Quinolinic Acid Lesions Research Articles

Discrete quinolinic acid lesions of the rat prelimbic medial prefrontal cortex affect cocaine- and MK-801-, but not morphine- and amphetamine-induced reward and psychomotor activation as measured with the place preference conditioning paradigm

As a part of the mesocorticolimbic system, the medial prefrontal cortex (mPFC) is thought to participate in the regulation of locomotor activity, motivation and reward. The mPFC consists of at least three different subareas. In previous lesion studies examining this region usually large parts of the mPFC were destroyed, with little discrimination between the different subareas. Therefore, this study was designed to selectively lesion the prelimbic area of the mPFC using a relatively low dose of quinolinic acid. In a conditioned place preference (CPP) experiment, lesioned and control animals were treated with cocaine (15 mg/kg), amphetamine (4 mg/kg), morphine (10 mg/kg) or MK-801 (0.3 mg/kg) to induce CPP. The lesion blocked the development of CPP only in animals receiving cocaine, but not in animals receiving amphetamine or morphine. MK-801 failed to produce a CPP in both lesioned and unlesioned animals. During the conditioning experiment, the acute locomotor response to the different drugs was also measured. Only the response (in terms of locomotion and rearing) to cocaine and MK-801 was reduced to a significant extent by the lesion, while the response to amphetamine and morphine was not affected. Also, the lesions did not cause any changes in the spontaneous activity of the animals when tested without drug. These results show that even small lesions of the prelimbic subarea of the mPFC are sufficient to produce behavioral effects. However, these are apparent only when the animals are challenged with cocaine or MK-801, but not with amphetamine or morphine, or when drug-free. This suggests that the mPFC might have a special role in mediating cocaine and MK-801 effects.

The development of cocaine-induced behavioral sensitization is affected by discrete quinolinic acid lesions of the prelimbic medial prefrontal cortex

The brain circuitry thought to be involved in the development of behavioral sensitization to psychostimulants consists of the mesocorticolimbic dopaminergic system and its afferent and efferent structures, including the medial prefrontal cortex (mPFC). The mPFC can be further subdivided into several regions, one of which being the prelimbic area (PL). This study sought to examine the role that the PL mPFC plays in the development of cocaine-induced behavioral sensitization. Intact and lesioned animals were treated with cocaine (10 mg/kg) or saline once daily for 14 days and tested in an open field and in a `sniffing box' on day 1, and then again on day 16, 48 h after the last drug injection. Behavioral parameters analyzed included locomotion, rearing, sniffing and grooming. It was found that the lesion affected the development of sensitization to cocaine. In the open field, lesioned animals showed a smaller increase in locomotion and rearing, but a larger increase in grooming as compared to the intact animals. While total sniffing scores in the sniffing box remained unchanged with repeated cocaine in the non-lesioned group, the lesioned group showed a decrease in sniffing. Finally, similar to what was seen in the open field, lesioned rats showed a strong tendency towards increased grooming. These results show that small discrete lesions of the PL mPFC can affect the development of behavioral sensitization to cocaine in a characteristic way. It is suggested that this effect might be mediated by the destruction of descending glutamatergic projections from the mPFC to the ventral tegmental area and/or nucleus accumbens.

The effects of globus pallidus lesions on dopamine-dependent motor behaviour in rats

Motor effects of bilateral lesions of the globus pallidus induced by quinolinic acid (30 and 60 nmol in 0.5 μl) were investigated in rats. Globus pallidus lesions with 60 nmol quinolinic acid produced a significant reduction of spontaneous motor activity measured by a reduced locomotor activity in an open field and by a reduced sniffing activity in an experimental chamber. In addition, d-amphetamine (1 mg/kg, i.p.)-induced hyperlocomotion and d-amphetamine (3 mg/kg, i.p.)-induced stereotyped sniffing were significantly reduced in animals with quinolinic acid lesions (60 nmol). Globus pallidus lesions with 60 nmol quinolinic acid potently reversed catalepsy induced by systemic administration of the dopamine D 1 receptor antagonist SCH23390 (0.75 and 1 mg/kg, i.p.) or the dopamine D 2 receptor antagonist raclopride (1.25 and 5 mg/kg, i.p.), while lesions with 30 nmol quinolinic acid exerted anti-cataleptic effects which were only partly significant. In line with current models of basal ganglia functions, these findings indicate that inactivation of the globus pallidus reduced spontaneous motor activity and motor hyperactivity after dopamine receptor stimulation. However, the present data also demonstrate that inactivation of the globus pallidus reversed motor hypoactivity induced by a blockade of dopamine D 1 and D 2 receptors. Therefore, a more complex functional model of the globus pallidus is required to account for the opposite effects on motor behaviour observed after lesions of this basal ganglia nucleus.

