Obsessive-compulsive disorder: a disorder of pessimal (non-functional) motor behavior.

OBJECTIVE: To determine whether in addition to repetitiveness, the motor rituals of patients with obsessive-compulsive disorder (OCD) involve reduced functionality due to numerous and measurable acts that are irrelevant and unnecessary for task completion. METHOD: Comparing motor rituals of OCD patients with behavior of non-patient control individuals who were instructed to perform the same motor task. RESULTS: Obsessive-compulsive disorder behavior comprises abundant acts that were not performed by the controls. These acts seem unnecessary or even irrelevant for the task that the patients were performing, and therefore are termed 'non-functional'. Non-functional acts comprise some 60% of OCD motor behavior. Moreover, OCD behavior consists of short chains of functional acts bounded by long chains of non-functional acts. CONCLUSION: The abundance of irrelevant or unnecessary acts in OCD motor rituals represents reduced functionality in terms of task completion, typifying OCD rituals as pessimal behavior (antonym of optimal behavior).

Disintegration of the spatial organization of behavior in experimental autoimmune dementia.

Experimental autoimmune dementia is a rat model designed to examine the potential role of anti-cholinergic neurons antibodies in neuronal degeneration in dementia and Alzheimer's disease. We have previously shown that sera of patients with Alzheimer's disease contain antibodies which bind specifically to the high molecular weight neurofilament protein of the purely cholinergic electromotor neurons of Torpedo. Production of such antibodies in experimental autoimmune dementia rats by prolonged immunization with the Torpedo cholinergic high molecular weight neurofilament subunit results in accumulation of antibodies in the septum and hippocampus of the immunized rats, in a marked decrease in the density of forebrain cholinergic neurons, and in memory deficits. In the present study we characterized the open-field behavior of experimental autoimmune dementia rats, and examined whether, like in dementia, the spatiotemporal organization of their behavior is impaired. The results obtained revealed that experimental autoimmune dementia rats travel shorter distances; explore a smaller part of the open-field; and perform less round-trips to the key location--the home base--in reference to which their behavior is normally organized. The shrinkage of the explored space and the reduced number of round trips are independent of the amount of locomotion and represent a deterioration in the organization of behavior in time and space. These behavioral changes are specific to the anti-cholinergic immune response of experimental autoimmune dementia rats as they are not observed in rats which were immunized with chemically heterogeneous high molecular weight neurofilament subunit.(ABSTRACT TRUNCATED AT 250 WORDS)

Compulsive checking behavior of quinpirole-sensitized rats as an animal model of Obsessive-Compulsive Disorder(OCD): form and control.

BACKGROUND: A previous report showed that the open field behavior of rats sensitized to the dopamine agonist quinpirole satisfies 5 performance criteria for compulsive checking behavior. In an effort to extend the parallel between the drug-induced phenomenon and human obsessive-compulsive disorder (OCD), the present study investigated whether the checking behavior of quinpirole rats is subject to interruption, which is an attribute characteristic of OCD compulsions. For this purpose, the rat's home-cage was placed into the open field at the beginning or the middle of a 2-hr test. RESULTS: Introduction of the home-cage reduced checking behavior, as rats stayed inside the cage. After 40 min, checking resurfaced, as quinpirole rats exited the home-cage often. An unfamiliar cage had no such effects on quinpirole rats or saline controls. CONCLUSIONS: Checking behavior induced by quinpirole is not irrepressible but can be suspended. Results strengthen the quinpirole preparation as an animal model of OCD compulsive checking.

Quinpirole induces compulsive checking behavior in rats: a potential animal model of obsessive-compulsive disorder (OCD).

Rats treated chronically with the dopamine agonist quinpirole (0.5 mg/kg, twice weekly x 10) met 5 criteria for performance of compulsive checking. Specifically, in a large open-field with single small objects in 4 of 25 locales, quinpirole rats revisited two places/objects excessively often and rapidly, compared with other locations in the environment or saline controls. They performed a ritual-like set of behavioral acts at these two places/objects and stopped in relatively few locales before returning to the preferred places/objects. Finally, they shifted their behavior to a new location when the object was moved there. Clomipramine (10 mg/kg, daily) postponed but did not prevent the development of the quinpirole effect. Quinpirole-induced compulsive checking may be an exaggeration of normal checking of home site in rats. Results suggest an animal model of obsessive-compulsive disorder and a role for dopamine in this disorder.

