Biomedical subjects
Publications and source records attributed to I J Mitchell.
Patients with Huntington's disease show deficits in recognizing disgust in the facial expressions and vocal intonations of others. In this study, the authors demonstrate that these disgust-related deficits extend to foul-smelling olfactory stimuli and inappropriate combinations of taste stimuli.
Abnormal corticosteroid release is extensively associated with mood disorders. This association may result from the toxic actions of endogenous corticosteroids which can induce apoptosis of hippocampal neurons. Similarly, dexamethasone, a synthetic corticosteroid, can induce lethal and sublethal damage to rat hippocampal and striatal neurons and can result in steroid-induced psychoses in humans. The experiments reported here tested the hypothesis that pre-treatment with oestrogen would also attenuate dexamethasone-induced neuronal damage as oestrogens have neuroprotective actions against a variety of insults and falling levels of oestrogen are associated with increased vulnerability to mood disorders. Male Sprague-Dawley rats received three systemic injections which were a combination of vehicle, 17-beta-oestradiol (0.2 mg/kg, s.c.), the oestrogen receptor antagonist tamoxifen (10 mg/kg, s.c.) and dexamethasone (0.7 mg/kg, i.p.) and were killed 24 h after the final injection. Injections of dexamethasone (when preceded by vehicle injections) resulted in elevated levels of apoptosis and sub-lethal damage, as demonstrated by reduced levels of microtubule-associated protein-2-immunopositive neurons, in the striatum and hippocampus. This damage was regional with the dorsomedial caudate putamen and the dentate gyrus and CA1 and CA3 hippocampal sub-fields being particularly affected. Pretreatment with oestrogen substantially attenuated the dexamethasone-induced neuronal damage. This oestrogen-induced neuronal protection was in turn virtually eliminated by giving an initial injection of tamoxifen. These results suggest, therefore, that oestrogens can protect from corticosteroid-induced neuronal damage via an oestrogen receptor-mediated process.
Chronic administration of typical neuroleptics is associated with tardive dyskinesia in some patients. This dyskinetic syndrome has been associated with loss of GABAergic markers in the basal ganglia but the cause of these GABAergic depletions remains uncertain. Haloperidol, a commonly prescribed typical neuroleptic, is known to be toxic in vitro, possibly as a consequence of its conversion to pyridinium-based metabolites and potentially by raising glutamate-mediated transmission. We report here that the in vivo, acute administration of a large dose of haloperidol resulted in a microglial response indicative of neuronal damage. This was accompanied by an increase in the number of apoptotic cells in the striatum (especially in the dorsomedial caudate putamen) and in the substantia nigra pars reticulata. These apoptotic cells were characterised by the stereotaxic injection of a retrograde neuroanatomical tracer into the projection targets of the striatum and substantia nigra pars reticulata prior to the systemic injection of haloperidol. This procedure confirmed that the dying cells were neurones and demonstrated that within the striatum the majority were striatopallidal neurones though relatively high levels of apoptotic striatoentopeduncular neurones were also seen.The possibility that chronic administration of haloperidol could induce cumulative neuronal loss in the substantia nigra pars reticulata and thereby induce the pathological changes which lead to tardive dyskinesia is discussed.
It has been shown previously that the synthetic corticosteroid dexamethasone induces apoptosis of granule cells in the dentate gyrus and striatopallidal neurons in the dorsomedial caudate-putamen. We investigated whether or not dexamethasone can induce damage to other neuronal populations. This issue was addressed using OX42 immunohistochemistry to visualise activated microglia and thereby gauge the extent of dexamethasone-induced neuronal death. A single dose of dexamethasone (20mg/kg, i.p.) administered to young male Sprague-Dawley rats induced a strong microglial reaction which was restricted to the striatum, the dentate gyrus and all of the CA subfields of the hippocampus. Some OX42-immunoreactive cells were also seen in the lateral septal nucleus. Subsequent quantitative analysis of silver/methenamine-stained sections confirmed that acute administration of dexamethasone induced apoptosis in the striatum and all regions of the hippocampus at doses as low as 0.7mg/kg. In contrast, dexamethasone failed to induce apoptosis in the lateral septal nucleus at doses up to 20mg/kg. The levels of dexamethasone-induced striatal and hippocampal apoptosis were attenuated by pretreatment with the corticosteroid receptor antagonist RU38486 (Mifepristone), which implies that the cell death was mediated by a corticosteroid receptor-dependent process. We further determined whether dexamethasone induced sublethal damage to neurons by quantifying reductions in the number of microtubule-associated protein-2-immunoreactive striatal and hippocampal cells following injection of the corticosteroid. Dexamethasone induced dramatic decreases in the striatum, with the dorsomedial caudate-putamen being particularly affected. Similar damage was seen in the hippocampus, with the dentate gyrus and CA1 and CA3 subfields being particularly vulnerable.Equivalent corticosteroid-induced neuronal damage may occur in mood disorders, where the levels of endogenous corticosteroids are often raised. Corticosteroid-induced damage of striatal and hippocampal neurons may also account for some of the cognitive deficits seen following administration of the drugs to healthy volunteers.
