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W J Schmidt

Publications and source records attributed to W J Schmidt.

At least 37 records · Page 2Linked to original sources
PubMed2003

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.

Acamprosate↗
PubMed2002

Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats.

Rotenone (an inhibitor of mitochondrial NADH dehydrogenase, a naturally occurring toxin and a commonly used pesticide) appears to reproduce the neurochemical, neuropathological and behavioural feature of Parkinson's disease (PD) in the rat. In this study, rotenone was administrated on a daily basis systemically by intraperitoneal injection of two different doses: 1.5 mg/kg (low dose) and 2.5 mg/kg (moderate dose), over a period of 2 months. This treatment caused depletion of dopamine in the posterior striatum (CPu) and prefrontal cortex and also reduced tyrosine hydroxylase-immunoreactivity in CPu. Behavioural experiments showed dose-dependent catalepsy in the two treatment groups of rats. Data from this study indicate that in rats rotenone is capable of causing degeneration of dopaminergic neurons and induction of parkinsonian symptoms. It is concluded that the causal mechanisms of neuronal degeneration implicate a complex I deficiency in the aetiology of rotenone-induced and perhaps in some cases of sporadic PD.

Animals↗
PubMed2001

Changes in serotonin, dopamine and noradrenaline levels in striatum and nucleus accumbens after repeated administration of the abused drug MDMA in rats.

The selective neurotoxic action of the abused drug 3,4-methylenedioxymethamphetamine (MDMA) on the serotonergic axons ascending from the dorsal raphe nucleus (DRN) is well known. The present study examined the long-term effects of subchronic MDMA treatment on rat brain tissue contents of catecholaminergic neurotransmitters. Two and four weeks after cessation of repeated MDMA treatment (ten consecutive days, 20 mg/kg/day), the tissue neurotransmitter concentrations were measured by means of electrochemical detected HPLC in several forebrain areas and DRN. We found reduced serotonin levels in the whole forebrain at both instants of time. In nucleus accumbens (NAC), the noradrenaline levels were also decreased, whereas dopamine levels were increased 4 weeks after treatment. It is concluded that MDMA causes changes of monoamine transmitter levels outlasting cessation of drug intake for at least 4 weeks. Decreased noradrenaline and/or serotonin may subsequently cause the augmentation of dopamine in NAC, a structure crucially involved in motivation circuits. With exception of transmitter alterations in the NAC, the post drug effects are opposite to the acute effects of MDMA and may underlie the psychiatric changes after MDMA intake in humans.

Animals↗
PubMed2001

NMDA receptor antagonists do not block the development of sensitization of catalepsy, but make its expression state-dependent.

Dopamine (DA) receptor blockade induces catalepsy in rats which increases in strength upon retesting. This increase in catalepsy represents a form of sensitization which has been shown to be completely context dependent. Sensitization of catalepsy therefore represents a good model for studying the neurobiological mechanisms underlying the interaction between the cellular effect of a drug (DA-receptor blockade) and the context. This study investigated whether glutamatergic mechanisms are involved in the development of sensitization. Rats were treated with either haloperidol or haloperidol plus an N-methyl-D-aspartate (NMDA) receptor antagonist. Haloperidol consistently induced catalepsy which developed sensitization upon retesting. Co-administration of D-CPPene (5 mg/kg and 10 mg/kg, i.p.), eliprodil (30 mg/kg, i.p.) or Ro 25-6981 (15 mg/kg, i.p.) did not have any effect on sensitization, although all three drugs exerted some anticataleptic effects. When sensitization developed under haloperidol plus NMDA receptor antagonist, the sensitized response was expressed only in the presence of the NMDA receptor antagonist. This strongly suggests that the NMDA receptor antagonists represent contextual stimuli to which catalepsy has been conditioned, and this implies that the expression of sensitization has been rendered state-dependent.

Animals↗
PubMed2000

Differential effects of quinolinic acid lesions of the medial prefrontal cortex on the expression of morphine- and dizocilpine- induced behavioural plasticity in the rat.