Electrolytic lesion of globus pallidus ameliorates the behavioral and neurodegenerative effects of quinolinic acid lesion of the striatum: a potential novel treatment in a rat model of Huntington's disease

Bilateral electrolytic pallidal lesion ameliorated the deleterious effects of bilateral quinolinic acid (QA) lesion to the striatum on post-surgery weight, activity level, and performance in a water maze task, and reduced the extent of striatal damage. Given that the neurodegenerative and behavioral effects of QA striatal lesion are thought to mimic those seen in Huntington's disease, these results may point to a potential novel treatment for this disease.

Potassium-stimulated taurine release and nitric oxide synthase activity during quinolinic acid lesion of the rat striatum.

The microdialysis technique was used to study the effect of nitric oxide synthase (NOS) activity on taurine release. Taurine release was characterized in rat striatum that was excitotoxically lesioned compared to normal conditions. The basal taurine level of the dialysate decreased during quinolinate (QUIN) lesion in parallel to the cell degeneration process. The K+-stimulated taurine concentration also decreased during QUIN-lesion, but to an extent that was different from that of basal values. K+-stimulated taurine levels were further markedly lowered by coapplication of the NOS inhibitor L-NAME in control and in lesioned animals up to 30 days after QUIN-injection. Postdegenerative tissue did not show any NOS-dependency in K+-induced taurine release. We conclude that a substantial part of K+-induced taurine release depends on NOS-activity both in normal brain tissue and in excitotoxically induced neurodegeneration. The main source of K+-induced taurine release in control rats are neurons but in lesioned animals are activated astroglial cells.

Differential involvement of the dorsal anterior cingulate and prelimbic-infralimbic areas of the rodent prefrontal cortex in spatial working memory.

The present study examined the effects of quinolinic acid lesions of the dorsal anterior cingulate and prelimbic-infralimbic cortices on spatial working memory and spatial discrimination using go/no-go procedures. All testing occurred in a 12-arm radial maze. In a working memory task, rats were allowed to enter 12 arms for a cereal reward. Three or 4 arms were presented for a 2nd time in a session, which did not result in a reward. In a spatial discrimination task, rats had successive access to 2 different arms. One arm always contained a reward, and the other never contained a reward. Prelimbic-infralimbic lesions impaired spatial working memory but only produced a transient spatial discrimination deficit. Dorsal anterior cingulate lesions did not induce a deficit in either task. These findings suggest that the prelimbic-infralimbic cortices, but not the anterior cingulate cortex, are important in spatial working memory.

Electrolytic lesion of the globus pallidus reduces the neurodegenerative effects of quinolinic acid lesion of the striatum in the rat

Electrolytic lesion of the globus pallidus reduces the neurodegenerative effects of quinolinic acid lesion of the striatum in the rat

Electrolytic lesion of globus pallidus ameliorates the behavioral effects of quinolinic acid lesion of the striatum: A potential novel treatment in a rat model of Huntington's disease

Electrolytic lesion of globus pallidus ameliorates the behavioral effects of quinolinic acid lesion of the striatum: A potential novel treatment in a rat model of Huntington's disease

Grafts of EGF-responsive neural stem cells derived from GFAP-hNGF transgenic mice: trophic and tropic effects in a rodent model of Huntington's disease.

