Neonatal ventral hippocampal lesions in male and female rats: effects on water maze, locomotor activity, plus-maze and prefrontal cortical GABA and glutamate release in adulthood.

Schizophrenia is characterized by diverse behavioural and neurochemical abnormalities that may be differentially expressed in males and females. Male rats with neonatal ventral hippocampal lesions (nVHL) have commonly demonstrated behavioural and neurochemical abnormalities similar to those in schizophrenia. Fewer studies have used female rats.

Subchronic MK-801 behavioural deficits in rats: partial reversal by the novel nitrate GT 1061.

Cognitive deficits are a core feature of schizophrenia that may be linked to abnormalities in GABA and nitric oxide (NO). Subchronic treatment with glutamate receptor antagonists produces similar deficits, providing a useful model to examine potential therapeutics. The present study investigated the effects of subchronic MK-801 (intraperitoneally; 0.

Excitotoxicity of quinolinic acid: modulation by endogenous antagonists.

Quinolinic acid (QUIN), a product of tryptophan metabolism by the kynurenine pathway, produces excitotoxicity by activation of NMDA receptors. Focal injections of QUIN can deplete the biochemical markers for dopaminergic, cholinergic, gabaergic, enkephalinergic and NADPH diaphorase neurons, which differ in their sensitivity to its neurotoxic action. This effect of QUIN differs from that of other NMDA receptor agonists in terms of its dependency on the afferent glutamatergic input and its sensitivity to the receptor antagonists.

Cognitive effects of neurotoxic lesions of the nucleus basalis magnocellularis in rats: differential roles for corticopetal versus amygdalopetal projections.

The cholinergic hypothesis states that cholinergic neurons of the basal forebrain nucleus basalis magnocellularis (nbm) that project to cortical and amygdalar targets play an important role in memory. Biochemical studies have shown that these target areas are differentially sensitive to different excitotoxins (e.g.

Neurosteroids and glutamate toxicity in fibroblasts expressing human NMDA receptors.

We characterized glutamate receptor-mediated toxicity in mouse fibroblasts expressing the human NR1a/2A or NR1a/2B NMDA receptor. After induction of NMDA receptors, cells in both lines died over a 24 h time period. This toxicity was associated with a progressive increase in the glutamate content of the media.

Neonatal exposure to the glutamate receptor antagonist MK-801: effects on locomotor activity and pre-pulse inhibition before and after sexual maturity in rats.

Neonatal lesions of the ventral hippocampus in rats lead to post- but not pre-pubertal behavioral changes suggesting adolescent onset of dopaminergic hypersensitivity and providing an animal model of schizophrenia. Neonatal exposure to glutamate receptor antagonists produces accelerated apoptosis leading to neuronal loss in central nervous system structures including the hippocampus. This suggested that neonatal MK-801 might lead to behavioural changes like those reported following ventral hippocampal lesions.

Neuroprotection against ischemic brain injury conferred by a novel nitrate ester.

Nitrates exhibit a selectivity of action in different tissue types not fully recognized: in particular, the neuromodulatory and cardiovascular properties can be dissociated. A novel nitrate showed relatively weak systemic effects, but in the middle cerebral artery occlusion rat model of focal ischemia, reduced the cerebral infarct by 60-70% when administered 4 h after the onset of ischemia.

Neurosteroids and reward: allopregnanolone produces a conditioned place aversion in rats.

The neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone) has been reported to have rewarding properties in mice tested for place conditioning. Another study found that allopregnanolone reduced dopamine (DA) output in the nucleus accumbens (NAc) of rats. As many rewarding stimuli increase accumbens DA, these results may appear contradictory.

Nucleus basalis injections of N-methyl-D-aspartate enhance memory of rats in the double Y-maze.

N-methyl-D-aspartate (NMDA) receptors have been implicated in learning and memory. Many findings show that NMDA receptor antagonists impair memory. Few studies, however, have investigated the role of NMDA receptor agonists in mnemonic function.

Quinolinic acid lesion of the nigrostriatal pathway: effect on turning behaviour and protection by elevation of endogenous kynurenic acid in Rattus norvegicus.

Endogenous excitotoxins have been implicated in degeneration of nigral dopaminergic neurons in Parkinson's disease. It may be possible to reduce neurodegeneration by blocking the effects of these endogenous agents. The present study shows that contralateral turning seen following quinolinic acid-induced lesions of the nigrostriatal dopaminergic pathway was reversed by a treatment that increased brain levels of kynurenic acid, an endogenous excitatory amino acid antagonist.

