Age-dependence of malonate-induced striatal toxicity.

Malonate is an inhibitor of cellular metabolism, which, following intrastriatal injection, induces a striatal pathology similar to that seen in Huntington's disease. In two parallel studies, we have investigated the suggested relationship between the neuronal vulnerability to metabolic toxicity and the decline in metabolic function with increasing age. The first experiment investigated malonate-induced neuronal loss in animals aged from 6 weeks up to 27 months, and the second assessed the activities of two mitochondrial enzymes, succinate dehydrogenase and cytochrome oxidase (CYTOX) in animals aged 6 weeks, 3, 8 and 18 months. In the first study, male Lister-Hooded rats received intrastriatal stereotaxic injections of malonate (0.5 or 1.0 M). Animals were killed 10 days after surgery, and the brains were stained with cresyl violet and processed for NADPH-diaphorase activity and glial fibrillary-acidic-protein (GFAP) immunohistochemistry. Animals aged 6 months and older exhibited over 60% striatal neuronal loss. However, the degree of neuronal loss did not show any age-related increase in rats between 6 and 27 months of age, indicating that the extent of malonate-induced toxicity does not increase with age in animals older than 6 months. Infusion of 0.5 M malonate produced smaller lesions, which also demonstrated a consistent extent of neuronal loss from 6 months onwards. Metabolic enzyme activities were decreased in the striatum with increasing age, although this effect was only significant for CYTOX activity. Thus, the pattern of malonate-induced neuronal loss in aged animals partially reflects the changes in metabolic activity during ageing.

Effects of systemic 3-nitropropionic acid-induced lesions of the dorsal striatum on cannabinoid and mu-opioid receptor binding in the basal ganglia.

Systemic administration of 3-nitropropionic acid (3NPA) in experimental animals produces bilateral striatal lesions similar to those seen in Huntington's disease (HD) caudate and putamen. 3H[-CP55,940 binding to cannabinoid receptors in human basal ganglia nuclei has been shown to be highly susceptible to the earliest pathological changes in the HD brain. In this study, to assess further the suitability of 3NPA-induced striatal lesions as a model for HD neuropathology, we examined the effects of striatal lesions induced by the systemic administration of 3NPA on the binding of 3H[-CP55,940 to pre- and postsynaptic cannabinoid receptors in striatum, globus pallidus, entopeduncular nucleus and substantia nigra pars reticulata and also the effect of 3NPA-induced striatal lesions on the binding of 3H[-DAMGO to mu-opioid receptors in striatal striosomes. Systemic administration of 3NPA induced bilateral and symmetrical lesions in dorsolateral striatum. Within the lesion core, 3H[-CP55,940 and 3H[-DAMGO binding density was reduced to background levels. Beyond the immediate borders of the central core of the 3NPA-induced lesion, striatal binding density was not significantly different from that measured in unlesioned rats. 3H[-CP55,940 binding in globus pallidus, entopeduncular nucleus and substantia nigra in 3NPA-lesioned rats was significantly reduced compared to controls, and the individual decreases were similar for each site. However, these reductions were statistically marginal. These data suggest that, while producing striatal lesions which bear some similarity to those seen in HD, the consequences of 3NPA for striatopallidal and striatonigral efferent projections do not reflect the reported neurodegenerative changes seen in the HD brain.

The problem of antipsychotic treatment for functional imaging in Huntington's disease: receptor binding, gene expression and locomotor activity after sub-chronic administration and wash-out of haloperidol in the rat.

