Deletion of the N-terminus of murine map2 by gene targeting disrupts hippocampal ca1 neuron architecture and alters contextual memory.

Microtubule-associated protein-2 (MAP2) is a brain specific A-kinase anchoring protein that targets the cyclic AMP-dependent protein kinase holoenzyme (PKA) to microtubules. Phosphorylation of MAP2 by different protein kinases is crucial for neuronal growth. The N-terminus of MAP2 contains the binding site for regulatory subunit II of cAMP-dependent protein kinase (PKA-RIIbeta). Using homologous recombination, we created a mutant line of mice (delta1-158) that express truncated MAP2 lacking the N-terminal peptide and the PKA binding site. Deletion of the PKA binding site from the MAP2 gene resulted in decreased efficiency of MAP2 phosphorylation. Biochemical and immunohistochemical studies demonstrate major changes in the morphology of hippocampal neurons in delta1-158 mice. Behavioral tests indicate that delta1-158 mice were impaired (exhibited less conditioned freezing) relative to Wild-Type (WT) controls during a test of contextual, but not during auditory cue, fear conditioning when tested at 8 weeks or 8 months of age. The delta1-158 mice displayed a heightened sensitivity to shock at 8 weeks, but not at 8 months of age. We conclude that PKA binding to MAP2 and MAP2 phosphorylation is essential for the selective development of contextual memory.

Methods for inducing neuronal loss in preweanling rats using intracerebroventricular infusion of kainic acid.

Excitotoxins, such as kainic acid (KA), have been shown to produce neuronal degeneration in the adult rat brain. While preweanling rats have been shown to be relatively resistant to the neurotoxicity of lower doses of KA, the presence of neuronal loss at higher doses (of KA) has only begun to be investigated in such animals. A reliable method of producing neuronal loss in preweanling rats is to administer nmol concentrations of KA via intracerebroventricular (i.c.v.) injections on postnatal day 7 (P7). Using a three-dimensional, non-biased cell counting technique, we have shown that neuronal loss is observed in the CA3 subfield of the hippocampal formation at P45 and P75. Further, immunohistochemical studies of markers for cell death may be useful to examine the types of cellular processes associated with such neuronal loss. Data from our own experiments suggest the activation of immediate-early genes in the neuronal loss produced by KA administration at P7. This developmental animal model of neuronal loss may be useful in studying neurodevelopmental disorders where the onset of symptoms or cognitive deficits is thought to follow an early developmental insult.

Maturation of locomotor and Fos responses to the NMDA antagonists, PCP and MK-801.

Antagonists at the N-methyl-D-aspartate (NMDA)-type glutamate receptor, such as phencyclidine (PCP) and dizocilpine (MK-801), are well-known to evoke increases in locomotor activity in adult rats and mice. However, little is known about the effects of NMDA antagonists on locomotor activity as a function of development. The present study examined locomotor responses to PCP or MK-801 in male rats of varying ages and found that prepubertal rats were more sensitive to the locomotor-elevating effects of PCP (1.5 mg/kg and 3. 0 mg/kg, s.c.) than were adults. Locomotor responses to MK-801 (0.1 and 0.2 mg/kg, s.c.) were not dependent on age. The age-dependent response to PCP may be related to developmental events in the motor cortex, since more Fos-immunoreactive neurons were observed in the motor cortex of prepubertal animals after PCP administration relative to adult animals. An opposite pattern of age-dependent Fos responses was observed in the posterior retrosplenial cortex. The results suggest that locomotor responses to NMDA antagonists can be influenced in an age- and drug-dependent manner and that maturational events in the motor cortex may modify responses to PCP.

Locomotor activity and accumbens Fos expression driven by ventral hippocampal stimulation require D1 and D2 receptors.

