in male mice only to a small extent, and this action does not seem to depend on the actual extracellular dopamine concentration. Nor is it mediated through compensatory changes in dopamine D₁ and D₂ receptor levels. In dopaminergic neurons, the contribution of intracellular COMT remains secondary in conditions when dopamine is released by d-amphetamine.     

Reversal of the increase in apomorphine-induced stereotypy and aggression in REM sleep deprived rats by dopamine agonist pretreatments

REM sleep deprivation (REMSD) induces augmented responses to dopaminergic agonists. Prolonged administration of neuroleptics induces a similar state, probably by the production of supersensitivity of dopaminergic receptors. Such a supersensitive state could be induced by REMSD as a result of impairment of dopamine neurotransmission. In order to test this hypothesis, bromocriptine, nomifensine, amphetamine,l-dopa, imipramine and electroconvulsive shock (ECS) were administered to rats during REMSD, and aggressive and stereotyped behaviors were measured. Amphetamine andl-dopa pretreatment attenuated the increases in apomorphine-induced stereotypy and aggression in REMSD rats, but ECS selectively reduced apomorphine-induced aggression. The other drugs tested were ineffective on both behavioral tests. Such a selective action may reflect different effects of ECS on different dopaminergic systems such as those involved with stereotypy and aggression. The results suggest that REMSD induces an increase in dopaminergic sensitivity which may be reversed by pretreatment with some dopaminergic agonists.1 Fellowship from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)2 Universidade Federal de Goiás3 Fellowship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)     

Morphine-conditioned single-trial place preference: role of nucleus accumbens shell dopamine receptors in acquisition, but not expression

Rationale A large body of evidence indicates an involvement of the mesolimbic dopamine (DA) pathway innervating the ventral striatum in the motivational effects of drug abuse.Objective The goal of the study is to clarify the role of DA D₁ and D₂ receptors of the rat nucleus accumbens (NAc) shell and core in the motivational effects of morphine as studied by conditioned place preference (CPP).Methods The effect of the intracerebral infusion of DA antagonists specific for DA D₁ (SCH 39166) and D₂ receptors (l-sulpiride) was studied in a single-trial place conditioning paradigm with fixed assignment of the drug to the unpreferred compartment.Results Morphine induced significant CPP at all the doses tested (0.5, 1.0, and 2.0 mg/kg, subcutaneously). A dose of 1.0 mg/kg was selected for further studies. Intra-NAc shell infusion of SCH 39166 and l-sulpiride at doses of 25 and 50 ng/1 μl per side impaired the acquisition of CPP by morphine. No effect was observed at 12.5 ng/1 μl per side. Intra-NAc core infusion of SCH 39166 (12.5, 25, and 50 ng/1 μl per side) did not affect the acquisition of morphine-induced CPP, while l-sulpiride (12.5, 25, and 50 ng/1 μl per side) impaired CPP acquisition only at the dose of 50 ng/1 μl per side. No effect on morphine-induced CPP was observed when the DA antagonists were infused into the NAc shell or core 10 min before the test session.Conclusion These results indicate that DA D₁ and D₂ receptors in the NAc shell are involved in the acquisition of morphine-induced CPP.     

Chronic carbamazepine down-regulates adenosine A2 receptors: studies with the putative selective adenosine antagonists PD115,199 and PD116,948

Carbamazepine (CBZ), an anticonvulsant with psychotropic and anti-pain properties, has been reported to displace ligands at adenosine binding sites. This paper describes biochemical and behavioural studies in rodents comparing CBZ to the adenosine agonistsl-phenylisopropyl-adenosine (l-PIA) and N-ethylcarboxamido-adenosine (NECA), the new antagonists PD116,948 and PD115,199 which are also relatively A₁ and A₂ specific respectively, and the mixed antagonists theophylline and caffeine, attempting to determine functional correlates of the binding studies. Changes in cAMP synthesis and behavioural syndromes produced by the drugs, alone and in combination, were monitored. Classification of the observed effects in terms of A₁ and A₂ activity was complex, probably due to functional interactions between A₁ and A₂ subtypes. Nevertheless, it was found that chronic CBZ administration (0.25% in food for 3 days, followed by 0.5% for 11 days) produced a pattern of interaction identical to that of PD115,199 (10–100 mg/kg IP). Thus, both treatments attenuated the behavioural syndrome produced byl-PIA (0.1 or 0.5 mg/kg SC), but did not affect that produced by NECA (0.03 mg/kg SC). CBZ mildly increased hypoactivity after clonidine (0.2 mg/kg IP) which was used as a control. By contrast, the A₁ antagonist PD116,948 (0.1–10 mg/kg IP) antagonised both behavioural syndromes. Similarly in the biochemical experiments both chronic CBZ and PD115,199 (10–100 µM) reduced stimulation of cAMP synthesis byl-PIA (confirming that this is mediated by A₂ receptors), while only basal cAMP synthesis was affected by PD116,948 (10 µM) and theophylline (60 µM). Acute CBZ did not alterl-PIA stimulated cAMP synthesis at concentrations up to 100 µM (i.e. within the therapeutic plasma concentration). Chronic CBZ did not alter motor activity stimulated by caffeine (5 mg/kg IP). These results suggest that PD155,199 and PD116,948 may be useful in defining the functions of adenosine receptor subtypes, and that chronic CBZ appears to functionally down-regulate A₂ receptors.     