The present study examined whether implants of epidermal growth factor (EGF)-responsive stems cells derived from transgenic mice in which the glial fibrillary acid protein (GFAP) promoter directs the expression of human nerve growth factor (hNGF) could prevent the degeneration of striatal neurons in a rodent model of Huntington's disease (HD). Rats received intrastriatal transplants of GFAP-hNGF stem cells or control stem cells followed 9 days later by an intrastriatal injection of quinolinic acid (QA). Nissl stains revealed large striatal lesions in rats receiving control grafts, which, on average, encompassed 12.78 mm3. The size of the lesion was significantly reduced (1.92 mm3) in rats receiving lesions and GFAP-hNGF transplants. Rats receiving QA lesions and GFAP-hNGF-secreting grafts stem cell grafts displayed a sparing of striatal neurons immunoreactive (ir) for glutamic acid decarboxylase, choline acetyltransferase, and neurons histochemically positive for nicotinamide adenosine diphosphate. Intrastriatal GFAP-hNGF-secreting implants also induced a robust sprouting of cholinergic fibers from subjacent basal forebrain neurons. The lesioned striatum in control-grafted animals displayed numerous p75 neurotrophin-ir (p75NTR) astrocytes, which enveloped host vasculature. In rats receiving GFAP-hNGF-secreting stem cell grafts, the astroglial staining pattern was absent. By using a mouse-specific probe, stem cells were identified in all animals. These data indicate that cellular delivery of hNGF by genetic modification of stem cells can prevent the degeneration of vulnerable striatal neural populations, including those destined to die in a rodent model of HD, and supports the emerging concept that this technology may be a valuable therapeutic strategy for patients suffering from this disease.

N-Acetylaspartylglutamate (NAAG) protects against rat striatal quinolinic acid lesions in vivo

We examined the effects of N-acetylaspartylglutamate (NAAG), an endogenous peptide thought to be involved in neurotransmission and neuromodulation, on striatal quinolinate lesions, a rodent model of Huntington's disease. We found that NAAG (500 and 1000 nmol) co-injected with quinolinic acid significantly reduced lesion volumes (by 50% and 65%, respectively). A 1000 nmol dose of the non-hydrolyzable analogue, β-NAAG, also reduced quinolinic acid lesion volumes by 78.4%, indicating that the protection observed was not secondary to cleavage of NAAG into N-acetyl-aspartate (NAA) and glutamate. Likewise, co-injection of both NAA and glutamate (1000 nmol each) with quinolinic acid did not significantly alter the size of lesions. NAAG's protective effect may be mediated through actions on N-methyl- d-aspartate receptors or metabotropic glutamate receptors.

Glial cell line-derived neurotrophic factor attenuates the excitotoxin-induced behavioral and neurochemical deficits in a rodent model of Huntington's disease

The present study determined the effects of intraventricularly administered glial cell line-derived neurotrophic factor on the behavioral and neurochemical sequelae of unilateral excitotoxic lesions of the striatum. Distinct asymmetrical rotational behavior in response to peripheral administration of amphetamine (5 mg/kg) was noted one and two weeks following injections of quinolinic acid (200 nmol) into two sites in the left striatum. In rats given a single intraventricular injection of glial cell line-derived neurotrophic factor (10-1000 μg) 30 min before the toxin, amphetamine-induced rotational behavior was significantly attenuated. Analysis of Nissl-stained coronal sections showed marked neuronal loss in the striatum ipsilateral to the quinolinic acid injections, which was at least partially prevented by glial cell line-derived neurotrophic factor. D 1 and D 2 dopamine binding sites in the striatum, the majority of which are localized to subpopulations of GABAergic neurons, were decreased to a similar extent by quinolinic acid. Moreover, the reduction was attenuated by glial cell line-derived neurotrophic factor treatment to a similar degree, suggesting that the two subpopulations of GABAergic striatal output neurons are equally vulnerable to excitotoxic damage. Concomitant changes in neurotransmitter function as a result of the lesion were also observed: [ 3H]GABA uptake into striatal target tissues (globus pallidus and substantia nigra) was considerably reduced in the lesioned compared to the contralateral unlesioned tissues, as were [ 3H]choline and [ 3H]dopamine uptake into striatal synaptosomes. Similarly, striatal choline acetyltransferase activity was decreased by the lesion. Decrements in neuropeptide levels of similar magnitude were evident ipsilateral to the lesion; substance P, met-enkephalin and dynorphin A contents in the globus pallidus and substantia nigra were significantly reduced. Striatal somatostatin and neuropeptide Y levels were not altered. All of the neurochemical deficits induced by striatal quinolinic acid lesions were attenuated by intraventicular delivery of glial cell line-derived neurotrophic factor. Continuous intraventricular infusion of this trophic factor (10 μg/day) over a two-week period did not afford notable improvement compared to the single injection of 10 μg. In contrast, continuous infusion of brain-derived neurotrophic factor (10 μg/day) directly into the striatum did not affect any of the neurochemical parameters studied. However, neurotrophin-3 (10 μg/day) delivery into the striatum significantly increased [ 3H]GABA uptake, but only modestly affected [ 3H]choline uptake. The results indicate that glial cell line-derived neurotrophic factor counteracts neuronal damage induced by a striatal excitotoxic insult and support its potential use as a treatment for central nervous system disorders that may be a consequence of excitotoxic processes, such as Huntington's disease.