It has been demonstrated that withdrawal from chronic treatment with haloperidol is associated with a long-lasting increase in the number of striatal dopamine D(2) receptors and variable changes in D(1) receptors. We have investigated the effect of withdrawal from sub-chronic administration of haloperidol on the density of dopamine receptors, dopamine receptor gene expression, and spontaneous locomotor activity. Following a 3-week treatment period with haloperidol (1.5 mg/kg, i.p.), spontaneous locomotor activity measurements, autoradiography of D(1) and D(2) receptors and in situ hybridisation histochemistry of D(1) and D(2) mRNA were performed. Using [3H]raclopride as the ligand, sub-chronic haloperidol administration produced a robust upregulation in D(2) binding in the striatum of rats which correlated with parallel increases in spontaneous locomotor activity from 24 h to 4 weeks. Using, [3H]SCH23390 as the ligand, D(1) binding was largely unaffected by the drug treatment. Non-significant changes were measured in the striatal expression of D(1) receptor mRNA or the nigral or striatal expression of D(2) receptor mRNA. Our findings have implications for the use of dopaminergic ligands in positron emission tomography (PET) imaging of patients under regimens of chronic neuroleptics in particular in the context of forthcoming trials of neural grafts in Huntington's disease (HD) striatum.

3-Nitropropionic acid-induced changes in the expression of metabolic and astrocyte mRNAs.

Systemic administration of 3-nitropropionic acid (3NPA) in rats produces bilateral striatal lesions which are similar to those seen in Huntington's disease (HD). We examined the effects of systemic 3NPA on the expression of cytochrome oxidase (COX-II and COX-IV), succinate dehydrogenase (SDH) and astrocytic glial fibrillary acidic protein (GFAP) mRNAs and on the activity of COX and SDH as assessed by the density of histochemical staining. COX-II and COX-IV mRNA was reduced in rats with 3NPA-induced lesions, but not in those without, whereas SDH, but not COX, staining was significantly and dose-dependently reduced in both 3NPA treated groups. GFAP mRNA expression was increased in both intact striatum and cortex but was absent from the lesion core.

The cerebral metabolic effects of manipulating glutamatergic systems within the basal forebrain in conscious rats.

N-methyl-D-aspartate (NMDA) and non-NMDA receptor-mediated manipulations of the cortical cholinergic input arising from the basal forebrain differentially affect cognitive function. We used [14C]-2-deoxyglucose autoradiography in conscious rats to map the effects of excitatory amino acid agonist infusions into the nucleus basalis magnocellularis (NBM) on cerebral functional activity, as reflected by local rates of glucose utilization. Acute stimulation of NBM neurones by local infusion of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), 15 min before glucose use measurement, resulted in glucose use reductions in nine cortical regions innervated by NBM efferents including prefrontal, frontal, sensorimotor and cingulate cortices. NMDA infusions altered glucose use in two cortical areas. Both AMPA and NMDA markedly increased glucose use in the striatum and globus pallidus, with concomitant perturbations in striato-pallidal projection targets including the substantia nigra, entopeduncular nucleus, subthalamic nucleus and lateral habenular nucleus. In contrast, the GABAA agonist muscimol did not affect glucose use in the NBM or neocortical regions, but induced glucose use increases in several subcortical nuclei including the substantia nigra and entopeduncular nucleus. The delayed effects of excitotoxic lesions were assessed 3 weeks after basal forebrain infusions of AMPA, NMDA, ibotenate or quisqualate. Statistically significant glucose use changes only occurred in the hypothalamus after NMDA, and the NBM after ibotenate infusions, although reduced cortical metabolism was apparent following AMPA-induced lesions of the NBM. Results support a dissociation between the functional sequelae of NMDA and non-NMDA receptor-mediated events in the basal forebrain, and long-term compensatory functional adaptation following cortical denervation.

The expression of Huntingtin-associated protein (HAP1) mRNA in developing, adult and ageing rat CNS: implications for Huntington's disease neuropathology.

Using radioactive in situ hybridization, we have mapped the expression of Huntingtin-associated protein (HAP1) mRNA in rat brain at developmental stages (E12-E19, PO-P21), in adult rats (3 months) and in 'aged' (19-21 months) rats. Using two pairs of 45mer oligonucleotide probes specific for HAP1A and a probe which recognizes regions of both the HAP1A and HAP1B mRNA sequences (panHAP1), we find that the expression of HAP1 mRNA is specific to the CNS and restricted predominantly to anatomically connected limbic structures, particularly the amygdala (medial and corticomedial nuclei), the hypothalamus (arcuate, preoptic, paraventricular and lateral hypothalamic area), bed nucleus of the stria terminalis (BNST) and the lateral septal nuclei. HAP1 mRNA was detected in embryos at E12 and displayed a prevalent distribution in the developing limbic structures by E15. In aged, 19-21-months-old, rats there is a downregulation of HAP1 mRNA expression across all CNS loci where HAP1 was previously abundant. The lowest levels of HAP1 mRNA expression corresponded with the areas of greatest pathological cell loss in Huntington's disease (HD); the caudate putamen, globus pallidus and neocortex. These observations support the suggestion that HAP1 plays an important role in the neuropathology of HD.