Development and expression of behavioural sensitization have been shown to be differentially affected by drugs and lesions. Here we assessed the effects of quinolinic acid lesions of the rat medial prefrontal cortex on the expression of enhanced locomotion and rearing that has been induced prior to the lesions by 14 daily injections of morphine (10 mg/kg), dizocilpine (MK-801) (0.3 mg/kg) or the combination of both drugs. Expression of tolerance to morphine-induced behavioural inhibition was blocked by the lesions while the expression of MK-801 -induced sensitization was not affected and the expression of the sensitization induced by the drug combination was only mildly attenuated. These results suggest that the expression of behavioural plasticity induced by different drugs is mediated at least in part by different neural substrates.

Analysis of Variance↗
PubMed2000

Immediate early gene expression in rat basal ganglia after destruction of the dopaminergic system.

In the present study, we performed immunocytochemical mapping of cFos and c-Jun as markers for changes in neural activity in the brains of dopamine denervated rats. We observed a prolonged c-Fos and c-Jun expression in basal ganglia motor and limbic circuits over 96 h. This might be due to alterations in transmitter balances. We conclude, that changes in neural activities are involved in the development of 'extranigral' pathology of Parkinson's disease.

Journal Article↗
PubMed2000

The neuroprotectant properties of glutamate antagonists and antiglutamatergic drugs.

In the slowly progressive neurodegenerative disorders like Parkinson's disease and Alzheimer's disease very different neuronal populations undergo degenerative processes, although the cascades of cellular events leading to death are supposed to be similar. We suggest that the complex pattern of degeneration in Parkinson's disease depends on two processes, a 'primary neurodegeneration' that takes place in the striato-nigral dopamine neurons and a 'secondary degeneration', occurring in distant structures of the basal ganglia network. For the purpose of explaining the regionally different expression of 'primary neurodegeneration' in different diseases, we postulate that the origin of neurodegeneration is associated with the local release of a neurotransmitter. For Parkinson's disease this would mean that the metabolism of dopamine in the striatum, nucleus accumbens and presumably the pedunculopontine tegmental nucleus, together with one or more pathological factors contribute to the initial neurodegeneration. There are recent studies indicating that a transneuronal retrograde degeneration of the substantia nigra pars compacta neurons might be induced by a loss of function of dopaminergic synapses in the striatum. We have recently established an animal model of retrograde striato-nigral degeneration, where the assessment of markers for cellular stress is possible. In Parkinson's disease, several structures distal from the substantia nigra pars compacta undergo neuropathological changes, characterizing the 'secondary neurodegeneration. Our recent studies provide experimental evidence for a chronic cellular stress in these structures because of a relative or absolute glutamatergic overactivity due to the initial loss of dopaminergic innervation. Thus, a loss of dopamine transforms the basal ganglia to a 'destructive network'. Both processes, the 'primary' and 'secondary neurodegeneration', affecting each other, characterize the progress of chronic neurodegeneration. From this point of view, we would further like to develop strategies for symptomatic amendment. Excitatory amino acids seem to be involved not only in the secondary processes of neurodegeneration, but also in initiation of the 'primary degeneration' of the substantia nigra pars compacta. Therefore, a reduction of glutamatergic overactivity constitutes a promising neuroprotective strategy. Especially the new antagonists of the NMDA-receptors with high affinity to the NR2B subunit of the receptor are in focus of our interest, since they reveal a favourable profile of side effects, therefore providing a promising tool for neuroprotection.

Journal Article↗
PubMed2000

Activation of striatal group II metabotropic glutamate receptors has a differential effect on dopamine-D1 and -D2 receptor antagonist-induced hypokinesia in the rat.

