Reduced Preference for Sucrose in Autoimmune Mice: A Possible Role of Interleukin-6

In a continuous one-bottle sucrose intake test, 4-month-old autoimmune MRL-lpr mice show a shift to the right along the X-axis of the concentration-intake function, compared to congenic MRL +/+ controls. Using a brief (60-min) and a continuous (48-h) two-bottle test, the present report examines potential factors that could account for the reduced responsiveness to a palatable stimulus. Study 1 examines whether preference for sucrose is associated with age, changes in food/water intake, or impaired renal function. Reduced preference for sucrose was observed in 5–6-week-old MRL-lpr males, although food/water intake or blood creatinine levels did not differ from control values. Immunosuppressive treatment abolished this deficit, suggesting a role of immune factor(s). Study 2 tests the hypothesis that chronic upregulation of the neuroactive cytokine interleukin-6 (IL-6), reported to occur from 3 weeks of age in young MRL-lpr mice, reduces preference for sucrose. Sustained administration of IL-6 was produced by infecting healthy MRL +/+, C3H.SW and Balb/C mice with adenovirus vector carrying cDNA for murine IL-6. This resulted in high serum IL-6 levels over 5 days, a rapid decline in preference for sucrose and low blood glucose levels. The results from Study 1 indicate that impaired sensitivity to sucrose in MRL-lpr mice can be detected before autoimmune disease is florid in MRL-lpr mice. The results from Study 2 are consistent with altered motivation/emotional states after infection, and point to sustained IL-6 production as an early mechanism in behavioral alterations during chronic autoimmune/inflammatory conditions.     

A behavioral profile of autoimmune lupus-prone MRL mice.

Manifestations of the human autoimmune disease systemic lupus erythematosus (SLE) include a number of behavioral and cognitive deficits. The present study asks whether neurobehavioral dysfunction is present also in MRL mice that spontaneously develop most of the fundamental immunological aberrations of SLE. There are two congenic substrains of MRL mice that differ in the time of disease onset: MRL-lpr mice develop lupus early and MRL(-)+/+ develop the typical signs of disease relatively late in life. The behavior of these substrains was assessed at 7 to 11 weeks of age, a time that coincides with the onset of disease in MRL-lpr mice and the absence of known lupus symptoms in the MRL(-)+/+ group. When compared to the congenic MRL(-)+/+ control substrain, MRL-lpr mice were spontaneously less active, traversed a crossbeam slower, and ceased responding to the novelty of a new environment sooner. They were also more reluctant to leave their home base or travel far away from it and perseverated in their response bias during extinction and reversal learning. Immunological status was characterized by moderate proteinuria in both substrains and high titers of antinuclear antibodies in MRL-lpr but not MRL(-)+/+ mice. Histological analysis revealed minimal or no signs of joint pathology in MRL-lpr mice. Thus, this study shows the presence of behavioral dysfunction in mice with early stages of autoimmune disease and gives support for the idea that MRL mice may provide a useful model of neurobehavioral dysfunction in SLE. It is suggested that the behavioral profile of MRL-lpr mice may indicate increased "timidity," related to genetics, autoimmunity, or both.     

Impaired response to amphetamine and neuronal degeneration in the nucleus accumbens of autoimmune MRL-lpr mice

Spontaneous development of lupus-like disease in MRL-lpr mice is accompanied by a constellation of behavioral deficits, including blunted responsiveness to sucrose. Although autoimmunity-induced damage of limbic areas is proposed to underlie this deficit, the systemic nature of the disease precludes inference of a causal relationship between CNS damage and functional loss. Based on the stimulatory effects of d-amphetamine sulfate (AMPH) on sucrose intake, the present study pharmacologically probes the functional status of central dopaminergic circuits involved in control of behavioral reward. The response rates were compared between diseased MRL-lpr mice and congenic MRL +/+ controls tested in the sucrose preference paradigm. Neuronal loss was assessed by Fluoro Jade B (FJB) staining of nucleus accumbens and the CA2/CA3 region. While control mice significantly increased intake of sucrose solutions 60 min after administration of AMPH (i.p., 0.5 mg/kg), the intake in drugged MRL-lpr mice was comparable to those given saline injection. Increased FJB staining was detected in the nucleus accumbens and hippocampus of diseased mice, and AMPH treatment neither altered this nor other measures of organ pathology. The results obtained are consistent with previously observed changes in the mesolimbic dopamine system of MRL-lpr mice and suggest that the lesion in the nucleus accumbens and deficits in dopamine release underlie impaired responsiveness to palatable stimulation during the progress of systemic autoimmune disease. As such, they point to a neurotransmitter-specific regional brain damage which may account for depressive behaviors in neuropsychiatric lupus erythematosus.     