Phencyclidine (PCP) has recently been shown to induce apoptosis of a subpopulation of striatopallidal neurons which lie in the dorsomedial caudate-putamen. The pharmacological mechanisms underlying this PCP-induced striatal death were investigated in a series of small experiments. Striatal silver-methenamine-stained sections from rats injected acutely with dizocilpine (MK-801; 1.5-5 mg/kg, i.p.) were analysed to determine whether other non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists could induce apoptotic-like changes in striatal cells. The effects of amphetamine (3-12 mg/kg, i.p.) were similarly investigated as PCP can elevate extracellular dopamine levels and dopamine has the potential to be neurotoxic. The potential involvement of dopamine transmission in PCP-induced striatal apoptosis was also tested by determining the effect of co-administering SCH23390 (D1 dopamine receptor antagonist) and quinpirole (D2 dopamine receptor agonist) on PCP (80 mg/kg, s.c.)-induced striatal apoptotic-like cell death. Equivalent experiments were performed using scopolamine (cholinergic antagonist) as this drug blocks PCP-induced damage of the retrosplenial cortex and RU38486 (corticosteroid receptor antagonist) as a similar subpopulation of striatal neurons undergoes apoptosis following dexamethasone administration. Injection of neither MK-801 nor amphetamine induced elevations of apoptotic-like cells in the striatum nor did co-administration of SCH23390 or scopolamine affect the levels of PCP-induced striatal cell death. In contrast, quinpirole elevated the levels of PCP-induced apoptotic-like striatal cell death and RU38486 markedly reduced it. Within the retrosplenial cortex, scopolamine lowered PCP-induced apoptotic-like cell death whereas RU38486 was without effect. These results suggest that PCP-induced striatal apoptosis results from a corticosteroid-dependent mechanism. The results further demonstrate that different pathological mechanisms underlie PCP-induced neuronal damage in the striatum and the retrosplenial cortex.
Phencyclidine (PCP), a non-competitive antagonist of the NMDA subtype of glutamate receptor, which also acts as an indirect dopamine agonist and at sigma sites, can induce a long lasting psychotic state when taken acutely. It is well established that PCP is toxic to specific limbic structures and we have recently demonstrated that it induces apoptosis of a subpopulation of striatal neurons. These neurons lie predominantly in the dorsomedial striatum and project to the globus pallidus. The mechanisms mediating this neuronal death are unclear though manipulations of dopamine transmission can induce striatal c-fos expression and continuous c-fos expression has been implicated in the molecular cascades controlling apoptosis. We accordingly undertook a series of experiments to determine the action of PCP on striatal Fos-like immunoreactivity (FLI). PCP (80 mg/kg, s.c.) elicited FLI in three distinct striatal areas, namely dorsomedial, dorsolateral and the nucleus accumbens. The level of PCP-induced FLI was consistently attenuated by the co-administration of the D-1 antagonist, SCH 23390. Vehicle injections also induced modest levels of FLI in the dorsomedial striatum and the nucleus accumbens which again were attenuated by SCH 23390. The type of striatal neuron in which PCP-induced FLI was determined by the use of a retrograde anatomical tracer. A colloidal gold tracer was thus injected into the major areas of termination of striatal projection neurons prior to the administration of PCP. This procedure demonstrated that the majority of the FLI positive striatal cells were striatopallidal neurons, though some FLI positive striatoentopeduncular neurons were also seen. The potential pharmacological mechanisms underlying the results are discussed. It is argued that the complex pattern of PCP-induced striatal FLI might be accounted for by a differential action upon extracellular dopamine levels whereby they are elevated in some striatal areas and simultaneously reduced in others.