The morphogenesis of motor rituals in rats treated chronically with the dopamine agonist quinpirole.

Rats injected repeatedly with the dopamine agonist quinpirole develop motor rituals that evolve through a cascade of 4 behavioral processes. The 1st involves increased activity. The 2nd involves increased path stereotypy, reflected in traveling repeatedly along the same few paths. The 3rd is an increase in the frequency of stopping in a few places, along with a decrease in stopping in other places. The 4th is a decrease in the repetition of movements performed in the specific stopping places. Altogether, these processes culminate in stereotypy, a typical short set of movements composed of a single performance of each movement type. Thus, stereotypy arises from changes in the temporal and spatial organization, but not the content, of behavioral patterns. These results provide a model for the development of motor rituals and their linkage to normal behavior and to the physical properties of the environment.

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.

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.

Decreased density of forebrain cholinergic neurons and disintegration of the spatial organization of behavior in experimental autoimmune dementia (EAD).

Experimental autoimmune dementia (EAD) is a rat model designed to examine the potential role of anti-cholinergic neurons antibodies (Abs) in the neuropathology of Alzheimer's disease (AD) and dementia. We have previously shown that sera of AD and Down's syndrome patients contain Abs which bind specifically to the high molecular weight neurofilament protein (NF-H) of the purely cholinergic electromotor neurons of Torpedo. Production of such Abs in EAD rats by prolonged immunization with Torpedo cholinergic NF-H results in the accumulation of IgG in the septum and hippocampus of the immunized rats and in memory deficits. In the present study, we examined immunohistochemically whether the anti-cholinergic NF-H immune response of the EAD rats affects their brain cholinergic neurons. In addition, since dementia is associated with severe deterioration in the spatio-temporal organization of behavior, we examined whether EAD rats also mimic this important feature of dementia. The results obtained show that production in EAD rats of anti-cholinergic NF-H Abs similar to those found in AD patients results in a marked decrease in the density of forebrain cholinergic neurons and in derangements in the spatio-temporal organization of their behavior. These findings may replicate pathogenic processes in AD and support a role for anti-cholinergic NF-H Abs in the degeneration of cholinergic neurons in the disease.

Home base behavior in amphetamine-treated tame wild rats (Rattus norvegicus).

When a rat treated with amphetamine (0.5-5 mg/kg) locomotes in an unfamiliar environment, there are one or two places which it visits most often. In these one or two places the mean duration of a visit (stop) is the longest, and, compared to other places, the incidence of grooming and rearing are the highest. Since in intact rats these features of place characterize it as a 'home base', it is concluded that under amphetamine rats also establish one or two home bases. One home base was generally established by rats treated with low doses of amphetamine, while two bases were most evident in those treated with high doses. Since the paths of locomotion in amphetamine-treated rats were previously described to be stereotyped, it is suggested that home base location under this drug may be used as a reference point in the assessment of the organization of stereotyped locomotor behavior.

Home base behavior of rats (Rattus norvegicus) exploring a novel environment.

When rats are placed in a novel environment, they alternate between progression and stopping: in the course of a session they stop briefly in many places, but in one or two places they also stop for very long periods. The place in which they stay for the longest cumulative time is defined as the rat's home base. In this place the incidences of grooming and of rearing are high and often the highest. In addition, the number of visits to the home base is typically the highest. Some rats establish a secondary base with similar properties to those of the main home base. The location of the base influences the mode of progression throughout the environment: progression away from base is slower and includes more stops than progression back. It is suggested that this paradigm may be used for the analysis of the spatial organization of locomotor behavior in neuroscience research.

Stopping behavior: constraints on exploration in rats (Rattus norvegicus).