Taste responsiveness and diet preference in autoimmune MRL mice

One of the most profound behavioural deficits in lupus-prone MRL-lpr mice is blunted responsiveness to sweet solutions. Given the systemic nature of autoimmune/inflammatory disease, it was not clear whether impaired taste sensitivity or motivated response to palatable food underlie this deficit. The present study compares response rates of MRL-lpr mice (which develop disease early), congenic MRL +/+ mice (which develop disease later in life) and non-autoimmune Swiss Webster (SW) mice to different tastes and diets. Healthy SW mice showed the highest responsiveness to palatable stimulation throughout the study. Conversely, the preference for palatable solutions progressively declined in MRL-lpr mice as the disease developed. No differences between the two MRL substrains were seen in responsiveness to quinine or saline, suggesting that blunted responsiveness to palatable solutions cannot be accounted for by reduced taste sensory function (hypogeusia). In addition, changes in response rates to palatable solutions were associated with systemic upregulation of pro-inflammatory cytokines. With a new cohort of mice fed on carbohydrate-rich and fat-rich diets, we also examined whether reduced sucrose intake in MRL-lpr mice can be accounted for by a reduced craving for carbohydrates. Contrary to this expectation, diseased MRL-lpr mice preferred carbohydrate-rich food while consuming a food mass comparable to controls. These results further support the hypothesis that the onset of lupus-like disease alters motivated behaviour, independent of changes in neurologic function and food metabolism.     

Proclivity to self-injurious behavior in MRL-lpr mice: implications for autoimmunity-induced damage in the dopaminergic system

Systemic lupus erythematosus is frequently accompanied by psychiatric manifestations of unknown origin. Although damage of central neurons had been documented, little is known about neurotransmitter systems affected by the autoimmune/inflammatory process. Recent studies on lupus-prone MRL-lpr mice point to imbalanced dopamine function and neurodegeneration in dopamine-rich brain regions. We follow up on anecdotal observations of singly housed mice developing chest wounds. Compulsive grooming and/or skin biting accounted for open lesions, lending itself to the operational term 'self-injurious behavior' (SIB). Low incidence of spontaneous SIB increased significantly after repeated injections of dopamine-2/3 receptor (D2/D3R) agonist quinpirole (QNP). To further probe the dopaminergic circuitry and examine whether SIB is associated with development of lupus-like disease, we compared behavioral responses among cohorts that differed in the immune status. Two-week treatment with QNP (intraperitoneal, 0.5 mg kg(-1) body weight per day) induced SIB in 60% of diseased MRL-lpr mice, and exacerbated their splenomegaly. Although increased grooming and stereotypy were observed in less symptomatic MRL+/+ controls, only one mouse (10%) developed SIB. Similarly, SIB was not seen in young, asymptomatic groups despite dissimilar ambulatory responses to QNP. In situ hybridization revealed treatment-independent upregulation of D2R mRNA in substantia nigra of diseased MRL-lpr mice. The above results suggest that development of systemic autoimmunity alters sensitivity of the dopaminergic system and renders MRL-lpr mice prone to SIB. Although pathogenic factors were not examined, we hypothesize that immune and endocrine mechanisms jointly contribute to early neuronal damage, which underlies behavioral deficiency in the adulthood.     

Immunosuppression prevents neuronal atrophy in lupus-prone mice: evidence for brain damage induced by autoimmune disease?

An early onset of systemic, lupus-like disease in MRL-lpr mice is accompanied by deterioration in their behavioral performance and atrophy of pyramidal neurons in the parietal cortex and the hippocampal CA1 area. Using the immunosuppressive drug cyclophosphamide (CY) to attenuate the disease, we have tested the hypothesis that the autoimmune/inflammatory process is responsible for changes in brain morphology. A modified Golgi impregnation method revealed that, in comparison to saline-treated controls, immunosuppressive treatment with CY (100 mg/kg/week i.p. over 8 weeks) increased dendritic branching and spine numerical density in the CA1 region of MRL-lpr mice and MRL +/+ mice, which develop less severe manifestations of the disease. More interestingly, CY selectively prevented the atrophy and aberrant morphology of pyramidal neurons in the parietal cortex of MRL-lpr mice. The neuropathological measures (in particular reduced dendritic spine density) significantly correlated with increased serum levels of antinuclear antibodies and splenomegaly. The present results support the hypothesis that chronic autoimmune disease induces functionally important changes in neuronal morphology, and provide an empirical basis for understanding the behavioral dysfunction in systemic lupus erythematosus and autoimmune phenomena reported in some forms of mental illness.     