Changes in expression of ΔFosB and the Fos family proteins following NMDA receptor activation in the rat striatum

Receptor-induced expression of transcription factors of the activator protein-1 (AP-1) family in neurons occurs in a unique temporal pattern which regulates subsequent downstream gene expression. We investigated the expression of the Fos family proteins following injection of the NMDA receptor agonist quinolinic acid (QA) into the rat striatum. The c-Fos protein is rapidly and transiently expressed, followed by the sequential and overlapping expression in the same striatal neurons of FosB, from 4 to 8 h post-lesion and ΔFosB from 6 h to beyond 30 h post-lesion. Analysis confirms that mRNA transcripts of both fosB and alternatively spliced ΔfosB are expressed in the striatum after QA lesion. The Fos-related antigens Fra-1 and Fra-2 and three previously uncharacterized c-Fos-related proteins were additionally found in the striatum which do not increase following lesion. These proteins are related to the highly conserved DNA-binding domain of c-Fos but are not immunologically related to the FosB protein as has been previously reported for proteins induced following chronic stimulation of the striatum. We additionally demonstrate that the c-Fos and ΔFosB proteins expressed following QA lesion bind to the functional AP-1 site in the promoter of the nerve growth factor (NGF) gene, the regulation of which temporally and spatially coincides with the AP-1 protein increases in the QA-lesioned striatum. However, the levels of binding to the NGF AP-1 site do not increase throughout time following lesion despite the induced expression of Fos family proteins, suggesting that the regulation of the NGF gene in this paradigm does not simply involve increased binding to the AP-1 site in the NGF gene promoter.

The basolateral amygdala regulates sensorimotor gating of acoustic startle in the rat

The acoustic startle reflex is a co-ordinated contraction of the skeletal musculature in response to a sudden, intense sound. One form of startle plasticity, “prepulse inhibition”, is the normal suppression of the startle reflex when the intense startling stimulus is immediately preceded by a weak pre-stimulus. Prepulse inhibition is utilized as an operational measure of sensorimotor gating, and is significantly impaired in several neuropsychiatric disorders that are characterized by symptoms associated with central inhibitory deficits. In rats, prepulse inhibition is disrupted by central dopamine activation or by manipulations of limbic cortical structures including the prefrontal cortex and hippocampus. In the present study, we assessed prepulse inhibition in rats after surgical and pharmacologic manipulations of the basolateral amygdala. Quinolinic acid lesions of the basolateral amygdala significantly reduced prepulse inhibition without significantly changing startle amplitude. These lesions also blocked fear-potentiated startle, which is known to be regulated by the basolateral amygdala. The prepulse inhibition-disruptive effects of basolateral amygdala lesions were not reversed by systemic injection of the dopamine antagonist haloperidol at doses that totally restored prepulse inhibition in apomorphine-treated rats. In other studies, intra-amygdala infusion of the competitive N-methyl-d-aspartate antagonist dl-2-amino-5-phosphonovaleric acid (0, 0.15, 1.5, 4.5μg) dose-dependently reduced prepulse inhibition.These data suggest that the basolateral amygdala regulates sensorimotor gating by mechanisms that are independent of central dopamine hyperactivity.

