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ABSTRACT: The cannabinoid receptor agonists delta9-tetrahydrocannabinol (delta9-THC) and HU-210 were compared in terms of their effects on: (1) progressive ratio (PR) responding for food, and (2) free food intake. In the first experiment, food-deprived Wistar rats were trained on a time-constrained (60 min) PR-5 schedule for food reinforcement, in which the response requirement incremented by five lever presses for each successive reinforcer. One group of rats received vehicle, 0.5, 1 or 3 mg/kg delta9-THC (i.p.), and three other groups received HU-210 (i.p.) at three different dose ranges, spanning 0.001-0.1 mg/kg. In the second experiment, the effects of the two drugs on free food intake were tested in a separate group of non-deprived rats. For PR responding, delta9-THC significantly increased the break point (final ratio completed) and the total number of lever presses emitted. The same drug also significantly increased free food intake. However, the effects of HU-210 were quite different: it did not alter PR responding at any dose; instead, its only significant effect was to reduce free food intake at 0.06 mg/kg. These data suggest that increased motivation to obtain food might underlie the hyperphagic effects of delta9-THC. However, the synthetic agonist HU-210 has different effects: it only acts to reduce feeding behaviour, an outcome that probably reflects non-specific behavioural disruption. These findings suggest important differences between the two CB1 receptor agonists in terms of their pharmacological effects.
Behavioural Pharmacology 10/2005; 16(5-6):389-93. · 2.72 Impact Factor
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ABSTRACT: 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.
Neuroscience 02/2002; 109(1):89-99. · 3.38 Impact Factor
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ABSTRACT: 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.
Brain Research 03/2000; 855(1):1-10. · 2.73 Impact Factor
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ABSTRACT: 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.
Progress in Neurobiology 01/2000; 59(6):691-719. · 8.87 Impact Factor
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ABSTRACT: 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.
Brain Research 04/1999; 821(1):177-89. · 2.73 Impact Factor
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ABSTRACT: 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.
Neuroscience 05/1998; 84(2):489-501. · 3.38 Impact Factor
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ABSTRACT: 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.
Neuroscience Letters 01/1996; 201(3):251-4. · 2.11 Impact Factor
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ABSTRACT: 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.
Neuroscience Letters 11/1995; 198(3):153-6. · 2.11 Impact Factor
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ABSTRACT: 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.
Neuroscience Letters 08/1995; 194(1-2):73-6. · 2.11 Impact Factor
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ABSTRACT: 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.
Neuroscience Letters 04/1995; 187(3):189-92. · 2.11 Impact Factor
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ABSTRACT: The motor symptoms of Parkinson's disease are caused by an increase in activity of striatal neurons which project to the globus pallidus. The discharge activity of these striatal cells is normally regulated by a balance between an inhibitory nigral dopamine input and an excitatory cortical glutamate input. The loss of nigrostriatal dopamine in Parkinson's disease allows the cortical glutamatergic input to dominate (see Fig. 1). Pharmacological or surgical manipulations which redress this imbalance in activity in the striatum, or prevent its propagation throughout the basal ganglia, alleviate the motor symptoms of Parkinsonism. We present evidence to suggest the existence of an endogenous mechanism which compensates for the striatal imbalance during the early stages of Parkinsonism. In the rat rendered parkinsonian by systemic administration of reserpine, selective deletion of striatal neurons was observed. The dying striatal neurons exhibited all of the morphological and biochemical hallmarks of apoptosis. This apoptotic cell death was blocked by either administration of glutamate antagonists or decortication. Our data demonstrate that unchecked endogenous glutamate can induce apoptosis of striatal projection neurons in vivo. This observation may have relevance to the neurophysiological mechanisms which maintain the balance of neural activity within the CNS and to the pathology of neurological diseases.
Neuroscience 12/1994; 63(1):1-5. · 3.38 Impact Factor
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ABSTRACT: The motor symptoms of Parkinson's disease are caused by an increase in activity of striatal neurons which project to the globus pallidus.17 The discharge activity of these striatal cells is normally regulated by a balance between an inhibitory nigral dopamine input and an excitatory cortical glutamate input.24 The loss of nigrostriatal dopamine in Parkinson's disease allows the cortical glutamatergic input to dominate (see Fig. 1). Pharmacological or surgical manipulations which redress this imbalance in activity in the striatum, or prevent its propagation throughout the basal ganglia, alleviate the motor symptoms of Parkinsonism.2,4,14 We present evidence to suggest the existence of an endogenous mechanism which compensates for the striatal imbalance during the early stages of Parkinsonism. In the rat rendered parkinsonian by systemic administration of reserpine, selective deletion of striatal neurons was observed. The dying striatal neurons exhibited all of the morphological and biochemical hallmarks of apoptosis. This apoptotic cell death was blocked by either administration of glutamate antagonists or decortication. Our data demonstrate that unchecked endogenous glutamate can induce apoptosis of striatal projection neuronsin vivo. This observation may have relevance to the neurophysiological mechanisms which maintain the balance of neural activity within the CNS and to the pathology of neurological diseases.
Neuroscience.