Striatal dopamine turnover and l-dopa treatment after short-term exposure of rats to manganese

The turnover rate of striatal dopamine (DA) and the effect of l-dopa treatment was investigated in rats after the daily oral administration of MnCl₂ · 4H₂O for a period of 30 days. The turnover rate of striatal DA, as determined by the administration of -methyl-p-tyrosine, increased significantly in manganese-exposed rats. l-Dopa administration resulted in a significant elevation in the levels of DA and its metabolite, homovanillic acid, in manganese-exposed rats, but these neurochemical changes could not be correlated with the concentration of manganese in the striatum. We therefore advise that l-dopa therapy should not be tried in early manganese intoxication, as it may aggravate manic symptoms due to marked increase in brain DA.     

The NMDA positive modulatord-cycloserine potentiates the neuroleptic activity of D1 and D2 dopamine receptor blockers in the rat

According to the view that N-methyl-d-aspartate (NMDA) agonists could be seen as putative therapeutic agents in schizophrenia, the present study was aimed at investigating whether the NMDA positive modulatord-cycloserine (DCS) could show neuroleptic activity. When given alone, DCS (1.5, 3, 6, 12 mg/kg) failed to affect the stereotyped behavior induced by 0.5 mg/kg SC apomorphine, a test routinely used to detect neuroleptic activity. Nevertheless, the administration of different doses of DCS (1.5, 3, 6 mg/kg) in combination with the D₁ dopamine receptor blocker SCH 23390 or the D₂ antagonist YM 09151-2, both given in doses which by themselves were ineffective in blocking apomorphine elicited behavior, induced a dose- dependent neuroleptic effect. Furthermore, the positive NMDA modulator allowed (–)-sulpiride, which given alone never antagonized the apomorphine-induced stereotypy, to exhibit a full neuroleptic activity. The lower dose of DCS effective in potentiating antipsychotic effect of dopaminergic blockers also counteracted the behavioral response (hypermotility) induced by the NMDA negative modulator MK-801 (0.25 mg/kg), thus indicating the specificity of DCS effect. The results strengthen the view that drugs which increase NMDA receptor function could be a useful supplement in the therapy of psychotic disorders.     

Effects of dizocilpine [(+)-MK-801] on the expression of associative and non-associative sensitization to <Emphasis Type="SmallCaps">d</Emphasis>-amphetamine

Blockade of glutamate receptors of the NMDA type inhibits the sensitization to psychostimulant drugs, such as amphetamine, that occurs after repeated administration. Both associative (conditioning) and non-associative (pseudo-conditioning) mechanisms may contribute to sensitization phenomena. The aim of the present study was, thus, to determine which type of sensitization is influenced by blockade of NMDA-type receptors by examining the expression (manifestation) of sensitization. Locomotor activity was assessed and, in some experiments, extracellular dopamine in the nucleus accumbens was also assessed using in vivo microdialysis in non-anaesthetized, almost freely moving rats. Male albino Wistar rats of 225–250 g were given 1 mg/kg i.p. d-amphetamine every 2nd day for 7 days and with saline on the other days. Half the rats were exposed to d-amphetamine in the presence of conditioning stimuli (test cage, auditory and olfactory stimulus) and to saline in the home cage in absence of these stimuli, the other half were treated with saline and exposed to the conditioning stimuli and were placed into their home cages (without conditioning stimuli) after treatment with d-amphetamine. Ten days after the end of this treatment, both groups were exposed to the conditioning stimuli and half of each group were pretreated with dizocilpine [(+)-MK-801, 0.1 mg/kg i.p.], a blocker of NMDA receptors, 30 min before administration of 1 mg/kg d-amphetamine.(+)-MK-801 reduced the locomotor activity in rats sensitized associatively, but not in those sensitized non-associatively. It had no significant effect on spontaneous locomotor activity or that induced by acute administration of 1 mg/kg d-amphetamine. Similarly, (+)-MK-801 inhibited the increase in extracellular dopamine in the nucleus accumbens induced by the test dose of d-amphetamine in rats sensitized associatively but not non-associatively. The results suggest that the expression of both types of sensitization to d-amphetamine are dependent on glutamatergic NMDA mechanisms, although in different ways. Inhibition of sensitization, in particular of the associative type, might be of therapeutic value in drug dependence.     