Numerous studies have suggested that excitatory projections from the ventral hippocampus to the nucleus accumbens modulate locomotor activity in rats. Furthermore, the ability of ventral hippocampal neurons to alter locomotor activity may involve the dense dopaminergic innervation found in the nucleus accumbens. The purpose of this study was to: (i) more fully characterize the locomotor effects of acute alterations in ventral hippocampal activity; (ii) ascertain the influence of dopamine agonists and antagonists on locomotor changes produced by altered ventral hippocampal activity; and (iii) use immediate early gene induction to determine whether dopamine antagonists alter the response of nucleus accumbens neurons to ventral hippocampal stimulation. By comparing a variety of excitatory amino acid agonists, it was found that ventral hippocampal infusion of N-methyl-D-aspartate elevated locomotor activity in a subconvulsive manner, while other excitatory amino acid receptor agonists did not. Inactivation of the ventral hippocampus achieved by lidocaine infusion did not suppress ongoing locomotor activity, nor did it affect amphetamine-induced increases in locomotor activity. Increases in locomotor activity induced by ventral hippocampal N-methyl-D-aspartate infusion were blocked by systemic administration of haloperidol (a D2 receptor antagonist), SCH-23390 (a D1 receptor antagonist) or reserpine. Cellular expression of the protein product of the immediate early gene, c-fos, was dramatically increased in the nucleus accumbens shell after ventral hippocampal N-methyl-D-aspartate infusion, and haloperidol, SCH-23390 and reserpine attenuated this effect. These results suggest that the increases, but not decreases, in ventral hippocampal activity have a measurable effect on ongoing rates of locomotion, and that this effect requires both D1 and D2 receptors. Moreover, the studies of Fos expression suggest that dopamine receptor antagonists attenuate neuronal responses to ventral hippocampal stimulation within the nucleus accumbens, a brain region important in the generation and maintenance of locomotor activity.

Gene targeting reveals a critical role for neurturin in the development and maintenance of enteric, sensory, and parasympathetic neurons.

Neurturin (NTN) is a neuronal survival factor that activates the Ret tyrosine kinase in the presence of a GPI-linked coreceptor (either GFR alpha1 or GFR alpha2). Neurturin-deficient (NTN-/-) mice generated by homologous recombination are viable and fertile but have defects in the enteric nervous system, including reduced myenteric plexus innervation density and reduced gastrointestinal motility. Parasympathetic innervation of the lacrimal and submandibular salivary gland is dramatically reduced in NTN-/- mice, indicating that Neurturin is a neurotrophic factor for parasympathetic neurons. GFR alpha2-expressing cells in the trigeminal and dorsal root ganglia are also depleted in NTN-/- mice. The loss of GFR alpha2-expressing neurons, in conjunction with earlier studies, provides strong support for GFR alpha2/Ret receptor complexes as the critical mediators of NTN function in vivo.

Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier.

The blood-brain barrier and a blood-cerebrospinal-fluid (CSF) barrier function together to isolate the brain from circulating drugs, toxins, and xenobiotics. The blood-CSF drug-permeability barrier is localized to the epithelium of the choroid plexus (CP). However, the molecular mechanisms regulating drug permeability across the CP epithelium are defined poorly. Herein, we describe a drug-permeability barrier in human and rodent CP mediated by epithelial-specific expression of the MDR1 (multidrug resistance) P glycoprotein (Pgp) and the multidrug resistance-associated protein (MRP). Noninvasive single-photon-emission computed tomography with 99mTc-sestamibi, a membrane-permeant radiopharmaceutical whose transport is mediated by both Pgp and MRP, shows a large blood-to-CSF concentration gradient across intact CP epithelium in humans in vivo. In rats, pharmacokinetic analysis with 99mTc-sestamibi determined the concentration gradient to be greater than 100-fold. In membrane fractions of isolated native CP from rat, mouse, and human, the 170-kDa Pgp and 190-kDa MRP are identified readily. Furthermore, the murine proteins are absent in CP isolated from their respective mdr1a/1b(-/-) and mrp(-/-) gene knockout littermates. As determined by immunohistochemical and drug-transport analysis of native CP and polarized epithelial cell cultures derived from neonatal rat CP, Pgp localizes subapically, conferring an apical-to-basal transepithelial permeation barrier to radiolabeled drugs. Conversely, MRP localizes basolaterally, conferring an opposing basal-to-apical drug-permeation barrier. Together, these transporters may coordinate secretion and reabsorption of natural product substrates and therapeutic drugs, including chemotherapeutic agents, antipsychotics, and HIV protease inhibitors, into and out of the central nervous system.

Delayed neuronal loss after administration of intracerebroventricular kainic acid to preweanling rats.

