Transcriptional alterations under continuous or pulsatile dopaminergic treatment in dyskinetic rats.

Continuous dopaminergic treatment is considered to prevent or delay the occurrence of dyskinesia in patients with Parkinson's disease (PD). Rotigotine is a non-ergolinic D(3) > D(2) > D(1) dopamine-receptor agonist for the treatment of PD using a transdermal delivery system providing stable plasma levels. We aimed to investigate the differential influence on gene expression of pulsatile L: -DOPA or rotigotine versus a continuous rotigotine treatment. The gene expression profile within the nigro-striatal system of unilateral 6-hydroxydopamine-lesioned rats was assessed in order to differentiate potential changes in gene expression following the various treatment using Affymetrix microarrays and quantitative RT-PCR. The expression of 15 genes in the substantia nigra and of 11 genes in the striatum was altered under pulsatile treatments inducing dyskinetic motor response, but was unchanged under continuous rotigotine treatment that did not cause dyskinetic motor response. The route of administration of a dopaminergic drug is important for the induction or prevention of motor abnormalities and adaptive gene expressions. The decline of neurotrophin-3 expression under pulsatile administration was considered of particular importance.

The role of NMDA and AMPA/Kainate receptors in the consolidation of catalepsy sensitization.

Daily injection of the dopamine D(2) receptor antagonist haloperidol is associated with the development of catalepsy sensitization in rats, which leads to a day to day increase of rigor and akinesia. The process of catalepsy sensitization incorporates different learning stages. Here we investigated the mechanisms underlying the consolidation of catalepsy sensitization. In particular, we asked whether NMDA- and non-NMDA (AMPA- and Kainate) receptors play a role in the consolidation of catalepsy sensitization. Accordingly, rats received post-training injections of the NMDA receptor antagonist MK-801 (single injection of either 0.1mg/kg or 0.25mg/kg; or a double injection of 0.1mg/kg immediately and 30 min after test cessation) or of the AMPA/Kainate receptor antagonist GYKI 52466 (single injection of 5mg/kg). Our results showed that the consolidation of catalepsy sensitization was decelerated by both glutamatergic AMPA/Kainate- and NMDA-receptor antagonists. With the higher MK-801 dosage, the deceleration was stronger, suggesting a dose dependent mechanism. We hence affirmed a role for the ionotropic glutamate receptors in the consolidation process of catalepsy sensitization.

Behavioural sensitization in addiction, schizophrenia, Parkinson's disease and dyskinesia.

Incentive learning takes place when dopaminergic neurons are activated, usually by rewards. As a result, previously neutral stimuli associated with reward acquire incentive salience and thus the ability to elicit approach or other responses in the future. Incentive learning is assumed to underlie psychostimulant-induced context-dependent sensitization that may play a prominent role in the development of addiction, in dyskinesia, and in amphetamine-induced psychosis. Assuming that these pathological states are due to the gradual process of sensitization, the effects of therapeutics might be manifested as a gradual desensitization. This assumption could explain the delay between onset of cellular effects of drugs (e.g., dopamine receptor blockade) and the improvement in symptoms (e.g., decreases in psychotic symptoms). Reduced dopamine activity results in behavioural changes that are opposite to psychostimulant-induced sensitization, i.e., rewarded behaviours decline in an extinction-like fashion despite the presence and consumption of rewards. We show here that also non reward-related behaviour, i.e., motor activity and catalepsy, follows the same rules: motility is not switched off by dopamine receptor blockade or by 6-hydroxydopamine lesions, but shows a test-to-test extinction-like decline. Thus, psychostimulant-induced sensitization and dopamine-deficiency induced decline of behaviour follows similar rules but in opposite directions.

Controversies on new animal models of Parkinson's disease pro and con: the rotenone model of Parkinson's disease (PD).