The different types of striatal neuron show a range of vulnerabilities to a variety of insults. This can be clearly seen in Huntington's disease where a well mapped pattern of pathological events occurs. Medium spiny projection (MSP) neurons are the first striatal cells to be affected as the disease progresses whilst interneurons, in particular the NADPH diaphorase positive ones, are spared even in the late stages of the disease. The MSP neurons themselves are also differentially affected. The death of MSP neurons in the patch compartment of the striatum precedes that in the matrix compartment and the MSP neurons of the dorsomedial caudate nucleus degenerate before those in the ventral lateral putamen. The enkephalin positive striatopallidal MSP neurons are also more vulnerable than the substance P/dynorphin MSP neurons. We review the potential causes of this selective vulnerability of striatopallidal neurons and discuss the roles of endogenous glutamate, nitric oxide and calcium binding proteins. It is concluded that MSP neurons in general are especially susceptible to disruptions of cellular respiration due to the enormous amount of energy they expend on maintaining unusually high transmembrane potentials. We go on to consider a subpopulation of enkephalinergic striatopallidal neurons in the rat which are particularly vulnerable. This subpopulation of neurons readily undergo apoptosis in response to experimental manipulations which affect dopamine and/or corticosteroid levels. We speculate that the cellular mechanisms underlying this cell death may also operate in degenerative disorders such as Huntington's disease thereby imposing an additional level of selectivity on the pattern of degeneration. The possible contribution of the selective death of striatopallidal neurons to a number of clinically important psychiatric conditions including obsessive compulsive disorders and Tourette's syndrome is also discussed.
Phencyclidine, a non-competitive N-methyl-D-aspartate receptor antagonist and indirect dopamine agonist, has neuroprotective properties. Phencyclidine, however, can also exert toxic effects and causes degeneration of neurons in the retrosplenial cortex. In this paper we demonstrate that acute administration of a high dose of phencyclidine to rats, (80 mg/kg), also causes death of a subpopulation of striatal neurons. The dying cells exhibited many of the morphological and biochemical features of cells undergoing apoptosis as revealed by a silver methenamine stain, propidium iodide fluorescence histochemistry and a TUNEL procedure. The majority of the dying cells tended to be clustered within the dorsomedial aspect of the striatum. The type of striatal cell undergoing apoptosis was determined by stereotaxically injecting a colloidal gold retrograde anatomical tracer into the major areas of striatal termination prior to the administration of phencyclidine. This procedure demonstrated that phencyclidine induced striatal apoptosis is almost exclusively limited to striatopallidal neurons. A similar series of experiments was conducted to determine whether the synthetic corticosteroid, dexamethasone, also induces apoptosis of striatal neurons. Corticosteroids are known to be toxic to hippocampal neurons and interact with striatal dopamine transmission. Acute administration of dexamethasone, (20 mg/kg), induced apoptosis of a subpopulation of striatal cells. As was the case with phencyclidine, most of the dexamethasone-induced apoptotic striatal cells were striatopallidal neurons located within the dorsomedial striatum. The pathology during the early stages of Huntington's disease is restricted to an equivalent subpopulation of striatal neurons. Many Huntington's patients are extremely psychotic during this stage in the progression of the disease. Psychosis is also associated with the acute administration of both phencyclidine and dexamethasone to humans. We accordingly speculate that the selective loss of striatopallidal neurons in the dorsomedial striatum may represent the neural substrate of many forms of psychosis.
Parkinsonism is characterised by overactive glutamatergic transmission in the cortico-striatal and subthalamo-medial pallidal pathways. Local blockade of glutamatergic transmission in these pathways can alleviate parkinsonian symptoms. The effectiveness of the treatment, however, is often limited by the simultaneous appearance of unwanted side-effects. These side-effects, including ataxia and dissociative anaesthesia, are particularly problematic when N-methyl-D-aspartate (NMDA) antagonists are used. In an attempt to overcome these problems we have attempted to manipulate excitatory amino acid (EAA)-mediated neurotransmission indirectly by targeting the NMDA receptor associated modulatory sites. We review evidence which demonstrates that antagonists for both the NMDA associated glycine and polyamine sites can reverse parkinsonian symptoms when injected intra-cerebrally in both MPTP-treated and bilateral 6-OHDA lesioned marmosets without eliciting unwanted side-effects. We further review preliminary data which suggest that ifenprodil, a polyamine site antagonist, has striking anti-parkinsonian actions in the marmoset. Potential mechanisms of action underlying these effects are discussed in terms of NMDA receptor subtypes and the neuroanatomical locus of action. The anti-parkinsonian efficacy of intra-striatally administered EAA antagonists leads us to question the view of dopamine acting in the striatum as a simple neuromodulator.