DARPP-32-rich zones in grafts of lateral ganglionic eminence govern the extent of functional recovery in skilled paw reaching in an animal model of Huntington's disease.

Grafts of striatal tissue comprise two different types of tissue: regions with (P-zones) and without (NP-zones) neurons that express markers characteristic of the striatum, such as dopamine- and cyclic AMP-regulated phosphoprotein with a mol. wt of 32,000 (DARPP-32). It remains unclear whether P-zones alone play a crucial role in functional effects of striatal grafts in an animal model of Huntington's disease. The present study has been performed to determine: (i) the yield of DARPP-32-positive neurons in grafts of lateral ganglionic eminence; (ii) whether treatment of graft tissue with the spin-trapping agent alpha-phenyl-tert-butyl nitrone enhances the survival of implanted DARPP-32-positive neurons; and (iii) the relationship between the number of DARPP-32-positive neurons in the grafts and functional effects of the grafts on paw-reaching ability in rats with unilateral quinolinic acid lesions of the striatum. Dissociated tissue derived from the lateral ganglionic eminence of rat embryos (embryonic day 14), with or without addition of alpha-phenyl-tert-butyl nitrone (3 mM), was implanted into the quinolinic acid-lesioned striatum. Compared to unlesioned normal animals, rats with striatal lesions showed substantial impairment in paw-reaching ability, particularly on the side contralateral to the lesion, as judged from the number of pellets retrieved by each paw. Intrastriatal grafts gave rise to a significant improvement in paw-reaching ability. The mean total number of surviving DARPP-32-positive cells in grafts without alpha-phenyl-tert-butyl nitrone treatment was estimated at 115 x 10(3), which did not significantly differ from that in alpha-phenyl-tert-butyl nitrone-treated grafts. The paw-reaching scores were significantly correlated with the volumes of P-zones and the number of DARPP-32-positive neurons, but with neither the volumes of NP-zones nor the total graft volume. The results suggest that P-zones in striatal grafts mediate graft-derived functional recovery in a complex task such as skilled forelimb use. Although the antioxidant treatment with alpha-phenyl-tert-butyl nitrone failed to promote graft survival, the positive correlation between the yield of DARPP-32-positive cells in the graft and the extent of the functional recovery highly warrants further attempts to increase the yield of the striatal component in the graft.

Configural learning, spatial navigation, and amphetamine-induced activity spared with ibotenic acid but not quinolinic acid lesions of the dorsomedial thalamus in rats

The connections that the dorsomedial (MD) thalamus makes with the frontal cortex and hippocampus suggest that it should share in their functions. This study examined the role of the dorsomedial nucleus (MD) of the thalamus in learning tasks that require the use of compound cues and in amphetamine-induced locomotion. The cell-specific neurotoxins ibotenic acid and quinolinic acid were injected into MD, and the animals were tested on a configural tactile—olfactory task, on a matching-to-place task in a swimming pool, and on spontaneous and amphetamine-induced locomotion. The ibotenic acid lesions produced cell death that was relatively confined to MD, while the quinolinic acid lesions produced widespread thalamic cell death and calcium deposits. The control and the ibotenic acid groups were not different, but the quinolinic acid lesions produced significant impairments on all of the tasks. The results suggest that although the frontal cortex and hippocampus may participate in solving the tasks used in this study, the MD, despite its reciprocal connections, does not share their involvement. The quinolinic acid results suggest either that very large lesions are required to produce deficits or that other thalamic nuclei are involved in the behaviors that were measured.

Comparison of the autoradiographic binding distribution of [3H]-gabapentin with excitatory amino acid receptor and amino acid uptake site distributions in rat brain.