A general complex I deficit has been hypothesized to contribute to neurodegeneration in Parkinson's disease (PD) and all toxins used to destroy dopaminergic neurons are complex I inhibitors. With MPTP or 6-OHdopamine, this hypothesis can not be tested since these toxins selectively accumulate in the dopaminergic neurons. However with rotenone, which penetrates all cells, the hypothesis can be tested. Thus, the proof of the hypothesis is whether or not rotenone-induced neurodegeneration mimics the degenerative processes underlying PD. Low doses of rotenone (1.5 or 2.5 mg/kg in oil i.p.) were administered to Sprague Dawley rats on a daily basis. After about 20 days of treatment, signs of parkinsonism occurred and the concentrations of NO and peroxidase products rose in the brain, especially in the striatum. After 60 days of treatment, rotenone had destroyed dopaminergic neurons. Behaviourally, catalepsy was evident, a hunchback posture and reduced locomotion. Other transmitter systems were not, or much less affected. L-DOPA-methylester (10 mg/kg plus decarboxylase inhibition) potently reversed the parkinsonism in rats. Also when infused directly into the dopaminergic neurons, rotenone produced parkinsonism which was antagonized by L-DOPA. Some peripheral symptoms of PD are mimiced by rotenone too, for example a low testosterone concentration in the serum and a loss of dopaminergic amacrine cells in the retina. These results support the hypothesis of an involvement of complex I in PD and render the rotenone model as a suitable experimental model. The slow onset of degeneration make it suitable also to study neuroprotective strategies. Evidence that rotenone-induced neurodegeneration spreads beyond the dopaminergic system is not contradictory given that, according to the new staging studies, also degeneration in PD is not confined to dopamine neurons.

The role of group I metabotropic glutamate receptors in acquisition and expression of contextual and auditory fear conditioning in rats - a comparison.

Glutamatergic neurotransmission in the CNS plays a predominant role in learning and memory. While NMDA receptors have been extensively studied, less is known about the involvement of group I metabotropic glutamate receptors in this area. The purpose of the present study was to evaluate the contribution of mGluR1 and mGluR5 to both acquisition and expression of behaviours in contextual and auditory fear conditioning models. The effects of both receptor types were tested using selective antagonists: (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM) for mGluR1, and [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) for mGluR5. Their effects on acquisition were compared to those of the NMDA receptor antagonist (+)MK-801, and the unselective muscarinic antagonist scopolamine, while diazepam and citalopram served as reference compounds in the expression experiments. EMQMCM (1.25 to 5mg/kg) impaired acquisition of contextual fear conditioning (CFC), but not auditory fear conditioning (AFC). Similarly, administration of MTEP during the acquisition phase impaired learning in CFC at doses of 2.5 to 10mg/kg, but was ineffective in AFC. When given before the retention test, both EMQMCM (1 and 3mg/kg) and MTEP (3mg/kg) impaired expression of CFC. In contrast, MTEP (2.5 and 5mg/kg) blocked the expression of AFC, while EMQMCM was ineffective. In conclusion, group I mGlu receptors are shown to be involved in the acquisition of hippocampus-dependent CFC, but not hippocampus-independent AFC. Unlike mGluR5, mGluR1 does not seem be involved in expression of AFC.

Functional interaction of NMDA and group I metabotropic glutamate receptors in negatively reinforced learning in rats.

RATIONALE: The role of glutamatergic system in learning and memory has been extensively studied, and especially N-methyl-D: -aspartate (NMDA) receptors have been implicated in different learning and memory processes. Less is known, however, about group I metabotropic glutamate (mGlu) receptors in this field. Recent studies indicated that the coactivation of both NMDA and group I mGlu receptors is required for the induction of long-term potentiation (LTP) and learning. OBJECTIVE: The purpose of the study is to evaluate if there is a functional interaction between NMDA and group I mGlu receptors in two different models of aversive learning. METHODS: Effects of NMDA, mGlu1, and mGlu5 receptor antagonists on acquisition were tested after systemic coadministration of selected ineffective doses in passive avoidance (PA) and fear-potentiated startle (FPS). RESULTS: Interaction in aversive learning was investigated using selective antagonists: (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM) for mGlu1, [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) for mGlu5, and (+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate [(+)MK-801] for NMDA receptors. In PA, the coapplication of MTEP at a dose of 5 mg/kg and (+)MK-801 at a dose of 0.1 mg/kg 30 min before training impaired the acquisition tested 24 h later. Similarly, EMQMCM (2.5 mg/kg) plus (+)MK-801 (0.1 mg/kg), given during the acquisition phase, blocked the acquisition of the PA response. In contrast, neither the combination of MTEP (1.25 mg/kg) nor EMQMCM (5 mg/kg) plus (+)MK-801 (0.05 mg/kg) was effective on the acquisition assessed in the FPS paradigm. CONCLUSION: The findings suggest differences in the interaction of the NMDA and mGlu group I receptor types in aversive instrumental conditioning vs conditioning to a discrete light cue.