Behavioral effects of infection with IL-6 adenovector

The onset of autoimmunity in lupus-prone mice is accompanied by a constellation of behavioral deficits, termed Autoimmunity-Associated Behavioral Syndrome (AABS). In particular, a spontaneous increase in serum interleukin-6 (IL-6) levels in five-week old MRL-lpr mice coincides temporally with blunted responsiveness to sucrose and excessive immobility in the forced swim test. These relationships, along with evidence that sucrose intake drops after systemic IL-6 overexpression is induced in healthy mice, have led to the hypothesis that sustained elevation in serum IL-6 also induces other aspects of AABS. This hypothesis is tested by comparing the behavioral profiles of healthy mice infected with Ad5mIL6 adenovirus (2 x 10(8) pfu of virus/mouse i.p.) with those of animals infected with control Ad5 virus. This methodology was used to achieve high circulating levels of IL-6, to overcome the problem of its short half-life, and to avoid the stressful effects of repeated injections. The Ad5mIL6 infection (known to induce excessive IL-6 levels over five days) transiently reduced food, water, and sucrose intake, as well as rectal temperature in MRL +/+ and AKR/J mice. Although the level of locomotor activity did not decline, Ad5mIL6-infected AKR/J mice demonstrated less novel object exploration. Performance in the step-down, plus-maze, and spontaneous alternation tests were disturbed to various degrees in all infected animals. The present results suggest that prolonged exposure to circulating IL-6 primarily impairs ingestive behavior, likely reflecting enhanced catabolism. The inability of circulating IL-6 to alter other aspects of behavior supports the hypothesis that multiple immuno-neuroendocrine mechanisms contribute to the pathogenesis of AABS.     

Blunted Sensitivity to Sucrose in Autoimmune MRL-lpr Mice: A Curve-Shift Study

Lupus-prone MRL-lpr mice show an autoimmunity-associated behavioral syndrome that has many features similar to the effects of chronic stress. The present study evaluated whether autoimmune MRL-lpr mice show reduced responsiveness to sucrose, as observed in normal animals exposed to chronic mild stress. Sixteen-week old MRL-lpr mice and their age-matched congenic MRL +/+ controls were given 0%, 0.5%, 1%, 2%, 4%, 8%, or 16% sucrose solution to drink every 48 h in a one-bottle test. The MRL-lpr mice drank less than controls at all concentrations, except at 16%. The amount of sucrose consumed vs. solution concentration followed a saturation curve. Estimates were obtained for the concentration yielding the half-maximum response (X₅₀) and the response at saturating concentration of sucrose (R_max). The X₅₀ was significantly higher in MRL-lpr than in MRL +/+ mice, indicating a shift to the right of the concentration-intake curve. The R_max did not differ significantly between substrains, suggesting that the autoimmune process did not affect performance capacity. Pretreatment with the immunosuppressant cyclophosphamide diminished the substrain difference in X₅₀, suggesting that reduced sensitivity to sucrose is related to autoimmune/inflammatory factors. These results support the similarity between autoimmunity-associated behavioral syndrome and behavioral changes produced by chronic stress, and suggest common neuroendocrine mechanisms. Because reduced sensitivity to palatable stimulus may reflect blunted hedonic responsiveness (“anhedonia”), it is hypothesized that an autoimmune/inflammatory factor(s) produces the depression found in human lupus, and some cases of affective disorder. Copyright © 1996 Elsevier Science Inc.     