Motor function of group II metabotropic glutamate receptors was investigated by quantifying motor effects of bilateral infusions of the preferential group II metabotropic glutamate receptor agonist (2S,3S,4S)-alpha-carboxycyclopropyl-glycine (15, 30, 60 nmol/0.5 microl) into the striatum of conscious rats. (2S,3S,4S)-alpha-carboxycyclopropyl-glycine reduced spontaneous sniffing activity in an experimental chamber, but did not affect spontaneous locomotor (line crossings) or exploratory behaviour (rearings, hole visits) in an open field equipped with a hole-board. Intrastriatal infusion of the selective group III metabotropic glutamate receptor agonist L-2-amino-4-phosphobutyric acid (15, 30, 60, 120 nmol/0.5 microl) did not influence spontaneous motor behaviour. Intrastriatal infusion of (2S,3S,4S)-alpha-carboxycyclopropyl-glycine (15 nmol/0.5 microl and 30 nmol/0.5 microl) further depressed spontaneous motor behaviour in rats pretreated with the dopamine-D1 receptor antagonist (-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H- benzo[d]naphtho-(2,1-b)azepine, but not if rats were pretreated with the preferential dopamine-D2 receptor antagonist haloperidol. It appears likely that the depression of spontaneous motor behaviour evoked by the preferential group II agonist (2S,3S,4S)-alpha-carboxycyclopropyl-glycine is mediated by activation of group II metabotropic glutamate receptors, since activation of group I metabotropic glutamate receptors has been shown to stimulate motor behaviour, and activation of group III metabotropic glutamate receptors had no effect, as shown in this study. Therefore, it is reasonable to speculate that the striatum may contribute to the motor-depressant effects of systemically applied group II metabotropic glutamate receptor agonists, as reported by us recently. The present findings further suggest that a functional dopamine-D1 antagonism contributes to the motor effects of group II metabotropic glutamate receptor agonists.

Amino Acids, Dicarboxylic↗
PubMed2000

Effects of the non-competitive NMDA-receptor antagonist memantine on morphine- and cocaine-induced potentiation of lateral hypothalamic brain stimulation reward.

RATIONALE: NMDA-receptor antagonists may be of potential therapeutic use in several states of disease. It has been reported that drugs like MK-801 can potentiate the rewarding effects of other drugs, which may complicate the therapeutic use of this class of drugs. However, since MK-801 appears to be an "atypical" drug in several respects, other NMDA-receptor antagonists may not share this effect of MK-801. OBJECTIVES: We tested the effects of memantine, a clinically used NMDA-receptor antagonist, in a paradigm that has previously shown the reward-potentiating effects of MK-801 to see if this drug would yield qualitatively comparable results. METHODS: The effects of memantine on morphine- and cocaine-induced potentiation of brain stimulation reward were examined, using the rate-free curve-shift paradigm. RESULTS: Low doses of morphine (2.5 mg/kg) and cocaine (5 mg/kg) produced moderate decreases in the reward threshold frequency reflected in moderate leftward shifts of the function relating response rate to stimulation frequency. These effects were not altered by co-administration of an intermediate dose of memantine (5 mg/kg), but maximum response rate was significantly increased by these drug combinations. Higher doses of morphine (7.5 mg/kg) and cocaine (10 mg/kg) had stronger effects on the rate-frequency function and reward threshold. These effects were enhanced by co-administration of a high dose of memantine (10 mg/kg), while the effects on maximum response rate were less pronounced. CONCLUSIONS: These results demonstrate that fairly high doses of memantine and morphine or cocaine have to be combined in order to observe an enhancement of the latter drugs' potentiation of brain stimulation reward. In this respect, memantine differs markedly from MK-801, another non-competitive NMDA-receptor antagonist which has been shown to interact with morphine and cocaine at very low doses.

Analgesics, Opioid↗
PubMed2000

Blockade of behavioral sensitization by MK-801: fact or artifact? A review of preclinical data.

RATIONALE: It is widely assumed that various forms of neural and behavioral plasticity, including sensitization, are strongly dependent on the activation of N-methyl-D-aspartate (NMDA)-receptors, but evidence also exists to suggest that not all forms of sensitization are unequivocally blocked by NMDA-receptor antagonism. Also, findings from studies examining the effects of NMDA-receptor blockade on forms of behavioral plasticity other than locomotor sensitization (various forms of tolerance, sensitization of catalepsy, and learning and conditioning) reinforce the view that forms of behavioral plasticity exist that are not blocked by NMDA-receptor antagonists. OBJECTIVES: Since the publication of two reviews addressing this issue in detail, this field of research has continued to be very active and controversial, and a number of further studies have been published in the meantime which are relevant to the topic. The aim of this review is to provide a summary of this literature and to consider new approaches that might make important contributions to the present discussion. RESULTS AND CONCLUSIONS: The studies reviewed herein have produced results both consistent with and in contradiction to the view that MK-801 and related drugs block behavioral plasticity, and the debate about how exactly MK-801 and related drugs interact with other drugs in sensitization experiments is still in full swing. What seems crucial for future studies relating to this subject is a careful experimental design to reduce the number of potential interpretations of the findings.