Excitotoxins, such as kainic acid (KA), have been shown to produce both immediate and delayed neuronal degeneration in adult rat brain. While preweanling rats have been shown to be resistant to the immediate neurotoxicity of KA, the presence of delayed neuronal loss has not been investigated in such animals. To determine whether intracerebroventricular (i.c.v.) administration of KA would produce delayed neuronal loss, preweanling rats were administered 5 nmol or 10 nmol KA i.c.v. on postnatal day 7 (P7) and then examined at P14, P45, and P75. Using three-dimensional, non-biased cell counting, neuronal loss was observed in the CA3 subfield of the hippocampal formation at P45 and P75 in animals administered 10 nmol KA, as compared to animals administered 5 nmol KA or artificial cerebrospinal fluid. Further, the amount of immunoreactivity to jun, the protein product of the immediate early gene, c-jun, adjusted for the number of remaining neurons was increased in the same brain areas. Antibody labeling of inducible heat shock protein and glial fibrillary acidic protein was not similarly increased in animals administered i.c.v. KA. The data suggest that while i.c.v. KA does not produce immediate neuronal loss in preweanling rats, the hippocampus is altered so that neuronal loss occurs after a delay, perhaps through apoptosis. These findings may be relevant to the pathogenesis of neuropsychiatric disorders, such as schizophrenia, that are characterized by early limbic-cortical deficits but onset of illness in young adulthood.

Progressive neurodegeneration after intracerebroventricular kainic acid administration in rats: implications for schizophrenia?

BACKGROUND: Intracerebroventricular (ICV) administration of kainic acid to rats produces limbic-cortical neuronal damage that has been compared to the neuropathology of schizophrenia. METHODS: Groups of adult rats were administered ICV kainic acid and then assessed for neuronal loss and the expression of proteins relevant to mechanisms of neuronal damage after one and fourteen days. Neuronal loss was assessed by two-dimensional cell counting and protein expression was assessed by immunohistochemistry. RESULTS: ICV kainic acid administration was associated with both immediate (day 1) and delayed (day 14) neuronal loss in the dorsal hippocampus. The immediate injury was largely limited to the CA3 hippocampal subfield, while the delayed injury included the CA1 subfield. Multiple mechanisms of cell death appeared to be involved in the delayed neuronal loss, as evidenced by changes in the expression of glutamate receptor subunits, heat shock protein and jun protein. CONCLUSIONS: ICV kainic acid administration to adult rats produces progressive damage to limbic-cortical neurons, involving both fast and slow mechanisms of cell death. Given the evidence for clinical deterioration, cognitive deficits and hippocampal neuropathy in some cases of schizophrenia, this animal model may be relevant for hypotheses regarding mechanisms of neurodegeneration in that disorder.

Induction of Fos protein by antipsychotic drugs in rat brain following kainic acid-induced limbic-cortical neuronal loss.

Antipsychotic drugs increase expression of the immediate early gene, c-fos, in the striatum, nucleus accumbens and prefrontal cortex of rat brain. Since intracerebro-ventricular (i.c.v.) infusion of kainic acid (KA) produces loss of limbic-cortical neurons that project to these brain areas, we postulated that the c-fos responses to antipsychotics in these brain areas would be altered following i.c.v. KA administration. To produce limbic-cortical lesions, rats received i.c.v. infusions of either KA (4.5 nmol) or vehicle. Then, 25 28 days later, rats received 0.13, 0.35, or 1.5 mg/kg haloperidol, 6.3, 17.5, or 30.0 mg/kg clozapine, or saline. In both KA-lesioned and control animals, haloperidol produced greater increases in Fos protein immunoreactivity in the striatum than in limbic-cortical areas, while clozapine produced greater increases in Fos protein immunoreactivity in limbic-cortical areas than in the striatum. In both KA-lesioned and control animals, haloperidol and clozapine administration also produced similar dose-dependent increases in Fos protein immunoreactivity in the striatum and nucleus accumbens. However, the ability of clozapine to increase Fos protein immunoreactivity in the infralimbic prefrontal cortex was significantly enhanced in KA-lesioned rats compared to controls. Since limbic-cortical pathology has been implicated in the negative symptoms of schizophrenia, the enhanced effect of clozapine on limbic-cortical expression of c-fos in KA-lesioned rats may be relevant to understanding clozapine's unusual therapeutic actions in patients with schizophrenia.

Haloperidol blocks increased locomotor activity elicited by carbachol infusion into the ventral hippocampal formation.