Dissociation of apolipoprotein and apolipoprotein receptor response to lesion in the rat brain: an in situ hybridization study.

The epsilon4 allele of apolipoprotein E is associated with increased risk for developing Alzheimer's disease. To further understand the anatomical distribution of apolipoprotein E and its native receptors in the brain, we studied their messenger RNA expression in the adult rat brain under normal conditions and in response to an excitotoxic lesion to the hippocampus. In situ hybridization using oligonucleotide probes for apolipoprotein E, apolipoprotein J, the low density lipoprotein receptor, very low density lipoprotein receptor, low density lipoprotein receptor related protein, 39,000 mol. wt receptor-associated protein and glycoprotein 330/Megalin messenger RNA were performed on adjacent sections throughout the rat forebrain. Apolipoprotein E messenger RNA was abundantly expressed in the rat brain in both white and gray matter localizing to astrocytes but not neurons. Low density lipoprotein receptor-related protein and receptor-associated protein messenger RNA had a similar regional distribution but low density lipoprotein receptor-related protein messenger RNA was expressed by both neurons and glia, while the expression of receptor-associated protein messenger RNA was more highly expressed in neurons. Apolipoprotein J messenger RNA was expressed by neurons, glia and choroid plexus. The low density lipoprotein receptor and very low density lipoprotein receptor messenger RNA were found in both neurons and glia. Glycoprotein 330/Megalin messenger RNA was not detectable in the adult rat brain. In response to hippocampal lesions, apolipoprotein E and apolipoprotein J messenger RNAs were significantly up-regulated seven and 11 days post-lesion but the expression of low density lipoprotein receptor, low density lipoprotein receptor-related protein, receptor-associated protein, glycoprotein 330/Megalin, and very low density lipoprotein receptor messenger RNAs were unchanged. The expression of apolipoprotein E messenger RNA increased gradually beginning at three days while the expression of apolipoprotein J messenger RNA began to increase at seven days post-lesion. These findings further implicate apolipoproteins in the response of the brain to injury in vivo and suggest that transcriptional up-regulation of the apolipoprotein receptors studied is not a prominent feature in the response.

Abeta deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse.

The PDAPP transgenic mouse overexpresses human amyloid precursor protein V717F (PDAPP minigene) and develops age-related cerebral amyloid-beta protein (Abeta) deposits similar to senile plaques in Alzheimer's disease. We find age-related cortical and limbic Abeta deposition that begins at 8 months and progresses to cover 20-50% of the neuropil in cingulate cortex, entorhinal cortex, and hippocampus of 18-month-old heterozygotic animals. The regional patterns of transgene expression and amyloid deposition suggest that Abeta deposits occur at the terminals of overexpressing neurons. Amyloid deposition is associated with dystrophic neurites and extensive gliosis. However, stereological analysis shows that there is no overt neuronal loss in entorhinal cortex, CA1 hippocampal subfield, or cingulate cortex through 18 months of age. In addition, there is no apparent loss of mRNA encoding neuronal synaptic, cytoskeletal, or metabolic proteins. Thus, widespread Abeta deposition in 18-month-old heterozygotic mice produces neuritic alterations and gliosis without widespread neuronal death.

Distribution of the messenger RNA for the extracellularly regulated kinases 1, 2 and 3 in rat brain: effects of excitotoxic hippocampal lesions.