Animals↗
PubMed2000

On the role of inhibitory glutamate receptors in N-methyl-D-aspartate- and dopamine-receptor mediated motor behavior of rats.

The physiological function of inhibitory group II metabotropic glutamate-receptors, a family of second messenger coupled glutamate-receptors, for motor behavior is almost unknown. The aim of this study is to address this topic by quantifying motor effects of the preferential group II agonist (2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine, administered i.c.v. (62.5, 125.0, 187.5, 250.0, 500.0nmol/4microl), in an open-field equipped with a hole-board. (2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine decreased spontaneous locomotor and exploratory behavior, which was blocked be the group II antagonist (2S)-alpha-ethylglutamic acid (250.0nmol/4microl). Locomotion induced by the N-methyl-D-aspartate-receptor antagonist dizocilpine (0.08, 0.16, 0.32mg/kg) was counteracted by the group II agonist (2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine, but an antagonism towards dizocilpine did not occur in all aspects of motor behavior evaluated. In contrast to the antagonism of dizocilpine induced locomotion, D,L-amphetamine (1.0, 2.0, 3.0mg/kg) induced locomotion was not antagonised by (2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine.The results suggest that group II agonists may be devoid of psychotomimetic effects in humans and even may antagonise this side effect of N-methyl-D-aspartate receptor antagonists. Since group II activation and N-methyl-D-aspartate-receptor blockade very efficiently protects against excitotoxic neurodegeneration, selective group II agonists may allow novel pharmacotherapeutical approaches in pathophysiological conditions characterised by a glutamatergic hyperactivity, like epilepsy, ischemia and trauma.

Animals↗
PubMed2000

Differential effects of discrete subarea-specific lesions of the rat medial prefrontal cortex on amphetamine- and cocaine-induced behavioural sensitization.

The medial prefrontal cortex (mPFC) of the rat is thought to be important for the initiation of behavioural sensitization. Since the mPFC is not a homogenous structure, we attempted to systematically examine the contribution of the different subareas - infralimbic (il), prelimbic (pl), anterior cingulate (cg) - of the mPFC to the induction of sensitization by selectively lesioning these areas or the whole mPFC with quinolinic acid (45 nmol in 0.5 microl). During an initial habituation session only il or whole mPFC lesions reduced spontaneous activity. Lesioned and sham-lesioned animals were then treated every other day with either saline, DL-amphetamine (3 mg/kg), or cocaine (20 mg/kg) for 2 weeks in their home cages and were then challenged with either DL-amphetamine (1.5 mg/kg) or cocaine (10 mg/kg) after 1 day and 2 weeks of withdrawal. None of the lesions affected the development of amphetamine-induced sensitization in any way, as assessed by several behavioural parameters including locomotion and sniffing. In contrast, cocaine-induced sensitization was significantly attenuated by pl and whole mPFC lesions, while il and cg lesions were without effect. These results show a double dissociation of the role of the mPFC in behavioural sensitization. The mPFC seems to be important only for cocaine- but not for amphetamine-induced sensitization, and only the pl area appears to be of relevance for cocaine-induced sensitization. It is suggested that these differences are due to differences in the pharmacological interaction of cocaine and amphetamine with the mesocortical dopamine system, and to the particular anatomical connections of each of the mPFC subregions.

Amphetamine↗
PubMed2000

Functional relationship among medial prefrontal cortex, nucleus accumbens, and ventral tegmental area in locomotion and reward.