Neurotoxic properties of cerebrospinal fluid from behaviorally impaired autoimmune mice

The chronic, lupus-like autoimmune disease in MRL-lpr mice is associated with leucocyte infiltration into the choroid plexus, brain cell death, and deficits in motivated behavior. The presence of lymphoid cells in the ventricular lumen and the increased number of TUNEL-positive cells in periventricular areas led to the hypothesis that immune cells enter into the cerebrospinal fluid (CSF) and induce primary neuronal damage in regions bordering the cerebral ventricles. Using an in vitro approach, we presently examine the possibility that CSF from autoimmune mice is neurotoxic and/or gliotoxic. The CSF and serum from diseased MRL-lpr mice, less symptomatic MRL +/+ controls, and healthy Swiss/Webster mice (non-autoimmune controls) were frozen until their effects on the viability of pyramidal neurons and astrocytes were assessed in a two-color fluorescence assay. Significant reduction in neuronal viability (in some cases as low as 67%) was observed in the co-cultures of hippocampal neurons and astrocytes incubated for 24 h with CSF from autoimmune MRL-lpr mice. The viability of astrocytes did not differ among the groups, and the CSF from autoimmune mice appeared more toxic than the serum. The behavior of MRL-lpr mice differed significantly from the control groups, as indicated by impaired exploration, reduced intake of palatable food, and excessive immobility in the forced swim test. The present results suggest that CSF from the behaviorally impaired lupus-prone mice is neurotoxic and are consistent with the hypothesis that neuroactive metabolites are produced intrathecally in neuropsychiatric lupus erythematosus.     

Elevated plus maze behavior, auditory startle response, and shock sensitivity in predisease and in early stage autoimmune disease MRL/lpr mice

Behaviors indicative of anxiety have been suggested to emerge with the onset of autoimmune disease in MRL/MpJ-Fas(lpr) (MRL/lpr) mice. This study extends the behavioral characterization of MRL/lpr and congenic MRL/MpJ+/+ (MRL/+) mice using the elevated plus maze (EPM), acoustic startle response, and foot-shock sensitivity tasks. In the elevated plus maze, predisease MRL/lpr mice exhibited less anxiety while MRL/lpr mice in the early stage of autoimmunity did not differ from age-matched control MRL/+ mice. MRL/lpr mice exhibited lower startle responses compared to MRL/+ mice. Similarly, predisease MRL/lpr mice were less reactive to various foot-shock levels than MRL/+ mice. Both the MRL/lpr and the MRL/+ strains exhibited startle habituation deficits, implicating the background MRL strain in the impairment in this process. These data do not support the hypothesis that increased anxiety is apparent with the emergence of autoimmune disease in MRL/lpr mice; however, anxiety may appear as the disease advances.     

Hippocampal damage in mouse and human forms of systemic autoimmune disease

Systemic lupus erythematosus (SLE) is frequently accompanied by neuropsychiatric (NP) and cognitive deficits of unknown etiology. By using autoimmune MRL-lpr mice as an animal model of NP-SLE, we examine the relationship between autoimmunity, hippocampal damage, and behavioral dysfunction. Fluoro Jade B (FJB) staining and anti-ubiquitin (anti-Ub) immunocytochemistry were used to assess neuronal damage in young (asymptomatic) and aged (diseased) mice, while spontaneous alternation behavior (SAB) was used to estimate the severity of hippocampal dysfunction. The causal relationship between autoimmunity and neuropathology was tested by prolonged administration of the immunosuppressive drug cyclophosphamide (CY). In comparison to congenic MRL +/+ controls, SAB acquisition rates and performance in the "reversal" trial were impaired in diseased MRL-lpr mice, suggesting limited use of the spatial learning strategy. FJB-positive neurons and anti-Ub particles were frequent in the CA3 region. Conversely, CY treatment attenuated the SAB deficit and overall FJB staining. Similarly to mouse brain, the hippocampus from a patient who died from NP-SLE showed reduced neuronal density in the CA3 region and dentate gyrus, as well as increased FJB positivity in these regions. Gliosis and neuronal loss were observed in the gray matter, and T lymphocytes and stromal calcifications were common in the choroid plexus. Taken together, these results suggest that systemic autoimmunity induces significant hippocampal damage, which may underlie affective and cognitive deficits in NP-SLE.     

Increased TUNEL staining in brains of autoimmune Fas-deficient mice

Profound changes in brain morphology and behavior coincide with the spontaneous development of systemic autoimmune/inflammatory disease in Fas-deficient MRL-lpr mice. The dendrites atrophy, the density of hippocampal and cortical neurons decreases, and an anxious/depressive-like behavior emerges while lymphoid cells infiltrate into the choroid plexus of MRL-lpr mice. We hypothesized that the inherited lack of the Fas-dependent anti-inflammatory mechanism would lead to unsuppressed immune activity, characterized by reduced apoptosis in the MRL-lpr brain. Using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeled (TUNEL) method as an indicator of apoptosis, a surprisingly high incidence of TUNEL-positive cells was observed in the hippocampus, choroid plexus and periventricular regions of MRL-lpr mice, 5-10-fold higher than that found in the MRL +/+ control brain. Immunostaining with anti-CD3, CD4 and CD8 monoclonal antibodies showed limited overlap between CD-positive and TUNEL-positive cells, suggesting that the dying cells are for the most part (approximately 70%) not T-lymphocytes. Although further characterization of the phenotype of the dying cells and the mechanism of cell death are required, the present results suggest the involvement of a Fas-independent apoptotic process in neurodegeneration induced by systemic autoimmune disease.     