Neurofibrillary tangles in Alzheimer's disease are composed of hyperphosphorylated forms of the microtubule-associated protein tau. Based on biochemical criteria, several enzymes have emerged as potential tau protein kinases, including the extracellularly regulated kinases 1, 2 and 3. In situ hybridization was used to map the messenger RNA distribution of extracellularly regulated kinase 1, 2 and 3 in the adult rat brain and their response to excitotoxic hippocampal lesions was examined. Extracellularly regulated kinase 1 messenger RNA was uniformly expressed by glia, but was also present in the dentate gyrus and some other neuronal populations. Extracellularly regulated kinase 2 was exclusively neuronal and concentrated within the cortical laminae and the CA subfields of the hippocampal formation. Extracellularly regulated kinase 3 messenger RNA expression was similar to extracellularly regulated kinase 2 and was also present in neurons but the level of expression was lower. Extracellularly regulated kinases 2 and 3 messenger RNA expression was lost following excitotoxic injury, further supporting a neuronal localization. Extracellularly regulated kinase 1 messenger RNA expression appeared unaltered, suggesting a non-neuronal localization and lack of responsiveness to lesion at the level of transcription. By contrast, messenger RNA of sgk, a recently described serine/threonine kinase, was up-regulated by glial cells following excitotoxic injury. Based on their messenger RNA distribution, cellular localization and response to lesion, it is clear that each kinase may function differently in various signaling pathways. Extracellularly regulated kinase 2, however, is the only kinase with the proper messenger RNA distribution to contribute to neurofibrillary tangle formation in Alzheimer's disease.

Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells.

Mutations in two recently identified genes appear to cause the majority of early-onset familial Alzheimer's disease (FAD). These two novel genes, presenilin 1 (PS1) and presenilin 2 (PS2) are members of an evolutionarily conserved gene family. The normal biological role(s) of the presenilins and the mechanism(s) by which the FAD-associated mutations exert their effect remain unknown. Employing in situ hybridization, we demonstrate that the expression patterns of PS1 and PS2 in the brain are extremely similar to each other and that messages for both are primarily detectable in neuronal populations. Immunochemical analyses indicate that PS1 and PS2 are similar in size and localized to similar intracellular compartments (endoplasmic reticulum and Golgi complex). FAD-associated mutations in PS1 and PS2 do not significantly modify either their migration patterns on SDS-polyacrylamide gel electrophoresis or their overall subcellular localization, although subtle differences in perinuclear staining were noted for mutant PS1.

The distribution of neurons coexpressing immunoreactivity to AMPA-sensitive glutamate receptor subtypes (GluR1-4) and nerve growth factor receptor in the rat basal forebrain.

The regional distribution of neurons containing alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor (GluR1-4) subunit immunoreactivity, relative to the distribution of cholinergic neurons within the basal forebrain of rats, was assessed using single- and dual-antigen immunocytochemistry. Analysis of serial sections stained with antibodies to nerve growth factor receptor (NGFr) and antibodies against each of the AMPA receptor subunits, GluR1-4, revealed a regional codistribution between NGFr- and GluR1- and GluR4-immunoreactive neurons in the medial septum, diagonal band nuclei and nucleus basalis magnocellularis. Quantitative dual-labelling immunocytochemistry using NGFr in combination with each of the GluR antibodies revealed > 65% colocalization between NGFr and GluR4 in each of the major cholinergic nuclei in the basal forebrain and 10-15% colocalization between NGFr, GluR1 and GluR2-3. The reticular nucleus of the thalamus, a structure known to be highly susceptible to AMPA-induced neurotoxicity, expressed GluR4 immunoreactivity exclusively. The observation that cholinergic neurons of the basal forebrain are also highly sensitive to AMPA and express the GluR4 subunit suggests that GluR4 may be important in AMPA receptor-mediated excitotoxicity.

AMPA-induced lesions of the basal forebrain differentially affect cholinergic and non-cholinergic neurons: lesion assessment using quantitative in situ hybridization histochemistry.

