Limb Flicking Research Articles

Behavioral effects evoked by SKF 38393 and LY 171555 in adult cats

The aim of the present work was to study the behavioral effects elicited in adult cats by the selective D 1 agonist, SKF 38393, and the D 2 agonist, LY 171555, comparing their effects with those evoked by apomorphine. In 10 adult cats, 0.5, 1.0, 4.0, and 8.0 mg/kg IP of SKF 38393 were administered at random. A dose-response effect was observed related to alertness, indifference, and locomotion. The overall effect of SKF 38393 was inhibitory. To the same 10 animals, LY 171555 in doses of 0.25, 0.5, and 1.0 mg/kg were injected IP. This drug had an excitatory and more complex effect than what was observed with the D 1 agonist. Increases in locomotion, in alertness, indifference, fear, olfaction, pupillary dilation, hallucination, limb flicking, and head shaking were recorded. Apomorphine given to the same cats, in a dose equimolar to 1.0 mg/kg of LY 171555, elicited behaviors that resembled those elicited by the latter drug, but of a lesser intensity and duration. The interval between the different treatments was approximately 2 months. These results show clearly that the D 2 receptor is the main dopaminergic receptor involved in the mechanism of production of most of the behavioral effects produced by some of the dopaminergic agonist drugs like apomorphine.

Comparative analysis of the behaviors evoked by bromocriptine and quinpirole (LY 171555) in adult cats

1. The aim of this work was to compare the behavioral effects of bromocriptine and quinpirole, two agonists of the D-2 dopaminergic receptor, either injected alone or combined with the D-1 dopaminergic receptor, SKF 38393. 2. In ten adult mongrel cats the following experimental series were carried out: i) a dose-response study with bromocriptine administering 0.5 – 1.0 – 4.0 and 8.0 mg/kg s.c.; ii) a behavioral study injecting 4.0 mg/kg of bromocriptine plus 2.0 mg/kg of SKF 38393; iii) the same analysis administering 0.5 mg/kg of LY 171555 plus 1.0 mg/kg of SKF 38393, compared with the same dose of LY 171555 plus 4.0 mg/kg of SKF 38393; iv) an analysis of the behavioral effects of 8.0 mg/kg of bromocriptine compared with 1.0 mg/kg of quinpirole. 3. The main findings were: i) bromocriptine injected, in four different doses evoked decrease in locomotion, and increase in indifference, inappetence, pupillary dilation and limb flicks; ii) the combined administration of 4.0 mg/kg of bromocriptine plus 2.0 mg/kg of SKF 38393 did not elicit behavioral changes different to those produced by bromocriptine alone; iii) quinpirole (1.0 mg/kg) evoked more intense behaviors than bromocriptine (8.0 mg/kg); iv) comparing quinpirole injected alone with the combination of quinpirole plus SKF 38393, this latter treatment produced more intense behaviors than the former. 4. It is concluded: i) SKF 38393 potentiates the behavioral effects produced by quinpirole; this potentiation was not found when bromocriptine was combined with SKF 38393 and ii) the more intense behavioral effect elicited by quinpirole compared with bromocriptine may be explained by the fact that the latter drug is a selective D-2 agonist, whereas the former one is an agonist of the D-2 and the D-3 receptors.

A silicone pellet for continuous cocaine: Comparison with continuous amphetamine

An inexpensive silicone pellet is described for the continuous administration of cocaine for up to 5 days. Rats implanted with this pellet show minimal skin irritation and go through distinct behavioral stages, with an initial period of hyperactivity followed by motor stereotypies. Then, at 3–4 days after implantation, a variety of hallucinogen-like (“late-stage”) behaviors appear, including limb flicks, sudden startle responses, and repetitive mid-air grasping movements. Compared to continuous d-amphetamine, continuous cocaine induces decreased motor stereotypies but heightened “late-stage” behaviors.

Comparative study of the behavioral changes evoked by d-amphetamine and apomorphine in adult cats. Dose-response relationship

The behavioral effects of d-amphetamine and apomorphine administration were studied in 17 adult cats. The doses of amphetamine administered were 0.1, 0.5, 1.0 and 5.0 mg/kg; those of apomorphine, 0.1, 0.5, 1.0 and 2.0 mg/kg. These two drugs evoked in the same animal market differences in behavioral responses. Amphetamine induced a dose-dependent hypomotility, which was marked with the higher doses. In addition, rhythmic, bilateral slow movements of the head as a mode of stereotypy, indifference to the environment and dose-dependent increase in respiratory rate. Apomorphine elicited limb flicking, dose-dependent hypermotility and increase in olfactory behavior, the last two reactions with stereotypy characteristics. The animals appeared as if being scared, hyperreacting to sudden stimuli and showing total indifference to the surrounding environment. There were marked differences in behavioral responses evoked by these two agonists of the catecholaminergic system. These data do not conform with the behavioral reactions reported in the rat by other investigators. The disagreement with other communications is probably due to differences in reactivity of the species employed. The processes involved in the diversity of the behavioral responses of the cat to the administration of amphetamine and apomorphine have not been delucidated.

Apomorphine-induced limb flicks in cats: the role of dopamine receptors located outside the blood-brain barrier.

