Effects of quinpirole on central dopamine systems in sensitized and non-sensitized rats.

The present study examined post mortem changes in central dopaminergic terminal regions following acute or chronic treatment regimens with the dopamine D2/D3 receptor agonist quinpirole, a psychomotor stimulant which induces pronounced behavioural sensitization when given chronically. Drug-induced changes in nucleus accumbens, striatum and amygdala were bilateral in nature, while in prefrontal cortex (medial prefrontal and anterior cingulate combined), left and right brain regions responded differentially to quinpirole. Acute drug treatment increased dopamine tissue levels in nucleus accumbens and right prefrontal cortex, while the dopamine metabolite 3,4-dihydroxyphenylacetic acid, was decreased in amygdala. In contrast, sensitization to quinpirole was associated with decreased dopamine levels in left prefrontal cortex, and increases in 3,4-dihydroxyphenylacetic acid levels in subcortical structures, particularly striatum and amygdala. Additionally, the increase in striatal 3,4-dihydroxyphenylacetic acid in chronic quinpirole animals was independent of drug treatment on the final day of injections. In summary, quinpirole induces a variety of simultaneous, regional changes in dopaminergic function, with the sensitized condition being primarily associated with an up-regulation of subcortical dopamine activity. While the nucleus accumbens and striatum play a well known role in motor activation and sensitized behaviour, it is concluded that the amygdala and prefrontal cortex have significant modulatory influences on these processes, with the role of the prefrontal cortex being asymmetrical in nature. Given the suggested relevance of behavioural sensitization to psychopathological states in humans, parallels are drawn between the present data and clinical findings, particularly in relation to obsessive-compulsive disorder.

Locomotor sensitization to quinpirole: environment-modulated increase in efficacy and context-dependent increase in potency.

This study examines whether behavioural sensitization to the dopamine agonist, quinpirole, reflects an increase in the drug's potency and/or efficacy to induce locomotion, and how these parameters are influenced by environmental context. Three experiments were conducted in which animals received either chronic quinpirole (10 x 0.5 mg/kg, twice weekly) or saline injections in either the home cage environment, an alternate environment or the testing environment (activity monitors), followed by a dose-response test for the expression of sensitization in the activity monitors. Compared to the acute dose-response relationship, chronic quinpirole increased the maximum response. This increase in efficacy was significantly higher in animals treated with quinpirole in a non-home cage environment compared to those that received chronic treatment in the home cage. A leftward shift in the dose-effect function was observed only in animals with prior drug experience in the testing environment. Results indicate that locomotor sensitization to quinpirole reflects an environment-modulated increase in the drug's efficacy, and an environment-dependent increase in drug potency. Efficacy and potency may be subject to sensitization by non-associational and associational mechanisms, respectively.

Associational and nonassociational mechanisms in locomotor sensitization to the dopamine agonist quinpirole.

A pairing paradigm was employed to explore the contribution of associational mechanisms to the expression of sensitization to the dopamine agonist quinpirole. Rats received ten quinpirole injections in the test environment (Group Paired) or in the home cage (Group Unpaired), and saline in the alternate environment. A third group received saline injections in both environments (Group Acute). Subjects received quinpirole on the 11th injection as a test for locomotor sensitization, and saline on the next injection as a test for conditioned activity. The range of discriminative stimuli predicting a drug versus a non-drug injection was increased across three independent experiments in an effort to detect a possible associational effect. Regardless of the strength of discriminative stimuli, both Paired and Unpaired groups showed locomotor sensitization to 0.5 mg/kg quinpirole compared with the Acute group. However, the Paired group showed more locomotion than the Unpaired group in the last minutes of the sensitization test. With a lower sensitizing dose of quinpirole (0.1 mg/kg) used in one experiment, only the Paired group showed locomotor sensitization. For both doses, the Paired, but not the Unpaired groups showed conditioned locomotion. It is suggested that with moderate doses of quinpirole, expression of locomotor sensitization does not require drug-signalling cues though such signals may have a modulatory influence. With lower quinpirole doses, however, quinpirole sensitization is context-dependent.

Disturbed emotionality in autoimmune MRL-lpr mice.

MRL-lpr mice develop symptoms of autoimmune lupus-like disease early in the life and MRL(-)+/+ mice develop it substantially later. The present study examines our previous suggestion that autoimmune MRL-lpr mice show altered emotional reactivity. In addition, it aims to identify the set of measures which best discriminate the behavior of MRL-lpr mice from their congenic controls (MRL +/+). Behavior of males from these two substrains (n = 40/substrain; 3-4 mo of age) was compared on a battery of tests presumed to be reflective of emotional reactivity. MRL-lpr mice explored the open field less, spent more time at home-base, and defecated less in comparison to congenic MRL +/+ controls. Moreover, MRL-lpr mice hesitated to step down from an elevated platform and to make contact with a novel object. They also visited open-arms of a plus-maze less often and showed extensive floating in the Porsolt's swim test. Discriminant analysis revealed that the performance of the MRL-lpr and MRL +/+ mice differed most profoundly on measures taken in the Porsolt's swim and step-down tests. In addition, in the MRL-lpr group high titers of serum antinuclear antibodies were associated with impaired exploration of a novel object. These results are consistent with the previously proposed notion of increased "timidity" in autoimmune MRL-lpr mice and of an immune factor contribution to altered emotional reactivity. Considering that behavior of autoimmune MRL-lpr mice resembles behavior of stressed animals, it is speculated that disturbed emotional reactivity reflects the effect of autoimmunity on the hypothalamic-pituitary-adrenal axis.