Drug-induced dyskinesias are a major drawback of the dopaminergic therapies currently employed to treat Parkinson's disease. It is commonly speculated that these dyskinesias may be mediated by functional changes within the striatum. Recent research has, therefore, focused on finding new modes of therapy which will alleviate parkinsonian symptoms without directly altering neurotransmission in the striatum. It has recently been demonstrated that the behavioural symptoms observed in dopamine-depleted rodents can be alleviated by blockade of excitatory neurotransmission in the entopeduncular nucleus. A series of experiments was conducted in order to determine whether this manipulation affected the pattern of Fos immunoreactivity in the basal ganglia elicited by dopamine depletion. The results demonstrated that the most striking change in Fos levels was found in the subthalamic nucleus, indicating that reversal of parkinsonian symptoms in this manner cannot be considered as a simple redress in the balance of activity in the output structures of the basal ganglia.
Pharmacological manipulations which result in abnormal levels of excitatory amino acid (EAA) mediated neurotransmission can result in neuronal apoptosis. We accordingly hypothesised that manipulations of the external environment which induce prolonged EAA-mediated transmission in sensory neurons may also induce apoptosis. This hypothesis was tested by placing groups of adult mice, housed in their home cage, on a turntable which slowly rotated (0.8 rev./min). This non-invasive manipulation will have resulted in abnormal discharge patterns in the vestibular nuclei. Significantly greater levels of neuronal apoptosis were seen in the vestibular complex after rotation for 48 h compared with non-rotated controls. This finding was also predicted independently from a computational approach.
Pharmacological depletion of dopaminergic neurotransmission can result in an elevation in striatal Fos levels. This elevation may occur as a direct result of decreased dopaminergic neurotransmission or indirectly via elevated corticostriatal glutamatergic neurotransmission which occurs secondary to dopamine depletion. To test the hypothesis that elevated N-methyl-D-aspartic acid (NMDA)-mediated corticostriatal transmission may underlie the increase in striatal Fos levels upon dopamine depletion, rats were unilaterally 6-hydroxydopamine lesioned under anaesthesia induced by either barbiturate or the NMDA antagonist, ketamine. Following surgery the animals remained under light anaesthesia for 6 h prior to sacrifice and quantification of striatal Fos immunoreactivity. The results demonstrate that dopamine depletion following 6-hydroxydopamine lesioning can result in elevated striatal Fos levels which can be attenuated by contiguous treatment with an NMDA antagonist. This suggests that the increase in striatal Fos levels observed following dopamine depletion may occur as a result of elevated cytoplasmic calcium levels in the striatal cells.
Parkinson's disease is characterized by an increased excitatory amino acid transmission in the internal segment of the globus pallidus and the substantia nigra pars reticulata. The effects of the kappa receptor agonist enadoline (CI-977) on glutamate transmission were investigated in vitro. Enadoline reduced the K(+)-evoked release of glutamate from slices of substantia nigra in a concentration-dependent manner (maximum effect: 78% inhibition at 200 microM). This effect was blocked by the selective kappa receptor antagonist nor-binaltorphimine. The endogenous ligand for kappa receptors is thought to be dynorphin. Dynorphin released from terminals of striato-pallidal and striato-nigral pathways might thus act as an endogenous modulatory agent on glutamatergic transmission in the basal ganglia. In vivo experiments were carried out in rodent and primate models of Parkinson's disease to assess the potential of manipulating kappa receptors as a potential treatment for Parkinson's disease. Enadoline reduced reserpine-induced akinesia when injected in the entopeduncular nucleus of the rat. Similarly, injections of CI-977 in the internal segment of globus pallidus (GPi) of the MPTP-treated marmoset alleviated parkinsonian symptoms and allowed the animal to recover its locomotor activity. This suggest that reducing the overactive glutamatergic transmission in the output regions of the basal ganglia by activating kappa receptors might potentially form the basis of a novel anti-parkinsonian therapy.
Experiments were conducted to characterise the Fos-immunopositive neurons that are observed in the dorsal rim of the striatum following monoamine depletion by the systemic administration of reserpine. Using a retrograde tract-tracer, some of these neurons could be shown to project to the globus pallidus but none were seen to project to the entopeduncular nucleus. In addition, these neurons were located in a region of both poor calbindin immunoreactivity and cholinesterase activity. It can be concluded that Fos levels are increased only in a subset of striatopallidal neurons following monoamine depletion. This subset of neurons is located in the dorsal region of the striatum where it has previously been shown that neurons can preferentially be induced to undergo apoptosis upon monoamine depletion.