1. Gabapentin is a novel anticonvulsant with an unknown mechanism of action. Recent homogenate binding studies with [3H]-gabapentin have suggested a structure-activity relationship similar to that shown for the amino acid transport system responsible for the uptake of large neutral amino acids (LNAA). 2. The autoradiographic binding distribution of [3H]-gabapentin in rat brain was compared with the distributions for excitatory amino acid receptor subtypes and the uptake sites for excitatory and large neutral amino acids in consecutive rat brain sections. 3. Densitometric measurement of the autoradiographic images followed by normalisation with respect to the hippocampus CA1 stratum radiatum, was carried out before comparison of each binding distribution with that of [3H]-gabapentin by linear regression analysis. The correlation coefficients observed showed no absolute correlation was observed between the binding distributions of [3H]-gabapentin and those of the excitatory amino acid receptor subtypes. The acidic and large neutral amino acid uptake site distributions demonstrated a much closer correlation to the [3H]-gabapentin binding site distribution. The correlation coefficients for D-[3H]-aspartate, L-[3H]-leucine and L-[3H]-isoleucine binding site distributions were 0.76, 0.90 and 0.88 respectively. 4. Concentration-dependent inhibition by unlabelled gabapentin of autoradiographic binding of L-[3H]-leucine and L-[3H]-isoleucine was observed, with non-specific binding levels being reached at concentrations between 10 and 100 microM. 5. Excitotoxic quinolinic acid lesion studies in rat brain caudate putamen and autoradiography were carried out for the amino acid uptake sites mentioned above. The resulting glial infiltration of the lesioned areas was visualized by autoradiography using the peripheral benzodiazepine receptor specific ligand [3H]-PK11195. A significant decrease in binding density in the lesioned area compared with sham-operated animals was observed for D-[3H]-aspartate, L-[3H]-leucine, L-[3H]-isoleucine and [3H]-gabapentin, whilst [3H]-PK11195 showed a significant increase in binding density indicative of glial infiltration into the lesioned area. These results suggest that the gabapentin binding site and the acidic and LNAA uptake site may be present on cell bodies of a neuronal population of cells. 6. From these studies it appears that [3H]-gabapentin, L-[3H]-leucine and L-[3H]-isoleucine bind to the same site in rat brain. The inhibition of [3H]-gabapentin binding by the LNAA uptake system-specific ligand, BCH, suggests that [3H]-gabapentin may label this uptake site, termed system-L. Conversely these ligands could be labelling a novel site that coincidentally has a similar structure-activity relationship to this uptake site. These results suggest a novel mechanistically relevant site of action for gabapentin and may enable further anti-epileptic agents of this type to be developed.

Induction of cytosolic NADPH-diaphorase/nitric oxide synthase in reactive microglia/macrophages after quinolinic acid lesions in the rat striatum: an electron and light microscopical study.

Induction of nitric oxide synthase and increased production of nitric oxide in microglia may play a crucial role in neuronal damage and neurodegenerative disorders. In the present study we have used light and electron microscopical NADPH-diaphorase histochemistry as the visualization procedure for nitric oxide synthase to investigate the time-course and subcellular patterns of NADPH-diaphorase expression in microglia/macrophages of quinolinic acid-lesioned rat striatum. For light microscopy, NADPH-diaphorase histochemistry sections were stained with nitroblue tetrazolium, while for ultrastructural analysis the tetrazolium salt 2-(2'-benzothiazolyl)-5-styryl-3(4'-phthalhydrazidyl) tetrazolium chloride (BSPT) was applied. Light microscopical inspection revealed a progressively increasing number of positive cells with increasing intensity of NADPH-diaphorase staining in microglia/macrophages from day 1 after quinolinic acid injection onward. Electron microscopical examination revealed a membrane bound NADPH-diaphorase in quiescent microglia as well as in activated microglia/macrophages through all stages of the lesion studied. Predominantly membranes of the nuclear envelope and the endoplasmic reticulum were labeled with BSPT-formazan, while in advanced stages selective membrane portions of mitochondria, Golgi apparatus and plasmalemma were also stained. From day 5 onward after lesion induction, a very distinctive type of NADPH-diaphorase was observed, forming accumulations of electron-dense grains that were distributed differentially throughout cytoplasmic areas and phagocytic vacuoles. Dynamics of expression, unique cytosolic localization and occurrence exclusively in activated microglia/macrophages suggest that this particular NADPH-diaphorase activity probably reflects the inducible isoform of nitric oxide synthase, whereas the membrane-bound precipitate may represent the neuronal and/or the endothelial isoform of the enzyme.