In the absence of an obvious reference place, rat locomotor behavior in a novel environment appears haphazard. In previous work, one or two places termed home bases, were shown to stand out from all the other places in the environment in terms of the behaviors performed in them and in terms of their behavioral stability. We use home base location as a reference place for rat movement in locale space, by defining an excursion as a trip starting at a home base and ending at the next stop at a home base. We then establish the uniform distribution as an appropriate model for the number of stops per excursion. This way we show that there is an intrinsic upper bound on the number of times a rat stops during an excursion. As a rat leaves the home base, home base attraction increases with every additional stop performed by it, first slowly and then fast. This cumulative process of attraction may be concluded after each stop, as long as the number of stops does not exceed an intrinsic upper bound; once the upper bound is reached, the rat concludes that excursion and returns to base. The session's upper bound does not increase with the size of the explored area.

Differential effects of D1 and D2 dopamine agonists on stereotyped locomotion in rats.

The study examines the effect of selective D1 dopamine stimulation with SKF38393 (1.25-10 mg/kg), on stereotyped locomotion induced by the D2 agonist, quinpirole (0.5 mg/kg). Quinpirole induces repeated travel along a few routes in a limited portion of the environment. Co-administration of low doses of SKF38393 (1.25-2.5 mg/kg) produces the following results: the rate of route perseveration is not affected; the area explored expands to encompass the entire periphery of the open field; and, spatial distribution of locomotion is transformed from routes that cross the center under quinpirole to travel only along the edge. Under higher doses of SKF38393, locomotion ceases. These findings suggest that D1 and D2 stimulation may control the spatial organization of locomotion in oppositional rather than synergistic manner.

Evidence that apomorphine and (+)-amphetamine produce different types of circling in rats.

Apomorphine and (+)-amphetamine are known to produce circling in naive rats. Frame by frame analysis of videotape recordings of the behaviour of Wistar rats treated with a subcutaneous injection of apomorphine (1.1 mg/kg; n = 8) or (+)-amphetamine (0.5 and 1.0 mg/kg; n = 8 and n = 8) was used to study this behaviour in more detail. In line with previously reported studies, apomorphine was found to change the functioning of hindlimb stepping. In contrast, (+)-amphetamine was found to change the functioning of forelimb stepping. These data imply that apomorphine and (+)-amphetamine produce their drug-specific circling via different substrates within the brain.

D2-agonist quinpirole induces perseveration of routes and hyperactivity but no perseveration of movements.

The behavior in an open field of rats injected with the D2-agonist quinpirole (2 mg/kg; n = 10) and saline (n = 10) was analyzed in terms of routes and movements. Quinpirole induces perseveration of routes without inducing perseveration of movements. Perseveration of routes consists of repeated travel along a few paths in a limited portion of the environment. Lack of perseveration of movements was evidenced by the same distribution of lateral, vertical, and forward movements as in saline-treated animals. Quinpirole also increased the total amount of progression and the total number of movements performed by the rat's body parts along all dimensions of movements. Thus, under quinpirole, animals were hyperactive, stereotyped in route, but free in movement. This profile resembles behavior under low doses of amphetamine but not the behavior under either apomorphine or high doses of amphetamine. Thus, contrary to the current view, administration of a D2-receptor agonist is sufficient to produce a major component of dopamine-induced stereotyped behavior. It is suggested that quinpirole induces perseveration of route by affecting presynaptic release of dopamine, and that the organization of route is independent of the organization of movement.

Biphasic effect of D-2 agonist quinpirole on locomotion and movements.

The effects of the D-2 agonist quinpirole on forward progression, and on vertical and lateral movements, were measured for 2 h in rats injected with either saline, 0.03, 0.125, 0.5 or 8 mg/kg of the drug. Results showed that the drug had a biphasic effect: the lowest dose decreased and the high doses increased the amount of locomotion and of movement. The decrease in activity produced by the low dose had its onset within minutes after administration of the drug; persistent and marked hyperactivity was observed from about 60-80 min after injection of 0.5-8 mg/kg of quinpirole. Moreover, in animals injected with intermediate doses, the excitation was preceded by a brief period of reduced locomotion. It is suggested that the biphasic effect may reflect two independent actions of the drug, possibly on activity in the nucleus accumbens.

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.

Animal model and in vitro studies of anti neurofilament antibodies mediated neurodegeneration in Alzheimer's disease.

