Effects of blockade of NMDA receptors and NO synthase on the expression of associative and non-associative sensitization to effects of cocaine.

After repeated administration of psychostimulant drugs, a sensitization rather than a tolerance to the behavioral effects can be observed. In our own previous studies, it was shown that both blockade of NMDA glutamate receptors and inhibition of NO synthase selectively inhibited the expression of associative but not non-associative sensitization to D-amphetamine. The present experiments were performed in order to study whether a similar selective inhibition of expression of associative sensitization to cocaine can be observed after blockade of NMDA receptors by MK-801 or inhibition of NO synthase by L-NAME.

Effects of blockade of glutamate NMDA receptors or of NO synthase on the development or the expression of associative or non-associative sensitization to locomotor activation by morphine.

The sensitization to the pharmacological actions of morphine is probably a critical factor in the addictive properties of this drug. A discrimination between associative and non-associative type of sensitization might be relevant for possible differences in drug effects on sensitization phenomena. Furthermore, blockade of NMDA receptors might lead to an inhibition of NO-synthesis, and, accordingly, both of these effects might influence sensitization phenomena in a similar way.

Effects of dizocilpine [(+)-MK-801] on the expression of associative and non-associative sensitization to D-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.

Discrimination of morphine- and haloperidol-induced muscular rigidity and akinesia/catalepsy in simple tests in rats.

The present study was conducted to establish a simple method for measuring muscular rigidity in rats, which could be used for screening and is able to discriminate between rigidity and akinesia/catalepsy. Therefore, we treated rats with morphine (30 mg/kg i.p.

Effect of repeated treatment with high doses of selegiline on behaviour, striatal dopaminergic transmission and tyrosine hydroxylase mRNA levels.

The anti-parkinsonian drug selegiline is a monoamine oxidase B (MAO-B) inhibitor and a potential neuroprotective agent which facilitates dopaminergic transmission. Its metabolites (-)-amphetamine and (-)-metamphetamine might contribute to the pharmacological effects as they are also able to increase dopaminergic transmission and in addition might lead to behavioural sensitization after repeated administration. We investigated the effects of acute and repeated treatment with a high dose of selegiline on dopamine overflow in the striatum as well as on behaviour and on tyrosine hydroxylase (TH) mRNA levels in midbrain.

Comparison of two independent aromatic hydroxylation assays in combination with intracerebral microdialysis to determine hydroxyl free radicals.

The phenylalanine- and salicylate assay were compared to investigate the production of hydroxyl free radicals. In vitro experiment: Phenylalanine (100 micromol/l) or salicylic acid (100 micropmol/l) were incubated in a hydroxyl radical generating in vitro Fenton system with increasing concentrations (1.25--40 micromol/l) of equimolar hydrogen peroxide and ferrous ions.

Sensitization to the behavioural effects of cocaine: alterations in tyrosine hydroxylase or endogenous opioid mRNAs are not necessarily involved.

After repeated administration of cocaine at intervals, sensitization phenomena can be observed, so that its behavioural effects are enhanced. Since this phenomenon is long-lasting, it was of interest to study which persistent alterations in the activity of dopaminergic neurones or of endogenous opioid systems downstream of dopaminergic synapses in the basal ganglia are involved in the sensitization. Cocaine (10 mg/kg i.

The associative type of sensitization to d-amphetamine is expressed as an NO-dependent dramatic increase in extracellular dopamine in the nucleus accumbens.

After repeated administration of psychomotor-stimulant drugs such as d-amphetamine, a sensitization to its stimulant effects such as locomotor activity and stereotyped behaviour can be observed depending on the treatment schedule. It was the aim of the present study to test whether (1) associative (conditioning) and non-associative (pseudoconditioning) types of sensitization differ in the corresponding alterations in extracellular dopamine in the nucleus accumbens, and (2) the inhibitor of nitric oxide synthase (NOS), N(G)-nitro-L-arginine methyl ester (L-NAME), influences the two types of sensitization in a different way. Rats were treated with d-amphetamine (1 mg/kg i.

The protective effects of PBN against MPTP toxicity are independent of hydroxyl radical trapping.

To study the mechanism of the protective effect of the spin-trapping agent alpha-phenyl-N-tert-butyl nitrone (PBN) against MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) toxicity hydroxyl radicals and functional parameters of neuroprotection were determined. C57BL/6 mice received PBN (100 mg/kg IP) over a time period of 15 days and on day 8 MPTP (40 mg/kg SC). On day 15 striatal levels of dopamine, serotonin, and metabolites were analyzed.

Salicylate protects against MPTP-induced impairments in dopaminergic neurotransmission at the striatal and nigral level in mice.

The analgesic and anti-inflammatory drug sodium salicylate was studied for its potential protective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. C 57BL/6 mice were treated with a single dose of sodium salicylate (50 mg/kg or 100 mg/kg i.p.

Effects of cytisine on hydroxyl radicals in vitro and MPTP-induced dopamine depletion in vivo.

The potential new iron-chelator cytisine and the radical scavenger N-tert-butyl-alpha-(2-sulfophenyl) nitrone (S-PBN) were incubated in a Fenton system and hydroxyl radical formation was measured with the salicylate trapping assay. Both cytisine and S-PBN reduced hydroxyl radical formation in a concentration-dependent manner. For in vivo studies, C57BL/6 mice were injected repeatedly with cytisine (0.

Effects of nicotine on hydroxyl free radical formation in vitro and on MPTP-induced neurotoxicity in vivo.