Previous studies have demonstrated that stimulation of the ventral hippocampal (VH) formation (including the ventral CA1 and subicular areas) elicits increased locomotor activity in rats. The locomotor-activating effects of VH stimulation have been hypothesized to be mediated via hippocampal output to cortical and subcortical dopamine (DA) systems. This study examined whether increased locomotor activity produced by VH stimulation was blocked by pretreatment with a DA receptor antagonist, and whether DA metabolism in subdivisions of the nucleus accumbens, caudate-putamen, and prefrontal cortex was elevated by VH stimulation. Stimulation of the VH (defined as the ventral CA1 and its borders, ventral subiculum, and entorhinal cortex) with the cholinergic agonist carbachol was found to elevate locomotor activity, while pretreatment with the D2 receptor antagonist haloperidol blocked this effect. Stimulation of the VH did not alter DA metabolism (i.e., ratio of the DA metabolites DOPAC or HVA/DA) in any of the brain regions studied. These results indicate that the increased locomotor activity elicited by VH stimulation is not associated with dramatic increases in DA metabolism, but that it does require tonic activation of D2 receptors.

Limbic-cortical neuronal damage and the pathophysiology of schizophrenia.

Neurobiological studies of patients with schizophrenia suggest that abnormalities of both anatomy and function occur in limbic-cortical structures. An anatomical circuit links the functioning of the ventral striatum (i.e., nucleus accumbens) with the hippocampus and other limbic-cortical structures where neurobiological abnormalities have been found. In animals, lesions of limbic-cortical neurons cause decreases in glutamatergic input to the nucleus accumbens and are also associated with decreases in presynaptic dopamine release, increases in the density of D2-like dopamine receptors, and insensitivity to the actions of dopamine antagonists such as haloperidol. These experiments suggest a plausible pathophysiology of schizophrenia, in that schizophrenic symptoms may be caused by an abnormal dopaminergic state brought about by a primary limbic-cortical lesion and deficits in glutamatergic inputs to the ventral striatum.

Glucocorticoid interactions with memory function in schizophrenia.

Glucocorticoid (GC) exposure can affect brain function, including potential adverse effects on hippocampal physiology and on specific elements of cognitive performance. In a prior study of healthy adult humans, decreased verbal memory performance was detected during four days of double-blind, placebo-controlled dexamethasone (DEX) treatment. Using an identical experimental design and sample size (n = 19), the cognitive effect of DEX treatment was studied in 11 subjects with schizophrenia, compared with 8 receiving placebo. In contrast to the effect in healthy adults, GC treatment with DEX at this dose (cumulative 3.5 mg) and duration did not decrease verbal memory performance or other measures of cognitive function in the patients with schizophrenia. When data from this experiment was compared with data from the previous study of healthy adults, covarying differences in baseline memory performance, a significant 3-way interaction was detected between subject group, treatment condition, and the repeated measurements of verbal memory performance across baseline, treatment and washout (F[3,87] = 4.84, p = .0066), suggesting differential cognitive effects of DEX in the patients versus the previously studied healthy subjects. Baseline plasma cortisol concentrations (0800 h) prior to DEX treatment were inversely correlated with baseline delayed (rs = -0.536, p = .03) verbal recall performance, supporting a previous report. The current results await replication using a larger sample size but provide preliminary evidence for an altered behavioral response to acute GC exposure in schizophrenic versus healthy subjects, and further evidence for a relationship between chronic changes in circulating cortisol and the memory impairments found in this disorder.

Higher cerebrospinal fluid MHPG in subjects with dementia of the Alzheimer type. Relationship with cognitive dysfunction.

The authors sought to determine the relationships between cerebrospinal fluid (CSF) levels of three neurotransmitter monoamine metabolites and cognitive function. CSF was collected from subjects with dementia of the Alzheimer's type ([DAT] n = 28) and control subjects (n = 10) for determination of CSF 5-hydroxyindole acetic acid (5-HIAA), 3-methoxy-4-hydroxy-phenylglycol (MHPG), and homovanillic acid (HVA) levels. All subjects underwent systematic assessment to determine cognitive function. Subjects with DAT had higher concentrations of CSF MHPG. In the overall sample, cognitive function was inversely correlated with CSF levels of MHPG but not with 5-HIAA or HVA. Within the DAT sample, these correlations did not achieve significance.