Taste aversion learning in autoimmune Mrl-lpr/lpr and Mrl +/+ mice

Conditioned taste aversion to a neutral stimulus paired with an immunosuppressive drug (cyclophosphamide) was assessed in lupus-prone MRL-lpr/lpr and congenic control (MRL +/+) mice. The presence of lymphoproliferation in MRL-lpr/lpr mice was associated with poorer taste aversion learning and varied as a function of the dose of cyclophosphamide. There were no differences in learning performance between MRL-lpr/lpr and MRL +/+ mice when the animals were tested at an age prior to the development of lymphadenopathy, or when lithium chloride or electric shock were used as unconditioned stimuli. These results are consistent with the hypothesis that the immune status of an organism has an impact on behavior and the possibility that behavior can serve an in vivo immunoregulatory function.     

Voluntary consumption of cyclophosphamide by Mrl mice

Fluid-deprived, lupus-prone Mrl-lpr/lpr and congenic Mrl +/+ mice were provided with a single drinking bottle containing varying concentrations of cyclophosphamide (CY) dissolved in chocolate milk. Eighteen- and 20-week-old Mrl-lpr/lpr males with manifest symptoms of autoimmune disease voluntarily consumed more of the CY solution than Mrl +/+ mice of the same age after 1 week of 1 hr/day exposures. The volume of CY-laced chocolate milk consumed was sufficient to attenuate lymphadenopathy and the elevated anti-DNA antibody titers in these animals. When testing began before the development of manifest symptoms of autoimmune disease, there were no differences between the two substrains. These results are consistent with the hypothesis that behavioral processes can act to correct homeostatic imbalances within the immune system.     

Purine receptor antagonist modulates serology and affective behaviors in lupus-prone mice: evidence of autoimmune-induced pain?

Neurologic and psychiatric (NP) manifestations are severe complications of systemic lupus erythematosus (SLE). As commonly seen in patients, spontaneous disease onset in the MRL/MpJ-Fas^lpr/J (MRL-lpr) mouse model of NP–SLE is accompanied by increased autoantibodies, pro-inflammatory cytokines and behavioral dysfunction which precede neuroinflammation and structural brain lesions. The role of purinergic receptors in the regulation of immunity and behavior remains largely unexplored in the field of neuropsychiatry. To examine the possibility that purinoception is involved in the development of affective behaviors, the P2X purinoceptor antagonist, suramin, was administered to lupus-prone mice from 5 to 14 weeks of age. In addition to food and water measures, novel object and sucrose preference tests were performed to assess neophobic anxiety- and anhedonic-like behaviors. Enzyme-linked immunosorbant assays for anti-nuclear antibodies (ANA) and pro-inflammatory cytokines were employed in immunopathological analyses. Changes in dendritic morphology in the hippocampal CA1 region were examined by a Golgi impregnation method. Suramin significantly lowered serum ANA and prevented behavioral deficits, but did not prevent neuronal atrophy in MRL-lpr animals. In a new batch of asymptomatic mice, systemic administration of corticosterone was found to induce aberrations in CA1 dendrites, comparable to the “stress” of chronic disease. The precise mechanism(s) through which purine receptor inhibition exerted beneficial effects is not known. The present data supports the hypothesis that activation of the peripheral immune system induces nociceptive-related behavioral symptomatology which is attenuated by the analgesic effects of suramin. Hypercortisolemia may also initiate neuronal damage, and metabolic perturbations may underlie neuro-immuno-endocrine imbalances in MRL-lpr mice.     