Prominent projections of the medial prefrontal cortex (mPFC) to the nucleus accumbens (NAS) and the ventral tegmental area (VTA) exist, but it has been difficult to assign a clear functional role to either of these projections. With some exceptions to be discussed in some detail, only a few neurochemical and behavioral effects of manipulating the mPFC can be explained by invoking the mPFC-NAS projection, while most effects are compatible with an involvement of the mPFC-VTA-NAS or mPFC-pedunculopontine tegmental nucleus (PPTg)-VTA-NAS circuits. What is known about the organization and function of these loops is generally consistent with the results obtained by stimulating or lesioning or injecting drugs into the mPFC, yet these findings are largely inconsistent with the functional organization of the mPFC-NAS projection. This review briefly summarizes some of the most important aspects of what is known about the functional interactions of the mPFC. NAS, VTA, and associated areas, and focuses on functional differences between the mesocortical and the mesoaccumbal dopaminergic projections, and between the corticomesencephalic and the corticoaccumbal glutamatergic projections.

Animals↗
PubMed1999

Memantine does not substantially affect brain stimulation reward: comparison with MK-801.

The non-competitive N-methyl-D-aspartate (NMDA)-receptor antagonist MK-801 (dizocilpine) has been shown to potentiate brain stimulation reward (BSR). Memantine (1-amino-3,5-dimethyladamantane) also binds to the PCP binding site of the NMDA receptor but with markedly different kinetics and affinity than MK-801. Here, we examined the effects of memantine on BSR and compared its effects to those of MK-801. MK-801 (0.05 mg/kg-0.4 mg/kg) produced clear, dose-dependent decreases in threshold frequency, manifest in clear leftward shifts of the function relating stimulation frequency to response rate. Memantine (1 mg/kg-17.5 mg/kg) had only small effects on threshold frequencies and only at high doses, manifest in only small shifts in the frequency-response function. The highest dose of each drug also produced a decrease in maximum response rate. This study shows that memantine failed to substantially influence BSR at low to intermediate doses, suggesting that this substance is likely to be largely devoid of rewarding effects in a therapeutic dose range.

Animals↗
PubMed1999

Modulation of striatal acetylcholine concentrations by NMDA and the competitive NMDA receptor-antagonist AP-5: an in vivo microdialysis study.

The effects of local perfusion with the competitive NMDA receptor antagonist 2-amino-5-phosphonovalerate (AP-5) and the glutamate receptor agonist N-methyl-D-aspartate (NMDA) on release of extracellular acetylcholine (ACh) and choline (Ch) in the dorsolateral striatum were studied using in vivo microdialysis in freely moving rats. AP-5 caused a dose-dependent decrease in ACh release that was counteracted by the addition of NMDA. Perfusion with AP-5 also decreased Ch levels. Local perfusion with NMDA induced an elevation of ACh release in low (10(-5) M), but not high (10(-2) M and 10(-3) M) concentrations, that were associated with massive cellular death. These inhibitory effects of AP-5 and the stimulatory effect of NMDA in non-neurotoxic dosages on ACh release provide further evidence for a tonic stimulation of striatal cholinergic interneurons by glutamatergic neurons via NMDA receptors.

2-Amino-5-phosphonovalerate↗
PubMed1999

State-dependent blockade of haloperidol-induced sensitization of catalepsy by MK-801.

NMDA receptor antagonists have been shown to block several forms of neural and behavioural plasticity. The prototypical and most widely-used noncompetitive NMDA receptor antagonist is dizocilpine (MK-801). Here we have examined the effect of MK-801 on the context-dependent augmentation ('sensitization') of catalepsy in rats which develops with repeated administration of haloperidol. It was found that over a 7-day treatment period animals receiving haloperidol (0.25 or 0.5 mg/kg) plus MK-801 (0.16 mg/kg) showed a context-dependent day-to-day increase in catalepsy similar to animals that received haloperidol alone. However, when all animals were treated with haloperidol alone on day 8 of the experiment, animals that had received haloperidol plus MK-801 before displayed a much smaller cataleptic response, similar to that observed in the haloperidol group on the first treatment day, i.e. the previously-established enhancement of catalepsy was no longer expressed. These results may be explained in terms of state-dependency effects induced by MK-801. Implications of these findings for the clinical use of NMDA receptor antagonists in the treatment of Parkinson's disease are discussed.

Animals↗