Repeated Catha edulis oral administration enhances the baseline aggressive behavior in isolated rats.

The effects of repeated oral administration of the psychostimulant plant, Catha edulis and its active principle, cathinone on rats were studied using isolation induced aggression paradigm. The behavioral responses were videotaped and scored later by offline data analyses. Rats were decapitated at the end of the behavioral experiment and in the relevant brain regions, monoamines were assessed. The results demonstrate that isolation of male rats produces a baseline aggression. Treatments with the psychostimulant plant, Catha edulis or commercial S-(--)-cathinone enhanced significantly: The locomotor activities and the baseline aggression behaviors compared with vehicle treated rats. Neurochemical correlates revealed a significant depletion of serotonin (5-HT) and its corresponding metabolites (5-HIAA) in both the anterior and posterior striatum. There was also a reduction in the level of homovanillic acid (HVA) in the hippocampus. Additionally, elevation of dopamine level was observed in the nucleus accumbens, especially, in those rats treated with Catha edulis extract. Cathinone, on the other hand, increased the level of HVA in the posterior striatum and decreased HVA in the nucleus accumbens. In conclusion, the present data demonstrate that repeated administration of Catha edulis or S-(--)-cathinone enhances aggression in rats, presumably by decreasing the level of serotonin and its corresponding metabolites. Besides, the data obtained do not rule out the involvement of dopamine in aggression behavior.

Repeated-testing of place preference expression for evaluation of anti-craving-drug effects.

In addiction research, the conditioned place preference (CPP) paradigm is a widely used animal model of conditioned reward. Usually, CPP development is studied, while only few studies examine CPP expression. In the present study, the suitability of a schedule allowing repeated testing of CPP expression was evaluated. Two groups of rats were either conditioned with cocaine or morphine then the repeated-testing-schedule was applied. This schedule consisted of four repeated applications of a sequence of drug- (i.e. cocaine or morphine), saline- and anti-craving-drug- (i.e. acamprosate, naloxone, their joint administration or saline as internal control) tests. Methodologically, the repeated-testing-schedule produced stable CPP expression in both groups over 12 subsequent tests. In conclusion, it is suggested as a useful method to study effects of anti-craving-drugs on CPP expression, thereby reducing the overall number of experimental animals. The evaluation of the anti-craving-drug effects revealed that neither acamprosate and naloxone given separately nor their combined administration significantly reduced cocaine- or morphine-CPP expression. Thus, we suggest that these anti-craving-drugs are unlikely to be effective for relapse prevention in cocaine- or morphine-addicts.

Effects of mGlu1 and mGlu5 receptor antagonists on negatively reinforced learning.

Effects on aversive learning of the novel highly selective mGlu5 receptor antagonist [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) and mGlu1 receptor antagonist (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM) were tested, after systemic administration, in the passive avoidance (PA) and fear potentiated startle (FPS) paradigms. Both MTEP at 10 mg/kg and EMQMCM at 5 and 10 mg/kg, given 30 min before training, impaired acquisition of the passive avoidance response (PAR). Co-administration of MTEP and EMQMCM at doses ineffective when administered alone, produced anterograde amnesia when given 30 min before the acquisition phase. Neither EMQMCM (5 mg/kg) nor MTEP (10 mg/kg) impaired retention of the PAR after direct post-training injections. EMQMCM (5 mg/kg), but not MTEP (10 mg/kg) blocked the PAR when given 30 min before testing. Pre-training administration of MTEP at doses of 2.5 and 5 mg/kg inhibited fear conditioning in the FPS when tested 24 h later. In contrast, EMQMCM was ineffective. Our findings suggest diverse involvement of mGlu1 and mGlu5 receptors in negatively reinforced learning.