Modulation of quinolinic acid-induced depletion of striatal NADPH diaphorase and enkephalinergic neurons by inhibition of nitric oxide synthase.

The present study was designed to examine the role of nitric oxide (NO) in quinolinic acid (QUIN)-induced depletion of rat striatal nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase and enkephalinergic neurons. Intrastriatal injection of QUIN produced a dose-dependent decrease in NADPH diaphorase and enkephalin positive cells, with cell loss being evident following the injection of 6 and 18 nmol QUIN, respectively. To evaluate the role of NO in QUIN-induced toxicity, animals were pretreated with the non-specific nitric oxide synthase (NOS) inhibitor, Nomega-nitro-l-arginine (l-NAME) or the selective neuronal NOS inhibitor, 7-nitro indazole (7-NI).

Role of zinc in blockade of excitotoxic action of quinolinic acid by picolinic acid.

This study examined whether picolinic acid (PIC) inhibits quinolinic acid (QUIN)-induced excitotoxicity through zinc chelation. Injection of QUIN into the nucleus basalis magnocellularis significantly depleted cortical choline acetyltransferase activity 7 days post injection and PIC inhibited this response. Zinc augmented the QUIN- but not NMDA-induced response.

Modulation of striatal quinolinate neurotoxicity by elevation of endogenous brain kynurenic acid.

1. Nicotinylalanine, an inhibitor of kynurenine metabolism, has been shown to elevate brain levels of endogenous kynurenic acid, an excitatory amino acid receptor antagonist. This study examined the potential of nicotinylalanine to influence excitotoxic damage to striatal NADPH diaphorase (NADPH-d) and gamma-aminobutyric acid (GABA)ergic neurones that are selectively lost in Huntington's disease.

Protection against quinolinic acid-mediated excitotoxicity in nigrostriatal dopaminergic neurons by endogenous kynurenic acid.

Endogenous excitotoxins have been implicated in the degeneration of dopaminergic neurons in the substantia nigra compacta of patients with Parkinson's disease. One such agent quinolinic acid is an endogenous excitatory amino acid receptor agonist. This study examined whether an increased level of endogenous kynurenic acid, an excitatory amino acid receptor antagonist, can protect nigrostriatal dopamine neurons against quinolinic acid-induced excitotoxic damage.

Malonate-induced degeneration of basal forebrain cholinergic neurons: attenuation by lamotrigine, MK-801, and 7-nitroindazole.

Previously, we have reported that intranigral infusions of malonate, an inhibitor of mitochondrial function, lead to the degeneration of the dopaminergic neurons of the nigrostriatal pathway that is mediated, at least in part, through NMDA receptor activation and nitric oxide formation. In the present study, unilateral focal infusions of malonate into the nucleus basalis magnocellularis (nbM) of male Sprague-Dawley rats (weighing 250-300 g) resulted in a dose-related depletion in ipsilateral cortical and amygdaloid choline acetyltransferase (ChAT) activity. Infusion of a 3 mumol dose of malonate into the nbM of vehicle-treated animals resulted in a 41 and 54% decrease in cortical and amygdaloid ChAT activity, respectively.

Differential action of 7-nitro indazole on rat brain nitric oxide synthase.

We examined the dose-response characteristics of brain nitric oxide synthase (NOS) inhibition following intraperitoneal administration of 7-nitro indazole (7-NI). 7-NI inhibited striatal, hippocampal, cortical, cerebellar and nigral NOS activity in a dose-dependent manner. NOS activity in the striatum and hippocampus could not be inhibited more than 60% while cerebellar and nigral activity was depleted by at least 85%, indicating that 7-NI has differential effects in different brain regions.

Attenuation of malonate-induced degeneration of the nigrostriatal pathway by inhibitors of nitric oxide synthase.

Focal infusions of the succinate dehydrogenase inhibitor, malonate, into the substantia nigra pars compacta (SNc) of adult Sprague-Dawley rats resulted in a substantial depletion of ipsilateral striatal tyrosine hydroxylase (TH) activity. The percentage decrease in striatal TH activity following intranigral malonate (0.5 mumol/0.

Differential action of NMDA antagonists on cholinergic neurotoxicity produced by N-methyl-D-aspartate and quinolinic acid.