The effects of kainic acid lesions on locomotor responses to haloperidol and clozapine.

Spontaneous and amphetamine-elicited locomotor activity in rats is reduced by most clinically effective antipsychotic drugs. We have recently demonstrated that intracerebroventricular infusion of kainic acid (KA), which produces cell loss in the hippocampus and other limbic-cortical brain regions, increases spontaneous and amphetamine-elicited locomotion. The present study determined if KA lesions alter the suppressive effects of the antipsychotic drugs, haloperidol and clozapine, on spontaneous and amphetamine-elicited locomotor behavior. Young adult male rats (70 days of age) received intracerebroventricular infusions of vehicle or KA, which produced hippocampal pyramidal cell loss in each rat and more variable cell loss or gliosis in the amygdala, piriform cortex, and laterodorsal thalamus. Thirty days post-surgery, lesioned and control rats were tested once a week for locomotor responses to drug treatments. As observed previously, spontaneous locomotor activity and hyperactivity elicited by amphetamine (1.50 mg/kg s.c.) were greater in lesioned animals than controls. In addition, the level of spontaneous activity and/or amphetamine-elicited hyperlocomotion observed in lesioned rats after haloperidol treatment (0.13, 0.35, or 1.50 mg/kg s.c.) was greater than that found in controls. Locomotor responses to low (6.30 mg/kg) and moderate doses of clozapine (20 mg/kg) were similar in lesioned and control rats, although lesioned rats were more active than controls following the administration of a high dose of clozapine (30 mg/kg). These data indicate that the hyperactivity associated with limbic-cortical lesions may be insensitive to reversal by haloperidol, yet uniquely sensitive to suppression by clozapine.

The effects of kainic acid lesions on dopaminergic responses to haloperidol and clozapine.

The antipsychotic drugs haloperidol and clozapine have the common action of increasing dopamine metabolism in the striatum (nucleus accumbens, caudate-putamen) of the rat. Intracerebroventricular administration of kainic acid (KA) produces neuronal loss in limbic-cortical brain regions which project directly or indirectly to the striatum. In the present study, dopamine metabolism in subregions of the striatum was examined in rats with KA lesions after acute and chronic haloperidol or clozapine administration. The main findings was that the elevating effect of acute haloperidol treatment on the dopamine metabolite, DOPAC, was blocked in the nucleus accumbens shell and diminished in medial and laterodorsal caudate-putamen of the KA-lesioned rats. In addition, the elevating effects of both acute and chronic haloperidol treatment on dopamine turnover were attenuated in the laterodorsal caudate-putamen of KA-lesioned rats. The levels of dopamine, DOPAC, and HVA after chronic clozapine treatment were greater in KA-lesioned than control rats. These results indicate that dopaminergic responses to haloperidol may be diminished by limbic-cortical neuropathology, while such pathology does not significantly alter dopaminergic responses to clozapine.

Kainic acid lesions enhance locomotor responses to novelty, saline, amphetamine, and MK-801.

Intracerebroventricular (i.c.v.) administration of kainic acid (KA) to rats produces neuronal loss in the hippocampus and other areas of the limbic system. The present study demonstrates that i.c.v. KA enhances the locomotor response to novelty and saline injection, as well as to amphetamine and MK-801. Sixteen to 18 days after i.c.v. administration of KA or vehicle, lesioned and control rats were placed in a novel cage, and locomotor activity and grooming were recorded for 30 min prior to and 60 min following a subcutaneous injection of saline, D-amphetamine, or MK-801. In response to the novel cage and after each injection, KA rats exhibited increased locomotor activity relative to controls. Grooming behavior was found to be elevated in the KA rats when compared to controls, but only in response to the novel cage and saline injection. The possibility that damage to the limbic system disrupts dopaminergic regulation of locomotor behavior is discussed, as well as implications for neuropathology in schizophrenia.

Correlated reductions in cerebrospinal fluid 5-HIAA and MHPG concentrations after treatment with selective serotonin reuptake inhibitors.