Serotonergic influence on the potentiation of D-amphetamine and apomorphine-induced rotational behavior by the alpha2-adrenoceptor antagonist 2-methoxy idazoxan in hemiparkinsonian rats.

The alpha(2)-adrenoceptor antagonists potentiate both ipsilateral and contralateral rotations induced by amphetamine and apomorphine respectively in hemiparkinsonian rats. The present study investigated the role of serotonergic transmission in this potentiation in unilaterally 6-hydroxydopamine nigral lesioned rats. D-amphetamine (0.5 mg/kg, i.p.) produced ipsilateral rotations, which were decreased by the dopamine receptor antagonist haloperidol (0.2 mg/kg, i.p.) and the alpha(1)-receptor antagonist prazosin (1 mg/kg, i.p.). The selective alpha(2)-antagonist 2-methoxy idazoxan (0.2 mg/kg, i.p.) potentiated the amphetamine-induced ipsilateral rotations, that were attenuated by haloperidol and prazosin. The selective serotonin re-uptake inhibitor citalopram (10 mg/kg, i.p.) and selective serotonin synthesis inhibitor p-chlorophenylalanine (150 mg/kg, i.p., 3 days) decreased and increased the observed potentiation respectively. Apomorphine (0.2 mg/kg, s.c.) produced contralateral rotations, which were decreased by haloperidol but not by prazosin. 2-methoxy idazoxan potentiated these rotations which were attenuated by haloperidol but not by prazosin. Citalopram and p-chlorophenylalanine increased and decreased the observed potentiation respectively. Citalopram and p-chlorophenylalanine had no effect by per se on D-amphetamine and apomorphine-induced rotations. 2-methoxy idazoxan alone increased both ipsilateral and contralateral spontaneous rotations. Taken together, these findings indicate that an increase in noradrenergic tone by 2-methoxy idazoxan potentiates both D-amphetamine-induced ipsilateral and apomorphine induced contralateral rotations. alpha(1)-Antagonism attenuates D-amphetamine induced ipsilateral rotations and its potentiation by 2-methoxy idazoxan but not apomorphine rotations or its potentiation. Increasing and decreasing the serotonergic transmission decreases and increases D-amphetamine potentiation, whereas increases and decreases apomorphine potentiation respectively. The possible mechanisms for these findings are discussed.

Mitochondrial complex I inhibition depletes plasma testosterone in the rotenone model of Parkinson's disease.

Age-related depletion of testosterone may increase the brain's vulnerability to parkinsonian- or Alzheimer's-like neurodegenerative disorders. In rats, rotenone, a mitochondrial complex I inhibitor, causes specific nigral dopaminergic neurodegeneration producing parkinsonian symptoms. In this study, rotenone was administered on a daily basis (2 mg/kg i.p.) to two groups of rats, over a period of 30 and 60 days, respectively. In order to contribute towards the validation of the rotenone rat model, the changing level of the peripheral sex steroid hormone, testosterone, which would also mimic those found in Parkinson's disease (PD) patients, was evaluated. Parallel to this, prolactin, luteinizing hormone (LH), the nonsexual steroid thyroid-stimulating hormone, and the corticosterone hormone levels in the peripheral blood plasma were measured to show whether other hormones have also been affected by complex I inhibition. The rotenone treatment caused a decrease of testosterone level in the peripheral blood plasma. There were no differences in the thyroid hormone and prolactin but increases in leutinizing hormone and corticosterone were observed. Data from this study indicate that rotenone depleted the sex steroid hormone which is preferentially produced in the periphery, e.g., adrenal gland and testis. In conclusion, because a decrease in testosterone levels is also one of the comorbidities which are found in male PD patients, our results indicate that the rotenone model mimics PD symptoms not only on a neuronal and behavioral level, but also on the testosterone levels.