Neuroimmunopathology in a murine model of neuropsychiatric lupus

Animal models are extremely useful tools in defining pathogenesis and treatment of human disease. For many years researchers believed that structural damage to the brain of neuropsychiatric (NP) patients lead to abnormal mental function, but this possibility was not extensively explored until recently. Imaging studies of NP-systemic lupus erythematosus (SLE) support the notion that brain cell death accounts for the emergence of neurologic and psychiatric symptoms, and evidence suggests that it is an autoimmunity-induced brain disorder characterized by profound metabolic alterations and progressive neuronal loss. While there are a number of murine models of SLE, this article reviews recent literature on the immunological connections to neurodegeneration and behavioral dysfunction in the Fas-deficient MRL model of NP-SLE. Probable links between spontaneous peripheral immune activation, the subsequent central autoimmune/inflammatory responses in MRL/MpJ-Tnfrsf6(lpr) (MRL-lpr) mice and the sequential mode of events leading to Fas-independent neurodegenerative autoimmune-induced encephalitis will be reviewed. The role of hormones, alternative mechanisms of cell death, the impact of central dopaminergic degeneration on behavior, and germinal layer lesions on developmental/regenerative capacity of MRL-lpr brains will also be explored. This model can provide direction for future therapeutic interventions in patients with this complex neuroimmunological syndrome.     

Elevated immunoglobulin levels in the cerebrospinal fluid from lupus-prone mice

The systemic autoimmune disease lupus erythematosus (SLE) is frequently accompanied by neuropsychiatric manifestations and brain lesions of unknown etiology. The MRL-lpr mice show behavioral dysfunction concurrent with progression of a lupus-like disease, thus providing a valuable model in understanding the pathogenesis of autoimmunity-induced CNS damage. Profound neurodegeneration in the limbic system of MRL-lpr mice is associated with cytotoxicity of their cerebrospinal fluid (CSF) to mature and immature neurons. We have recently shown that IgG-rich CSF fraction largely accounts for this effect. The present study examines IgG levels in serum and CSF, as well as the permeability of the blood-brain barrier in mice that differ in immune status, age, and brain morphology. In comparison to young MRL-lpr mice and age-matched congenic controls, a significant elevation of IgG and albumin levels were detected in the CSF of aged autoimmune MRL-lpr mice. Two-dimensional gel electrophoresis and MALDI-TOF MS confirmed elevation in IgG heavy and Ig light chain isoforms in the CSF. Increased permeability of the blood-brain barrier correlated with neurodegeneration (as revealed by Fluoro Jade B staining) in periventricular areas. Although the source and specificity of neuropathogenic antibodies remain to be determined, these results support the hypothesis that a breached blood-brain barrier and IgG molecules are involved in the etiology of CNS damage during SLE-like disease.     

Modulation of pre- and postsynaptic dopamine D2 receptor function by the selective kappa-opioid receptor agonist U69593

The repeated administration of selective kappa-opioid receptor agonists prevents the locomotor activation produced by acute cocaine administration and the development of cocaine-induced behavioral sensitization. Previous studies have shown that dopamine (DA) D2 autoreceptors modulate the synthesis and release of DA in the striatum. Evidence that kappa agonist treatment downregulates DA D2 receptors in this same brain region has recently been obtained. Accordingly, the present studies were undertaken to examine the influence of repeated kappa-opioid receptor agonist administration on pre- and postsynaptic DA D2 receptor function in the dorsal striatum using pre- and postsynaptic receptor-selective doses of quinpirole. Rats were injected once daily with the selective kappa-opioid receptor agonist U69593 (0.16-0.32 mg/kg s.c.) or vehicle for 3 days. Microdialysis studies assessing basal and quinpirole-evoked (0.05 mg/kg s.c.) DA levels were conducted 2 days later. Basal and quinpirole-stimulated locomotor activity were assessed in a parallel group of animals. The no-net flux method of quantitative microdialysis revealed no effect of U69593 on basal DA dynamics, in that extracellular DA concentration and extraction fraction did not differ in control and U69593-treated animals. Acute administration of quinpirole significantly decreased striatal DA levels in control animals, but in animals treated with U69593, the inhibitory effects of quinpirole were significantly reduced. Quinpirole produced a dose-related increase in locomotor activity in control animals, and this effect was significantly attenuated in U69593-treated animals. These data reveal that prior repeated administration of a selective kappa-opioid receptor agonist attenuates quinpirole-induced alterations in DA neurotransmission and locomotor activity. These results suggest that both pre- and postsynaptic striatal DA D2 receptors may be downregulated following repeated kappa-opioid receptor agonist administration. Synapse 39:343-350, 2001. Published 2001 Wiley-Liss, Inc.