The direct and transynaptic effects of lesions of the basal forebrain induced by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and ibotenic acid were investigated using quantitative in situ hybridization histochemistry. Probes complementary to the sequences of choline acetyltransferase mRNA, glutamate decarboxylase mRNA and preproenkephalin mRNA were used to assess direct lesion effects within the basal forebrain and probes for postsynaptic M-1 and M-3 muscarinic receptors were used to assess long-term changes in neocortical muscarinic receptor mRNA expression following cholinergic deafferentation. AMPA-induced basal forebrain lesions destroyed significantly more neurons that expressed choline acetyltransferase mRNA than ibotenic acid-induced lesions (90 versus 60%), but significantly fewer neurons which expressed either glutamate decarboxylase or preproenkephalin mRNA (61 versus 83% reduction in glutamate decarboxylase mRNA and 56 versus 79% reduction in preproenkephalin mRNA). AMPA-induced lesions did, however, destroy a significant proportion of the neurons which expressed glutamate decarboxylase and preproenkephalin mRNA (approximately 60%). The neurons spared following AMPA-induced lesions were typically situated dorsolaterally within the dorsal pallidum, although neurons expressing glutamate decarboxylase or preproenkephalin mRNA were frequently observed within the areas of greatest cholinergic neuronal loss, i.e. the region of the nucleus basalis magnocellularis. These findings suggest that there is a population of non-cholinergic pallidal neurons which are insensitive to AMPA but not to ibotenic acid, reflecting a possibly heterogeneous distribution of NMDA and non-NMDA subtypes of glutamate receptors within the rat basal forebrain. AMPA-induced lesions of the basal forebrain were, however, without significant effect on the levels of expression of M-1 and M-3 muscarinic receptor mRNAs in the cerebral neocortex.

Excitotoxic lesions of basal forebrain cholinergic neurons: effects on learning, memory and attention.

A substantial body of literature has suggested that the memory and learning deficits associated with Alzheimer's disease are attributable to degeneration of the cholinergic magnocellular neurons of the nucleus basalis of Meynert (nbM). Subsequently, lesion-induced damage to the cholinergic projections from the nbM to the neocortex has been utilized extensively as an animal model of dementia. Ibotenic acid lesions of the basal forebrain have been found, for example, to produce deficits in a wide variety of tasks involving learning and memory. However, recently, with the availability of more potent cholinergic excitotoxins such as AMPA, it has become apparent that nbM lesions do not provide a simple animal model of the cognitive deficits in ageing and Alzheimer's disease. Further analysis suggests that many of the learning and memory impairments traditionally attributed to the cholinergic corticopetal system are due not to destruction of cholinergic neurons in the nbM, but instead result from the disruption of cortico-striatal outputs passing through the dorsal and ventral globus pallidus. Furthermore, experiments utilizing quisqualic acid and AMPA have revealed that the most convincing deficit observed as a result of such lesions is in visual attention. This role for the basal forebrain-cortical cholinergic system in attentional function is further supported by results obtained from complementary pharmacological studies. This does not exclude a role for acetylcholine in learning and memory processes. Rather, such cognitive processes appear to depend not upon the integrity of the nbM itself, but upon more rostral elements of the cholinergic basal forebrain system.

Transsynaptic induction of c-fos in basal forebrain, diencephalic and midbrain neurons following AMPA-induced activation of the dorsal and ventral striatum.

In these experiments, induction of the immediate early gene c-fos following excitation of striatal neurons has been used to investigate the organization of the ventral and dorsal striatopallidal systems and the relationship between striatal neurons and cholinergic neurons of the nucleus basalis magnocellularis (of Meynert, nbM). The results demonstrate that FOS immunoreactivity (ir) can be detected in ventral and dorsal striatal neurons following infusions of the non-N-methyl-D-aspartic acid (NMDA) glutamate receptor agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA). This activation and increased expression of FOS in striatal neurons was itself associated with the sustained appearance of FOS-ir in neurons of the ipsilateral ventral and dorsal pallidum, subthalamic nucleus and some thalamic nuclei. Infusions of AMPA into the ventral striatum (VS), but not the dorsal striatum (DS), also resulted in the appearance of FOS-ir in a proportion (17%) of the cholinergic neurons of the nbM. By combining the retrograde transport of Fluoro-Gold with FOS immunocytochemistry, it was also possible to demonstrate that approximately 46% and 58% of the pallidal neurons containing FOS-ir after infusions of AMPA into the VS or DS, respectively, directly project to the subthalamic nucleus. Taken together, these observations suggest that visualizing the protein product of transsynaptic c-fos induction provides an effective way to study the topographic and transsynaptic, within-system consequences of striatal activation.