1. Injections of N-methyl-D-aspartate (NMDA) and quinolinic acid (Quin), agonists that activate NMDA receptors, into the rat nucleus basalis magnocellularis (nbM) produced a dose-related decrease in cholineacetyltransferase (ChAT) activity in the cerebral cortex and amygdala 7 days after injection. 2.

Involvement of adenosine and glutamate receptors in the induction of c-fos in the striatum by haloperidol.

The psychostimulant drugs amphetamine and cocaine induce the expression of immediate early genes, such as c-fos, in the striatum via D1 dopamine receptor activation. This occurs primarily in the striato-nigral neurons. Conversely, neuroleptic drugs, such as haloperidol, which block D2-type dopamine receptors, induce c-fos expression in striatal neurons projecting to the globus pallidus.

Physostigmine, but not 3,4-diaminopyridine, improves radial maze performance in memory-impaired rats.

The results of some studies suggest that 3,4-diaminopyridine (3,4-DAP), a drug that enhances the release of acetylcholine, may improve memory. The present study examined the ability of 3,4-DAP to reverse the memory impairment produced by scopolamine and the ability of 3,4-DAP and physostigmine to reverse the memory impairment produced by quinolinic acid lesions of the nucleus basalis magnocellularis (nbm) in rats. Mnemonic functioning was assessed with the use of a partially baited eight-arm radial maze.

Enhancement of 7-nitro indazole-induced inhibition of brain nitric oxide synthase by norharmane.

7-Nitro indazole (7-NI) has been used as a selective inhibitor of neuronal nitric oxide synthase (NOS) in vivo. This agent has a short duration of action which may be due to its metabolism. The structure of 7-NI resembles that of tryptophan which can be metabolized by the enzyme indolamine 2,3-dioxygenase (IDO).

Excitotoxic action of NMDA agonists on nigrostriatal dopaminergic neurons: modulation by inhibition of nitric oxide synthesis.

Focal infusions of N-methyl-D-aspartate (NMDA) or an endogenous NMDA agonist, quinolinic acid (QUIN), into the substantia nigra pars compacta (SNc) of adult Sprague-Dawley rats resulted in a dose-dependent depletion of ipsilateral striatal tyrosine hydroxylase (TH) activity, a biochemical marker for dopaminergic neurons. To assess the intermediary role of nitric oxide in the neurotoxicity elicited by these toxins, their action was tested in animals treated with N omega-nitro-L-arginine methyl ester (L-NAME). Systemic injections (2 injections; 8 h apart) of L-NAME (100, 150 and 250 mg/kg) produced a dose-related inhibition of cerebellar nitric oxide synthase (NOS) activity.

Nucleus basalis lesions: implication of basoamygdaloid cholinergic pathways in memory.

Previous studies have shown a lack of association between cortical choline acetyltransferase (ChAT) activity and severity of memory impairment following excitotoxic lesions of the nucleus basalis magnocellularis (NBM). It recently has been proposed that the differential effects of NBM injections of various excitotoxins on amygdaloid and cortical ChAT may explain this result. The present study evaluated the mnemonic effect of unilateral intra-NBM infusions of the excitotoxins phthalic acid and quisqualic acid, which decrease ChAT activity primarily in the amygdala and cortex, respectively.

Picolinic acid protects against quinolinic acid-induced depletion of NADPH diaphorase containing neurons in the rat striatum.

Previous studies in our laboratory have demonstrated that focal injections of picolinic acid (PIC) protect the cholinergic neurons of the nucleus basalis magnocellularis (nbm) against quinolinic acid (QUIN)-induced neurotoxicity. The present study was designed to examine the effects of chronic infusions of QUIN and PIC on nicotinamide adenine dinucleotide (NADPH) diaphorase containing neurons of the rat striatum. Using osmotic minipumps, QUIN (6 nmol/h) and PIC (18 nmol/h) were infused alone or in combination to examine the neurotoxic effects of QUIN and the potential anti-neurotoxic action of PIC.

Basal forebrain injections of the benzodiazepine partial inverse agonist FG 7142 enhance memory of rats in the double Y-maze.

Cholinergic replacement strategies have achieved little success in the treatment of Alzheimer's disease. It has been suggested that the mnemonic function of cholinergic neurons may be enhanced by treatments that reduce GABA-ergic inhibition, while preserving the normal pattern of activity in the cholinergic neurons. Following on these suggestions, the present study investigated the mnemonic effects of intra-nucleus basalis magnocellularis (NBM) injections of the benzodiazepine receptor partial inverse agonist N-methyl-beta-carboline-3-carboxamide (FG 7142).