Alzheimer's disease (AD) is associated with serum antibodies directed specifically against phosphorylated epitopes highly enriched in the heavy neurofilament protein NF-H of cholinergic neurons. Prolonged immunization of rats with these molecules but not with other NF-H isoforms results in cognitive impairments. This animal model, termed experimental autoimmune dementia (EAD), supports a role for such antibodies in neurodegeneration in AD. In the present study we investigated the cellular and immunological mechanisms underlying the cognitive defects in EAD. Immunohistochemical studies revealed that IgG accumulate in the septum, hippocampus and in the entorhinal cortex of the EAD rats. This is accompanied by a marked reduction in the density of septal cholinergic neurons. An inverse correlation was observed between the level of IgG in the septum of individual EAD rats and the density of their septal cholinergic neurons. Time course studies revealed that the decrease in the density of cholinergic neurons in the septum of EAD rats and the accumulation of IgG in this brain area have the same time course and are both significant by three to four months following the initiation of immunization with cholinergic NF-H. The cognitive deficits of the EAD rats evolve more slowly and are pronounced only after six months following the initation of immunization. In vitro studies revealed that anti NF-H IgG bind to the outer surface of neurons in tissue cultures of rat forebrain and can affect neuronal viability. These AD and in vitro findings provide model systems for studying the mechanisms underlying the neuropathological effects of specific anti NF-H antibodies.

Uphill locomotion in mole rats: a possible advantage of backward locomotion.

Mole rats were videotaped while locomoting in a Plexiglas tube to evaluate the effects of inclination on locomotion. Animals moving uphill preferred to go backward using plantigrade foot postures, presumably to prevent sliding. Uphill backward locomotion also allowed animals to cope with changes in weight distribution between the hind and forelimbs without modifying footfall pattern relative to the direction of progression. When the animals did use uphill forward strides, they switched to asymmetrical gaits, which are associated with increased propulsive forces. These and prior results suggest that weight distribution and direction of progression can modify the natural pattern of stepping in mammalian quadrupeds.

Histology and enzymatic activity in the postnatal development of limb muscles in rodents.

The present work examines how increases in spontaneous motor capabilities during postnatal development are reflected in enzymatic activity and the histology of hindlimb muscles of the dormouse (Eliomys melanurus), the jird (Meriones tristrami), the vole (Microtus socialis), and the spiny mouse (Acomys cahirinus). The precocial neonate of the spiny mouse had the most advanced developmental state of young myofibers with striations as early as 1 week after delivery. At the same age, the altricial neonate vole had less developed muscles compared to the spiny mouse, but was more mature compared to other altricial species. The dormouse was the least developed, with numerous myoblasts and few myotubes at 1 week after delivery. These differences in myogenic development were conspicuous throughout postnatal development. Similar differences between the species were also evident at the biochemical level, as measured in the kinetics of activity of the enzyme creatine-phosphokinase immediately after delivery. On postnatal day 7, the creatine-phosphokinase level in the spiny mouse was fourfold higher than in the dormouse or vole. The enzymatic activity of acid phosphatase decreased during the first week postdelivery in the spiny mouse while peaking in the first, second, and third week in the jird, vole, and dormouse, respectively. These results support the notion that precocial species undergo certain developmental stages in utero, whereas, the same stages commence in altricials only postnatally. For the tested altricial species, the results illustrate that limb muscles in the vole, which displays more basic gaits, mature before limb muscles of the jird and dormouse, which display more specialized gaits.

Dosing regimen differentiates sensitization of locomotion and mouthing to D2 agonist quinpirole.

The study examines whether the order of administering 2 doses of quinpirole (0.5 and 8 mg/kg) affects the development of behavioral sensitization, as measured by the amount of forward progression and mouthing. Results show that injection of the high dose greatly enhances the subsequent locomotor response to the low dose of quinpirole, but not vice versa. Mouthing activity is not influenced by order of administration but is significantly greater at the higher dose of quinpirole. The present findings are consistent with a hypothesis that locomotor sensitization involves down-regulation of a D1 tone normally inhibitory to D2 locomotor activation.