Differential activation and survival of basal forebrain neurons following infusions of excitatory amino acids: studies with the immediate early gene c-fos.

These experiments investigated, by studying patterns of c-fos expression, the distribution of neurons activated or destroyed by the infusion into the basal forebrain of various excitatory amino acids at toxic and subtoxic doses. The results of experiment 1 showed that N-methyl-D-aspartic acid (NMDA), quisqualic acid and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) differentially increased the expression of c-fos in magnocellular cholinergic nucleus basalis, dorsal and ventral pallidal neurons. AMPA was the most, and NMDA the least, effective in inducing FOS in nucleus basalis magnocellularis (nbM) neurons, with quisqualic acid having an intermediate effect, whereas the reverse was true in terms of the induction of FOS in pallidal neurons. In experiment 2, it was demonstrated that, in animals with ibotenic acid-induced lesions of the basal forebrain that were targetted on the nbM, virtually no pallidal neurons could be visualized that expressed FOS following AMPA-induced excitation of the dorsal and ventral striatum. By contrast, in animals with AMPA-induced lesions of the nbM, excitation of the striatum was followed by the expression of FOS in many dorsal and ventral pallidal neurons. Thus, infusions of AMPA into the basal forebrain appears preferentially to activate or destroy, depending on the concentration infused, cholinergic nbM neurons, whereas ibotenic acid or NMDA preferentially destroys or activates neurons of the dorsal and ventral pallidum. These results provide novel and complementary information regarding the organization of the basal forebrain and allow a clearer understanding of the different behavioural consequences of NMDA agonist-induced and non-NMDA agonist-induced excito-toxic lesions of this area.

Dissociable effects on spatial maze and passive avoidance acquisition and retention following AMPA- and ibotenic acid-induced excitotoxic lesions of the basal forebrain in rats: differential dependence on cholinergic neuronal loss.

Excitotoxic lesions of the basal forebrain were made by infusing either alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) or ibotenic acid. Acquisition and performance of spatial learning in the Morris water maze, over a ten day, two trials per day, training regimen were unaffected by the AMPA-induced lesions which reduced cortical choline acetyltransferase activity by 70%. However, acquisition was significantly impaired in rats with ibotenic acid-induced lesions that reduced cortical choline acetyltransferase by 50%. Additionally, ibotenic acid-lesioned rats swam further than either sham or AMPA-lesioned rats, in the "training" quadrant during a probe trial, in which the escape platform was removed, suggesting a perseverative search strategy. Lesions induced with AMPA, but not ibotenate, significantly impaired the acquisition of "step-through" passive avoidance. Both AMPA- and ibotenate-induced lesions significantly impaired the 96 h retention of passive avoidance, but the effect of AMPA was greater on latency measures. Histological analysis revealed that AMPA infusions destroyed more choline acetyltransferase-immunoreactive neurons than did ibotenate infusions but, unlike ibotenate, spared the overlying dorsal pallidum and also parvocellular, non-choline acetyltransferase-immunoreactive neurons in the ventral pallidal/substantia innominata region of the basal forebrain. The impairment in acquisition of the water maze following ibotenate-induced basal forebrain lesions therefore appears unrelated to damage to cholinergic neurons of the nucleus basalis of Meynert and to depend instead on damage to pallidal and other neurons in this area. The AMPA- and perhaps also the ibotenate-induced impairment in the retention of passive avoidance appears to be more directly related to destruction of cholinergic neurons of the nucleus basalis. These data are discussed in the context of cortical cholinergic involvement in mnemonic processes.

Comparative effects of ibotenic acid- and quisqualic acid-induced lesions of the substantia innominata on attentional function in the rat: further implications for the role of the cholinergic neurons of the nucleus basalis in cognitive processes.