Parkinson's disease (PD) is one of the most frequent disorders of the basal ganglia. From epidemiological studies there is a controversial discussion on the question whether tobacco smoking is correlated with a decreased incidence of PD. The present study aimed to elucidate the role of nicotine and its potential neuroprotective effects in a rodent model of PD.

In vivo effects of the kavapyrones (+)-dihydromethysticin and (+/-)-kavain on dopamine, 3,4-dihydroxyphenylacetic acid, serotonin and 5-hydroxyindoleacetic acid levels in striatal and cortical brain regions.

The in vivo effect of a single oral dose of 100 mg (+)-dihydromethysticin/kg body weight on striatal and cortical tissue concentrations of dopamine, serotonin, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid, as well as the dopamine and serotonin turnover, was tested in rats. Additionally, other rats were fed with a (+/-)-kavain containing food over a period of 78 days in order to calculate the influence of a chronic treatment with kavapyrones on the neurotransmitters. The results of the present in vivo study clearly demonstrate that neither (+)-dihydromethysticin in a high single dose, nor (+/-)-kavain chronically administered, altered the dopaminergic or serotonergic tissue levels in rats significantly.

In vivo microdialysis study of (+/-)-kavain on veratridine-induced glutamate release.

This is the first microdialysis study to address the effects of (+/-)-kavain on veratridine-induced glutamate release in freely moving rats. (+/-)-Kavain (100 mg/kg, p.o.

Effects of alpha-phenyl-tert-butylnitrone and selegiline on hydroxyl free radicals in rat striatum produced by local application of glutamate.

The hydroxyl radical is a very reactive oxygen species that damages biomolecules in the brain and in other tissues. The possible pharmacological intervention to prevent hydroxyl radical formation was studied in vivo using the microdialysis technique in brains of nonanesthetized rats. Hydroxyl radicals form stable adducts [mainly 2,3-dihydroxybenzoic acid (2,3-DHBA) and 2,5-DHBA)] via an aromatic hydroxylation reaction with salicylic acid.

Sensitization to d-amphetamine after its repeated administration: evidence in EEG and behaviour.

After repeated administration of cocaine or d-amphetamine, a sensitization to their behavioural effects is frequently observed instead of a tolerance. In a previous study, it was shown that a moderate dose of d-amphetamine produced a pattern of EEG power spectrum which indicated a selective activation of D1-like dopamine receptors, whereas a larger dose induced a selective increase of power in the alpha-1 frequency band and, to a lesser degree, in the alpha-2 band, suggesting an additional activation of D2-like receptors. Furthermore, it was recently found that under a certain dosage and schedule, cocaine could produce a shift from a D1-characteristic to a D2-like EEG pattern.

Sensitization phenomena after repeated administration of cocaine or D-amphetamine in rats: associative and non-associative mechanisms and the role of dopamine in the striatum.

In parallel studies, the contribution of non-associative and associative mechanisms to the development of sensitization to the effects of cocaine and D-amphetamine on locomotor activity and stereotyped behaviour were tested. Rats were pretreated with cocaine, 10 mg/kg s.c.

Biochemical studies support the assumption that dopamine plays a minor role in the EEG effects of nicotine.

In a previous study, it was shown that a moderate dose of nicotine (0.2 mg/kg s.c.

Effects of cocaine on the EEG power spectrum of rats are significantly altered after its repeated administration: do they reflect sensitization phenomena?

It was previously shown that a moderate dose of cocaine (10 mg/kg i.p.) produces a pattern in the EEG power spectrum which indicates a preferential activation of dopamine D1-like receptors, namely a decrease of power in most of the frequency bands.

A comparison of different sensory stimuli in producing conditioned apomorphine effects.

In previous studies, it was shown that apomorphine-induced stereotyped behaviour could be conditioned when apomorphine was repeatedly paired with sensory stimuli (CS). Since in these experiments, the sum of various sensory stimuli were applied, it seemed of interest to use each sensory stimulus separately in order to evaluate the relevance of each of the stimuli for the development of the conditioned responses (CRs). Therefore, apomorphine (0.

Effects of morphine on EEG in rats and their possible relations to hypo- and hyperkinesia.

It was previously shown in rats that administration of cocaine or d-amphetamine in moderate doses produced alterations in EEG characteristic for activation of D1 dopamine receptors, whereas large doses induced alterations resembling activation of D2 dopamine receptors. Since morphine, among other effects, enhances the dopaminergic transmission, it was investigated whether this effect might be apparent in the EEG which was recorded telemetrically in awake, not restrained rats. In a moderate dose (3 mg/kg IP), morphine produced a desynchronisation and a general decrease of power in all of the frequency bands except beta-2.

Activation of dopamine D1 receptors or alpha 1 adrenoceptors is not involved in the EEG effect of nicotine in rats.

Based on previous own EEG-studies and behavioural studies of other authors, it has been claimed recently that D1 receptors are involved in addictive properties of drugs. It seemed, therefore, of interest to study whether nicotine produces D1-characteristic EEG alterations in rats. EEG was recorded in non-anesthetized, freely moving rats, transmitted telemetrically and underwent power spectral analysis.

Effect of conditioning with d-amphetamine on the extracellular concentration of dopamine and its metabolites in the striatum of behaving rats.

The effect of classical conditioning with d-amphetamine on the extracellular concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum of awake, freely moving rats was studied using microdialysis. This was done in order to test, whether there occurred alterations in DA release as conditioned responses in the striatum. The first series of experiments studied the acute effects of d-amphetamine on the concentration of DA and its metabolites DOPAC and HVA.