Clomipramine enhances prolactin and growth hormone responses to l-tryptophan

The effects of the 5-hydroxytryptamine (5-HT) uptake inhibitor clomipramine on the prolactin (PRL) and growth hormone (GH) responses to l-tryptophan (LTP) were assessed in six normal subjects. Oral administration of 20 mg clomipramine 2 h prior to LTP infusion (50 mg/kg) significantly enhanced both endocrine responses, suggesting that the increases in plasma PRL and GH produced by LTP are mediated by 5-HT pathways. These findings, taken together with previous observations that 5-HT₂ receptor antagonists do not attenuate the PRL response to LTP, suggest that the 5-HT-induced release of PRL in man may be mediated by 5-HT₁ receptors.     

Normalization by antipsychotic drugs of biochemically induced abnormal behavior in rats

Male rats were trained to perform a conditioned avoidance response combined with a successive discrimination in a modified shuttle box. The administration of l-Dopa, 100 mg/kg i.p., after inhibition of peripheral aromatic amino acid decarboxylase, or apomorphine, 2 mg/kg i.p., was found to disrupt the discriminative but not the avoidance behavior. The dopamine receptor antagonist pimozide (0.5 mg/kg i.p.), but not the noradrenaline receptor antagonist phenoxybenzamine (10 or 20 mg/kg i.p.) completely antagonized the l-Dopa-induced abnormal behavior, indicating an involvement of central dopamine mechanisms. The present data show that antipsychotic drugs not only inhibit behavior but can also improve behavior in animals with a disturbed function.     

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.     

Dopamine and nitric oxide interaction on the modulation of prepulse inhibition of the acoustic startle response in the Wistar rat

Rationale The nitric oxide (NO)–arginine pathway is intimately connected to the release of dopamine (DA), a neurotransmitter system that may be dysfunctional in schizophrenia. Both schizophrenic patients and rats treated with DA agonists present deficits in sensorimotor gating measured by prepulse inhibition (PPI). Objective Our aim was to investigate the interaction between a NO synthase inhibitor, N ^G-nitro-l-arginine (l-NOARG), and the DA agonists, amphetamine (Amph), apomorphine (Apo), bromocriptine (BRC), quinpirole (QNP) and SKF38393, on the modulation of the PPI. Methods Male Wistar rats received two injections of either l-NOARG (40 mg/kg, i.p.) or saline, 1 h before the test, and the DA agonists or vehicle. Testing began 5 min after treatment with Amph (2 mg/kg, i.p.), Apo (0.5 mg/kg, s.c.) or QNP (0.3 mg/kg and 1.0 mg/kg, s.c.), 120 min after BRC (1 and 40 mg/kg, i.p.) and 15 min after SKF38393 (10 mg/kg, s.c.). The PPI test consisted of 60 presentations divided into pulse (100 dB), prepulse (65, 70, 75 and/or 80 dB) and prepulse + pulse. Results l-NOARG prevented the PPI disruption caused by Amph (2 mg/kg). Apo, QNP and BRC disrupted PPI, but these effects were not significantly changed by l-NOARG. SKF38393 had no significant effect on PPI whether or not preceded by l-NOARG. Conclusions Our findings show that l-NOARG interacted with Amph, an indirect DA agonist, but not with the direct DA agonists on PPI, suggesting that NO is involved on the dopaminergic modulation of sensorimotor gating, probably by a presynaptic mechanism.