L-DOPA reverses the hypokinetic behaviour and rigidity in rotenone-treated rats.

Peripherally and locally administered rotenone (an inhibitor of mitochondrial complex I) has been proposed as a model of Parkinson's disease (PD) as it induces nigrostriatal degeneration associated with alpha-synuclein inclusions. If rotenone-induced symptoms represent a model of PD, than they should be counteracted by L-DOPA. To answer this question, rats were treated with rotenone 2.5 mg/kg over 48 days. Behavioural data showed a strong increase in catalepsy, a decrease in locomotor activity and biochemical data showed a significant depletion of dopamine levels in the striatum (Cpu) and substantia nigra in rotenone treated animals compared to vehicle. To examine the effectiveness of L-DOPA in reversing the motor deficit in rats, a dose of L-DOPA (10 mg/kg) in combination with the peripheral amino acid decarboxylase inhibitor benserazide were daily administrated intraperitonially for a period of 10 days in the rotenone-treated rats. This treatment counteracted catalepsy and increased locomotor activity and number of rearings but decreased inactive sitting. In this animal model (rotenone model), catalepsy tests and motor activities showed that the clinically used anti-parkinsonian drug L-DOPA substitutes rotenone-induced dopamine (DA) deficiency.

The neurobehavioral changes induced by bilateral rotenone lesion in medial forebrain bundle of rats are reversed by L-DOPA.

Rotenone (an inhibitor of mitochondrial complex I) has been proposed as a model of Parkinson's disease (PD) as it induces nigrostriatal degeneration associated with alpha-synuclein inclusions. So far, only peripherally administered rotenone has been used as a model of PD. There has not been any investigation on the neurobehavioral changes induced by bilateral lesions of dopaminergic neurons by rotenone in rats. In the present study, rotenone (3 microg) was administered bilaterally stereotaxically into the medial forebrain bundle (MFB) to produce parkinsonian symptoms. Behavioural and biochemical data showed a strong increase in catalepsy, a decrease in locomotor activity and a significant depletion of dopamine levels in the striatum as compared to sham-lesioned animals. If the locomotor deficits are caused by the depletion of dopaminergic neurons, then L-DOPA should counteract motor deficits because L-DOPA therapy reverses mostly all motor deficits in human Parkinsonian patients. To examine the effectiveness of L-DOPA in reversing the motor deficit in rats, two different doses of L-DOPA (5 and 10 mg/kg) in combination with the peripheral amino acid decarboxylase inhibitor benserazide were daily administrated intraperitonially for a period of 31 days lesioned animals. L-DOPA plus benserazide counteracted catalepsy dose-dependently and increased locomotor activity. The results indicate that rotenone infused into the MFB destroys dopaminergic neurons, induces pakinsonian symptoms that are reversed by the clinically effective anti-parkinsonian drug L-DOPA. Therefore, sterotaxically infused rotenone may be useful for screening drugs for the treatment of PD.

Functional recovery of locus coeruleus noradrenergic neurons after DSP-4 lesion: effects on dopamine levels and neuroleptic induced-parkinsonian symptoms in rats.

Noradrenaline has been shown to control dopamine turnover and release in rat brain. Noradrenergic lesion with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) decreases dopamine release in the striatum and enhances catalepsy in experimental models of Parkinson's disease. However, in due course, sprouting of remaining noradrenergic axons, to compensate for the decreased noradrenaline is said to occur in specific brain regions. Though this is to some extent understood, the longstanding effects of noradrenergic lesion on dopaminergic neurons of the basal ganglia and in Parkinsonian behavior is not known. Here the question is addressed, whether locus coeruleus lesion with DSP-4 in rats alters dopamine concentration of the basal ganglia and influences Parkinsonian behavior in a long term (6 months). Parkinsonian behavior was assessed by catalepsy and activity cage after challenging with subthreshold dose of haloperidol (0.2 mg/kg), on 7, 30, 90, 120 and 180 days after DSP-4 lesion. The concentrations of noradrenaline and dopamine and its metabolites were estimated by HPLC. 6 months after DSP-4 lesion, increased concentration of noradrenaline was found in prefrontal cortex and hippocampus. Other regions remain unaffected. The concentration of dopamine remained unchanged. However, dopamine turnover appeared to be increased in prefrontal cortex and reduced in striatum and nucleus accumbens. Catalepsy and hypoactivity were observed in DSP-4 lesioned animals after haloperidol challenge on 7th, 30th and 60th day. Though dopamine turnover was reduced after 6 months in the striatum, haloperidol-induced catalepsy was not observed after 60 days. These results indicate a gradual functional recovery, perhaps hyperinnervation of noradrenergic neurons after DSP-4 treatment and the reversal of its effects on dopaminergic neurons and on Parkinsonian symptoms.