Transplantation of human striatal tissue into a rodent model of Huntington's disease: Phenotypic expression of transplanted neurons and host-to-graft innervation

The present study was undertaken to investigate the phenotypic expression and integration of human striatal neurons transplanted into an animal model of Huntington's disease. Sprague-Dawley rats were anesthetized and subjected to quinolinic acid lesions of the left striatum. Three human fetal cadavers were utilized for transplantation in this study (7,8, and 10 weeks in gestation). The striatal primordia was dissected from each fetus and subsequently dissociated into cell suspensions. Following the initial lesion surgeries (3–4 months), the rats were reanesthetized and transplanted with human striatal cells (400,000 cells per rat). The animals were processed for histochemical analysis 9–17 weeks posttransplantation. Histochemistry was performed utilizing thionin (Nissl staining), acetylcholinesterase, NADPH-diaphorase, and antibodies against tyrosine hydroxylase and glial fibrillary acidic protein. Examination of stained brain sections demonstrate that human striatal transplants grow to fill a substantial portion of the remaining striatum, and contain clusters of immature and mature cells. Acetylcholinesterase activity is present in the transplant neuropil, varying in intensity, and distributed in a heterogeneous fashion. In addition, host afferent dopaminergic fibers penetrate into the transplant, and are occasionally found in patches. NADPH-diaphorase histochemistry revealed medium sized aspiny striatal neurons of donor origin in the transplants. The results of this study are similar to those obtained with rodent fetal striatal transplants, and suggest that human striatal tissue is capable of surviving, expressing normal striatal cell phenotypes, and receiving host dopaminergic innervation.

Metabotropic receptors in excitotoxicity: ( S)-4-carboxy-3-hydroxyphenylglycine (( S)-4C3HPG) protects against rat striatal quinolinic acid lesions

Striatal quinolinate lesions mimic many of the neuropathological characteristics of Huntington's disease. This excitotoxicity is mediated by combined activity of N-methyl-n-aspartate and metabotropic glutamate receptors (mGluRs). Using recently developed phenylglycine derivatives, ( S)-4-carboxy-3-hydroxyphenylglycine (( S)-4C3HPG) and (+)-α-methyl-4-carboxyphenylglycine ((+)-MCPG), we investigated the role of the different sub-classes of mGluRs in the in vivo excitotoxic process. ( S)-4C3HPG (500 and 1000 nmol), co-injected with quinolinic acid, significantly reduced lesion volumes by 52 and 89%, respectively, whereas the same doses of (+)-MCPG had no effect on lesion size. The differential actions of these two drugs at Group 1 and Group 2 metabotropic receptors may explain their differential effects. These observations confirm the important role of mGluRs in excitotoxicity and identify them as promising targets for intervention.

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. Entries into arms that were never baited were defined as reference memory errors; entries into baited arms from which the food already had been eaten were defined as working memory errors. In Experiment 1, 0.1 mg/kg scopolamine produced a significant increase in working and reference memory errors. Various doses of 3,4-DAP had no significant ameliorative effect on the mnemonic deficit. In Experiment 2, cholinergic function was impaired using a unilateral intra-nbm injection of quinolinic acid (120 nmol in 1.0 μl). These lesions reduced the levels of the cholinergic marker, choline acetyltransferase, in the cortex by more than 40%. Results showed that the nbm lesion animals were significantly more impaired on the working than reference memory component of the task. Physostigmine (0.01, 0.05, 0.10, 0.20, 0.50 mg/kg) dose-dependently decreased the number of working but not reference memory errors. 3,4-DAP (10 −8, 10 −6, 10 −4, 10 −2, 10 0 mg/kg) had no reliable effect. It was concluded that physostigmine, but not 3,4-DAP, ameliorates memory impairments following decreases in cholinergic function.