We sought to determine whether fluvoxamine and fluoxetine, two different antidepressants with in vitro selectivity for the serotonin uptake transporter also demonstrated similar selectivity in vivo. To accomplish this, we measured cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and homovanillic acid (HVA) before and after 6 weeks of treatment with these two drugs. Twenty-four subjects who had major depression according to DSM-III-R criteria gave written, informed consent for the collection of CSF during a double-blind comparative treatment trial of fluvoxamine (50-150 mg/day) and fluoxetine (20-80 mg/day). The symptoms of subjects were assessed clinically on a weekly basis throughout the treatment trial. CSF samples were obtained after a 7- to 14-day washout period before treatment and again at the end of treatment. CSF samples were analyzed for 5-HIAA, HVA, and MHPG using high-pressure liquid chromatography coupled to electrochemical detection. Fluvoxamine- and fluoxetine-treated patients did not differ in clinical outcome or in the CSF concentrations of monoamine metabolite levels before or after treatment. Therefore, the CSF data were pooled. Drug treatment, overall, was associated with significant decreases in 5-HIAA and MHPG and a trend toward a reduction in HVA levels. Levels of 5-HIAA, MHPG, and HVA were reduced by 57%, 48%, and 17%, respectively. In addition, the magnitude of the decreases in 5-HIAA and MHPG appeared to be correlated (r = 0.83) across the subjects, although a Spearman rank correlation indicated that outlying values had an undue effect on this relationship. These results suggest that treatment with selective serotonin reuptake inhibitors, which are selective for serotonin uptake in vitro, does not show a similarly selective effect on serotonin in vivo during treatment of patients.

CSF excitatory amino acids and severity of illness in Alzheimer's disease.

Researchers have proposed that increased release of excitatory amino acids (EAAs) is involved in the pathogenesis of dementia of the Alzheimer type (DAT), and CSF EAA concentrations have been measured to obtain evidence in support of this hypothesis. However, previous comparisons of CSF EAA concentrations in patients with DAT and in controls have yielded inconsistent results, perhaps because patient samples have been heterogeneous as to dementia severity. To determine whether there are changes in CSF concentrations of EAAs related to severity of illness in patients with DAT, we measured CSF concentrations of glutamate, aspartate, and taurine in 32 subjects with DAT, in whom we also assessed the severity of illness using clinical and neuropsychological measures, and 11 age-matched controls. The results suggested that increased CSF aspartate and glutamate concentrations, as well as decreased taurine concentrations, may occur in some persons with more advanced symptoms of DAT.

The effects of chronic corticosterone on memory performance in the platform maze task.

Acquisition and reversal of a memory task dependent on hippocampal integrity were assessed in rats following chronic corticosterone treatment. Young adult male rats were injected daily with corticosterone (10 mg/kg, SC) for 8 weeks. Memory was assessed during the last week of treatment with an elevated platform maze. During acquisition trials, corticosterone-treated rats did not differ from vehicle-treated controls in either the location of first hole chosen nor in the latency to locate the escape hole. In the reversal trials, when the position of the escape hole was rotated 135 degrees, both groups successfully reversed their responses without persevering towards the previously rewarded escape hole location. These findings suggest that, despite the probability of corticosterone-induced changes in hippocampal physiology, chronic corticosterone treatment does not adversely affect performance in a memory task dependent on hippocampal integrity.

Kainic acid decreases hippocampal neuronal number and increases dopamine receptor binding in the nucleus accumbens: an animal model of schizophrenia.

Intracerebroventricular (i.c.v.) administration of kainic acid (KA) produces graded neuronal loss in the hippocampus and other regions of the medial temporal lobe. Many of these brain regions send excitatory projections to the nucleus accumbens, a dopaminergic brain area implicated in psychotomimetic and antipsychotic drug action. In the present study, neurochemical function in the nucleus accumbens and anterior caudate-putamen was examined one week after i.c.v. administration of 1.5, 4.5, or 6.6 nmol of KA. As expected, i.c.v. KA produced dose-dependent neuronal loss in the dorsal and ventral hippocampus. Extrahippocampal neuronal loss was also observed in the thalamus and piriform cortex in some of the KA-treated rats. While ambient levels of dopamine turnover and excitatory amino acids in the nucleus accumbens were unaltered by KA, administration of the highest KA dose elevated [3H]spiperone binding exclusively in the accumbens. Finally, behavioral hyperactivity was observed in KA-treated rats over a five-week period following i.c.v. administration. The pattern of neuronal loss, receptor upregulation, and behavioral hyperactivity found after i.c.v. KA administration may provide a useful animal model of the limbic neuropathology and neurochemical dysfunction associated with schizophrenia.