Dynamics of behavioral sensitization induced by the dopamine agonist quinpirole and a proposed central energy control mechanism.

The study characterizes the process of sensitization induced by intermittent administrations of quinpirole (0.5 mg/kg) in rats in a large open field. Sensitization was found to be self-limiting, with all measures of behavior reaching a plateau after the tenth twice-weekly injection. Kinetics of sensitization were a simple hyperbolic function of the number of drug injections for some measures (speed of locomotion, length of locomotor bouts) but showed positive co-operativity for others (distance travelled, duration of locomotion, frequency of stops, route stereotypy), suggesting potentiation of the effect by preceding injections. The pace of sensitization varied for different behaviors: locomotor speed changed fastest in the early portion of chronic treatment; stereotypy of route changed primarily during the late phase; mouthing did not sensitize. Sensitization evolved by a cascade of changes that included: advancing the onset of locomotor activation; prolonging the duration of locomotion; establishing new maxima of observable responses; altering the mode of locomotion; raising speed, rate and length of locomotor bouts; and increasing stereotypy of travel. These observations do not substantiate the prediction that development of behavioral sensitization is associated with emergence of disorganized activity and/or fractionation of response chains. Instead, it is proposed that development of sensitization may represent a build-up and strengthening of performance, reflecting enhanced central control of energy expenditure stimulated by repeated injections of quinpirole. Furthermore, it is suggested that for at least one response, the maximum observable amount of locomotion, development of sensitization requires only D2 stimulation, independent of D1 tone.

Behavior and immune status of MRL mice in the postweaning period.

The notion that the MRL-lpr substrain is a useful model of behavioral and cognitive deficits found in systemic autoimmune diseases is supported by the recent findings of behavioral dysfunction in autoimmune MRL-lpr mice compared to their congenic control MRL +/+ mice. However, it has not been established whether the altered behavioral profile in MRL-lpr mice is the result of the autoimmune process itself or reflects a subtle difference in genetic background or both. To address the question whether MRL-lpr mice are born with behavioral dysfunction the present study compares the behavior of the two MRL substrains in the early postweaning period, when their immune status does not show detectable difference. Results show that the prediseased (4- to 6-week-old) MRL-lpr mice are not distinguishable from the congenic MRL +/+ controls on most behavioral measures except for speed of locomotion and novelty-induced hyperactivity in activity monitors. The immune status of the two substrains is also similar except for a lower hematocrit in the MRL-lpr group. Surprisingly, low amounts of antinuclear and brain-reactive antibodies (possibly transferred from diseased mothers) were detected in the serum of about 50% of the mice in both groups. The lack of major differences in behavior in the premorbid period suggests that appearance of previously reported behavioral dysfunction in the disease state reflects the presence of autoimmunity, time-determined genetic activation, or both.

Environmental and behavioral components of sensitization induced by the dopamine agonist quinpirole.

Chronic intermittent injection of quinpirole (0.5mg/kg) to rats in a large non-standard open field (mirrored glass table without walls, 160 x 160cm and 60cm high) induces pronounced behavioral sensitization characterized by a 6-fold increase in locomotor distance and increased rigidity of travel along the same routes (path stereotype). Experiment 1 showed that equivalent treatment in the home cage induces much less sensitization of locomotor distance and no sensitization of path stereotypy, as evidenced by a test in the open field. In Experiment 2, transferring rats sensitized in one open field to a novel open field resulted in a 50% loss of sensitized locomotor distance and a virtual loss of sensitized path stereotypy. In Experiment 3, rotating the open field in relation to room cues did not affect sensitized responding, suggesting that the behavior is organized in relation to distal rather than local (open field) cues. Finally, an injection of saline in the sensitized environment failed to elicit conditioned locomotion (Experiment 4). These results are taken to indicate that the control of sensitization to quinpirole has components that are environment independent, behavior specific, and context dependent, each having a relatively different contribution and mechanism. It is suggested that under the experimental conditions of this study, the relative contributions to quinpirole sensitization were 50% for the context-dependent component, 30% for the behavior-specific component, and 20% for the environment-independent contribution. The mechanism for the context-dependent component may be related to development of path stereotypy and involve spatial learning.

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.

Dopaminergic control of locomotion, mouthing, snout contact, and grooming: opposing roles of D1 and D2 receptors.

The study compares the behavioral profiles induced in rats (N = 118) by the D2-dopaminergic receptor agonist quinpirole (0.03 and 0.5 mg/kg), and the D1-agonist SKF38393 (1.25-40 mg/kg), and both agonists administered together. Locomotion and snout contact frequency were reduced by the low but increased by the high dose of quinpirole; SKF38393 also reduced these behaviors and attenuated the effect of the high quinpirole dose. Only the high dose of quinpirole increased the duration of snout contact bouts and the frequency of mouthing; SKF38393 had no effect but in combination with the high dose of quinpirole, it enhanced the performance of these behaviors greatly. The duration of mouthing bouts was not affected by either agonist but was greatly extended when SKF38393 was administered together with the high dose of quinpirole. Grooming was inhibited by both the low and the high dose of quinpirole, and stimulated by the injection of SKF38393 or its addition to the low dose of quinpirole. These findings suggest that snout contact is controlled by modulating the frequency of episodes whereas mouthing is controlled by modulating the duration of episodes. Moreover, although they do not disprove the prevailing notion of D1-D2 receptor synergism, the present data are consistent also with an oppositional model of D1-D2 receptor interaction in the regulation of locomotion, snout contact, mouthing, and grooming in intact animals.