Two experiments examined the effects of excitotoxic lesions of the substantia innominata on cholinergic activity in the neocortex and on performance in a paradigm measuring selective attention in the rat. In Expt. 1, ibotenate-induced lesions produced approximately 30% reductions in cortical choline acetyltransferase (ChAT) activity, and damage to wide regions of the substantia innominata and ventral pallidum. The rats were impaired in their ability to localize brief visual targets in a serial reaction time task, as measured by reduced choice accuracy. This impairment was particularly evident at short stimulus durations, but the lesioned rats did not exhibit evidence of primary visual sensory dysfunction and exhibited only minor deficits when the stimuli were presented unpredictably. The deficit was exacerbated when distracting white noise was interpolated into the task. The rats with lesions were also slower to respond correctly, probably resulting partly from the adoption of a speed/error trade-off strategy, and were slower to collect earned food pellets, although they made no more errors of omission than controls. In Expt. 2, quisqualate-induced lesions produced fewer signs of non-specific damage and 50% reductions in cortical ChAT activity. This lesion produced generally qualitatively similar, but weaker effects to those of ibotenate-induced lesions. It was notable that many of the deficits following either ibotenate- or quisqualate-induced lesions lasted for several months after surgery. The results are discussed in terms of the cholinergic hypothesis of cognitive dysfunction. It is argued that lesions of the substantia innominata, including the magnocellular cholinergic neurons of the nucleus basalis of Meynert, produce deficits in attentional processing, which may not result from damage specifically to cholinergic cells. However, the longevity of the effects makes these preparations suitable for further exploration of the restorative effects of cholinergic treatments.

Comparative effects of quisqualic and ibotenic acid-induced lesions of the substantia innominata and globus pallidus on the acquisition of a conditional visual discrimination: differential effects on cholinergic mechanisms.

Two experiments tested the hypothesis that the deficits in conditional discrimination learning produced by ibotenic acid-induced lesions of the ventral pallidum and substantia innominata are produced by loss of the magnocellular cholinergic cells in the nucleus basalis and adjacent regions. Experiment 1 replicated the previously reported deficit in conditional learning produced by ibotenate-induced lesions of the ventral pallidum/substantia innominata, but failed to demonstrate any restoration of learning by a subchronic regimen of the acetylcholinesterase inhibitor physostigmine sufficient to produce significant (30%), but equivalent, degrees of inhibition in the frontal cortex of ventral pallidum/substantia innominata-lesioned or sham-operated rats. Experiment 2 examined the effects of quisqualic acid-induced lesions of the ventral pallidum/substantia innominata. According to most of the measures of learning employed, the quisqualic acid-induced lesion of the ventral pallidum/substantia innominata failed to impair conditional learning, even though the quisqualate-induced lesion produced greater degrees of cholinergic neuron destruction than the ibotenate-induced lesion, as measured in terms of reductions in cortical choline acetyltransferase activity (44% vs 27%). Although consideration of individual data suggested that very high (60%) levels of choline acetyltransferase reduction in Experiment 2 might have detrimental effects of conditional learning, the overall failure of the quisqualate-induced lesions of the ventral pallidum/substantia innominata to impair learning is to be contrasted with the significant behavioural effects of ibotenate-induced lesions. Histological and immunocytochemical analysis showed that the quisqualate-induced lesion, unlike that produced by ibotenate, tended to produce less damage to the overlying dorsal globus pallidus and to parvocellular neurons of the ventral pallidum/substantia innominata, thus implicating these nonspecific effects of ibotenate-induced lesions in their behavioural effects. The present results question previous interpretations of the behavioural effects of ibotenate-induced lesions of the ventral pallidum/substantia innominata in terms of damage inflicted on the cortically-projecting cholinergic cells of the nucleus basalis, and suggest that quisqualic acid, although also nonspecific in its excitotoxic effects, is nevertheless more selective for producing damage to cholinergic neurons in the ventral pallidum/substantia innominata than ibotenic acid.