Context-dependent catalepsy intensification is due to classical conditioning and sensitization.

Haloperidol-induced catalepsy represents a model of neuroleptic-induced Parkinsonism. Daily administration of haloperidol, followed by testing for catalepsy on a bar and grid, results in a day-to-day increase in catalepsy that is completely context dependent, resulting in a strong placebo effect and in a failure of expression after a change in context. The aim of this study was to analyse the associative learning process that underlies context dependency. Catalepsy intensification was induced by a daily threshold dose of 0.25 mg/kg haloperidol. Extinction training and retesting under haloperidol revealed that sensitization was composed of two components: a context-conditioning component, which can be extinguished, and a context-dependent sensitization component, which cannot be extinguished. Context dependency of catalepsy thus follows precisely the same rules as context dependency of psychostimulant-induced sensitization. Catalepsy sensitization is therefore due to conditioning and sensitization.

Caroverine inhibits the conditioned place aversion induced by naloxone-precipitated morphine withdrawal in rats.

Comparable to the anti-craving compound acamprosate, caroverine reduces alcohol withdrawal symptoms by an antagonism at ionotropic glutamate receptors and a blockade of calcium channels. The present study examines the effect of caroverine in a craving model, in which acamprosate has proved effective before. A place aversion was induced by a conditioned morphine withdrawal by administration of the opioid antagonist naloxone (0.1 mg/kg, s.c.) 5-6 days after the subcutaneous implantation of a morphine pellet in rats. Testing in the drug-free state, the acquisition of a conditioned aversion against the naloxone-associated cues was inhibited by pretreatment with caroverine (5 mg/kg, i.p.). This result corroborates the involvement of excitatory glutamate and calcium in the development of conditioned withdrawal and craving. It offers further evidence for the hypothesis that these neuronal systems are altered during withdrawal in a similar way by ethanol and opiates.

The effect of acamprosate on the development of morphine-induced behavioral sensitization in rats.

Recently we have shown that the alcohol anti-craving drug acamprosate (calcium acetylhomotaurinate), a functional N-methyl-D-aspartate (NMDA) receptor antagonist which is used therapeutically to prevent relapse in weaned alcoholics, was also effective in suppressing (1) conditioned place aversion induced by morphine withdrawal, and (2) expression of morphine-induced behavioral sensitization. Here, we addressed the question of whether the development of behavioral sensitization, induced by daily injections of morphine (10 mg/kg) over a period of 10 days, could also be suppressed by repeated pretreatment with acamprosate (200 mg/kg). Repeated intermittent injections of morphine produced sensitization of locomotor activity and sniffing behavior. Acamprosate did not block the development of morphine-induced behavioral sensitization. This lack of effect on the development of this phenomenon is inconsistent with the view that NMDA receptor antagonists block the development of sensitization. We suggest that this may derive from the relatively low NMDA receptor-specific antagonism of acamprosate as compared to other NMDA receptor antagonists used in this model. In conclusion, the effect of acamprosate on morphine-induced behavioral sensitization seems to be restricted to the expression of this phenomenon.

Is the Ecstasy-induced ipsilateral rotation in 6-hydroxydopamine unilaterally lesioned rats dopamine independent?