The glutamatergic cortico-striatal and subthalamo-entopeduncular pathways are both overactive in parkinsonism. Previous behavioural investigations have shown that intra-entopeduncular injection of either NMDA-site or glycine-site antagonists results in alleviation of parkinsonian symptoms, although injection of the former is associated with the appearance of anaesthetic-like side effects. These behavioural differences may be mediated by action on different NMDA receptor subtypes. Recent neurochemical and molecular pharmacological studies have indicated the existence of NMDA receptor subtypes which display differential modulation by glycine. In the present study, three potential modes of NMDA antagonism were differentiated in vitro by effects on [3H]-glycine binding to striatal sections. Specific [3H]-glycine binding was totally displaced by the glycine partial agonist (R)-HA-966; the NMDA-site antagonist D-CPP had no effect; and the NMDA-site antagonist D-AP5 displaced [3H]-glycine binding in a subpopulation of glycine sites. The anti-parkinsonian effects of (R)-HA-966, D-CPP and D-AP5 were assessed by intra-striatal injection in reserpine-treated rats and 6-OHDA-lesioned rats. Injection of (R)-HA-966 and D-CPP resulted in alleviation of parkinsonian akinesia, although the latter elicited anaesthetic-like side effects; D-AP5 was ineffective as an anti-parkinsonian agent. (R)-HA-966 was also effective as an anti-parkinsonian agent when administered systemically in the reserpine-treated rat. These data suggest that different classes of NMDA antagonist mediate different behavioural responses within the parkinsonian striatum. The behavioural response produced may depend on the exact nature of the conformational change induced by the antagonist and the location of the subtype most sensitive to that class of compound. Selection of a specific mode of NMDA receptor antagonism or targeting of striatal NMDA receptor subtypes may form the basis of a novel therapeutic approach to Parkinson's disease.
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We have investigated the potential of alleviating parkinsonian symptoms by manipulating excitatory amino acid (EAA) transmission, by several different pharmacological means, in a novel primate model of parkinsonism. The model is based on a two-stage bilateral 6-hydroxydopamine lesion procedure in marmosets, which produces a stable but marked parkinsonian condition. Parkinsonian symptoms were reversed in a dose-dependent manner by systemic administration of levodopa and intrastriatal injections of apomorphine administered into either the caudate nucleus or the putamen. (R)-HA-966, a partial agonist for the NMDA receptor associated glycine site, also alleviated parkinsonian symptoms when injected intrastriatally but not when injected systemically. Systemic injection of enadoline, a kappa opiate which blocks release of EAAs, reduced parkinsonian symptoms when injected systemically, though it did not restore completely normal motor behaviour. In contrast, ifenprodil, an antagonist for the NMDA receptor-associated polyamine modulatory site, when injected systemically at an optimal dose, resulted in apparently normal motor behaviour. These data suggest that attenuation of EAA transmission could be used to treat parkinsonism.
In the MPTP-treated primate model of Parkinson's disease, loss of dopaminergic afferents to the striatum leads to increased activity in striatal efferents to the external segment of the globus pallidus. This pathway utilizes both GABA and enkephalin as cotransmitters. Little is known regarding either the role of this cotransmission in the generation of parkinsonian symptoms or of the nature of any functional interaction between GABA and enkephalin. We have investigated the roles played by enkephalin and GABA in mediating parkinsonian symptoms by injection the GABAA antagonist bicuculline and the broad spectrum opioid antagonist naloxone directly into the globus pallidus in the reserpine-treated rat model of parkinsonism. Injections of bicuculline, but not naloxone, had marked antiparkinsonian effects. However, naloxone attenuated the antiparkinsonian effects of bicuculline. We interpret these findings as suggesting that increased GABAergic transmission in the globus pallidus is responsible for the generation of parkinsonian symptoms in the reserpine-treated rat. However, overactive enkephalinergic transmission is not responsible for the generation of symptoms and appears to act to reduce the effects of increased GABAergic transmission. In complementary studies in vitro, we have demonstrated a potential mechanism for this negative interaction. Met-enkephalin (3-10 microM) reduced depolarization-evoked release of GABA from terminals in slices prepared from rat globus pallidus (IC50, 0.38 microM). A better comprehension of the mechanisms by which enkephalin and other peptides modulate the action of amino acid transmitters in the basal ganglia is critical to the understanding of the neural processes underlying basal ganglia function and movement disorders.