3,4-Methylenedioxymethamphetamine (MDMA) has recently been hypothesized to be effective against the symptoms of Parkinson's disease. Therefore we tested the effects of MDMA-derivatives in the rotational behavioural model. Male Sprague Dawley rats were lesioned unilaterally with 6-hydroxydopamine at the medial forebrain bundle. MDMA was administered at doses of 2.5, 5.0 and 10.0 mg/kg, its derivatives N-Methyl-1-(1,3-benzodioxol-5-yl)-2-butananamine (MBDB), 3,4-Methylenedioxy-N-ethylamphetamine (MDE) and 3,4-Methylenedioxyamphetamine (MDA) at 5.0 mg/kg respectively. All substances induced ipsilateral rotations, MDA being the most effective. MDMA induced rotations were attenuated by the selective serotonin reuptake inhibitor Citalopram but were only slightly reduced by pre-treatment with the selective serotonin synthesis inhibitor PCPA (para-chlorophenylalanine). The effects of MDMA can therefore not fully be explained by serotonin release or by dopaminergic activity of the drugs.

Potentiation of parkinsonian symptoms by depletion of locus coeruleus noradrenaline in 6-hydroxydopamine-induced partial degeneration of substantia nigra in rats.

Parkinson's disease is characterized not only by a progressive loss of dopaminergic neurons in the substantia nigra but also by a degeneration of locus coeruleus noradrenergic neurons. The present study addresses the question of whether a partial neurodegeneration of dopaminergic neurons using 6-hydroxydopamine in rat, not sufficient to produce motor disturbances, is potentiated by prior selective denervation of locus coeruleus noradrenergic terminal fields using N-ethyl-2-bromobenzylamine. Two types of denervations, one causing dopamine deficiency alone and the other causing noradrenaline and dopamine deficiency, were performed. Noradrenaline, 5-hydroxytryptamine, 5-hydroxyindole acetic acid, dopamine and its metabolites were analysed in various brain regions. Behaviour was evaluated by catalepsy tests and activity box. N-ethyl-2-bromobenzylamine selectively depleted noradrenaline from neurons of locus coeruleus origin. Decreased dopamine content in the striatum, substantia nigra and pre-frontal cortex was observed after dopaminergic lesion with 6-hydroxydopamine (42.9%). Additional locus coeruleus noradrenaline depletion with N-ethyl-2-bromobenzylamine aggravated the dopamine depletion (61.2%). The lesion in the noradrenergic and dopaminergic neurodegenerated group was not sufficient to induce consistent catalepsy and akinesia. However, after a subthreshold dose of haloperidol (0.1 mg/kg), the expression of catalepsy and akinesia was strong in the dual-lesioned group and less in the 6-hydroxydopamine-lesioned group. These results indicate that denervation of locus coeruleus noradrenergic terminals with N-ethyl-2-bromobenzylamine potentiates the 6-hydroxydopamine-induced partial dopaminergic neurodegeneration and parkinsonian symptoms. Based on the present findings and existing reports, it can be concluded that noradrenergic neurons of locus coeruleus have neuromodulatory and neuroprotective properties on the dopaminergic neurons of basal ganglia and that noradrenergic degeneration may contribute to the aetiology and pathophysiology of Parkinson's disease.

Glutamatergic mechanisms in addiction.

Traditionally, addiction research in neuroscience has focused on mechanisms involving dopamine and endogenous opioids. More recently, it has been realized that glutamate also plays a central role in processes underlying the development and maintenance of addiction. These processes include reinforcement, sensitization, habit learning and reinforcement learning, context conditioning, craving and relapse. In the past few years, some major advances have been made in the understanding of how glutamate acts and interacts with other transmitters (in particular, dopamine) in the context of processes underlying addiction. It appears that while many actions of glutamate derive their importance from a stimulatory interaction with the dopaminergic system, there are some glutamatergic mechanisms that contribute to addiction independent of dopaminergic systems. Among those, context-specific aspects of behavioral determinants (ie control over behavior by conditioned stimuli) appear to depend heavily on glutamatergic transmission. A better understanding of the underlying mechanisms might open new avenues to the treatment of addiction, in particular regarding relapse prevention.