Apomorphine-induced limb flicks in cats have been ascribed to a central dopamino-mimetic action of the drug. In these experiments we investigated the role of receptors located outside the blood-brain barrier (BBB) in the induction of limb flicking. Domperidone, a dopamine-receptor blocker which does not readily pass through the BBB, antagonised the induction of limb-flicks induced by apomorphine. This suggests that limb flicking behaviour may involve interactions with receptors located before the BBB. In contrast, 6-amino-5,6,7,8-tetrahydro-1,2-naphtalenediol HBr (6-ATN), a dopamine-agonist which does not penetrate the BBB, did not induce limb flicks, indicating that receptor stimulation outside the BBB alone is not sufficient to induce limb flicks. We suggest that limb flicks in cats is a behaviour which can be elicited by combined activation of centrally located dopamine receptors and dopamine receptors in the area postrema.

Antagonism of behavioral effects of bromocriptine by prolactin in female cats

The effects of the dopaminergic agonist bromocriptine (BC) and exogenously administered prolactin (PRL) on the spontaneous behavior of female cats were investigated. The objective was to test whether BC-induced behavioral effects may be antagonized by PRL. BC (6 mg/kg ip) administration induced abnormal behaviors such as limb flicks, abortive grooms, head/body shakes, and hallucinatory-like behavior/escape as well as excessive grooming. PRL (5 mg/kg ip) administration induced biphasic changes in grooming. The first change was an increase in grooming frequency averaging 256% of baseline control values and lasting for 1 h. This change was followed by reductions in grooming of 75 and 82.5% below baseline during Hours 2 and 3 postinjection, respectively. Combined BC and PRL treatment antagonized the frequency of BC-induced motor effects such as limb flicks, abortive grooms, and head/body shakes. Limb flicks occurred nine times more often 2 h after BC alone than after BC and PRL. The combined treatment also antagonized the excessive grooming observed after separate administrations of BC and PRL. The observed interactions between PRL and BC behavioral effects support the notion that PRL may be an important modulator of dopamine-dependent motor behavior in female cats.

Metabolite involvement in the behavioral effects of bromocriptine in cats

There is a lag phase of 30–60 min before the onset of bromocriptine (BC) action. This delay may be necessary for the formation of active metabolites. The objective was to determine whether the abnormal behavioral effects induced by BC involve active hepatic metabolites. Thus, we studied the effect of an inhibitor of hepatic hydroxylation metabolism (SKF 525A) on the behavior of BC-treated cats. Experiments began after six weeks of habituation and involved i.p. injections of: (1) propylene glycol (drug vehicle); (2) SKF 525A (70 mg/kg); (3) BC (10 mg/kg); and (4) SKF 525A followed 30 min later by BC. Each cat received the four treatments with two weeks elapsing between consecutive experiments. The frequency of 12 behaviors was scored for 60 min after 1 h posttreatment. BC alone induced emergent behavioral changes (hallucinatory-like, limb flicks, abortive grooms) that were not observed following control injections (vehicle and SKF 525A). There was a complete elimination of BC-induced hallucinatory-like behavior/escape by SKF 525A pretreatment. Other emergent behaviors were similarly reduced but persisted in all cats. The large frequency of grooming induced by BC was significantly reduced. SKF 525A pretreatment was correlated with a significant increase in staring and quiet sitting and a failure of BC to increase activities such as rubbing, treading and kneading. But many other BC-induced behaviors showed no changes. The data demonstrated that particular BC-induced changes in cats are antagonized by SKF 525A. The behavioral suppression caused by SKF 525A is compatible with the involvement of active hepatic metabolites from BC. The findings suggest that hepatic metabolites resulting from hydroxylation, rather than hydrolysis, of the BC parent molecule are responsible for the hallucinatory-like behavior/escape.

Separation of tolerance to the behavioral effects of LSD from changes in serotonin receptor binding in rats

Nearly complete tolerance to a test dose of 50 μg/kg of LSD occurred within 24 h following an initial dose of 50 μg/kg of the drug, using limb flicking and abortive grooming as behavioral indices in the cat. No changes in serotonin receptor binding were observed at this time. However, chronic administration of LSD (50 μg/kg every 12 h for 6 days) produced a significant decrease in serotonin receptor binding in both the forebrain and brainstem plus spinal cord. These data suggest that the behavioral effects of LSD and tolerance to LSD as measured here are mediated predominantly by different sites.

Continuous low-level apomorphine administration induces motor abnormalities and hallucinogen-like behaviors

Continuous low-level (0.825 mg/kg/h for 20 h) administration of AP through SC in-dwelling silicone reservoirs in the rat induced behavioral and biochemical changes that were similar to those induced by low levels (0.1 mg/kg) of acutely administered AP (decreased behavioral activity and decreased dopamine metabolism in the striatum). With longer periods of continuous AP exposure (40 h or more) the activity-depressing effects of low-level AP diminished. Concurrently a novel behavioral syndrome emerged characterized by limb flicks, body shakes, sudden orienting responses, and motor abnormalities, such as tremors of the jaw muscles, chewing movements, prominent tongue extensions, and body 'tics'. This behavioral syndrome became more apparent following cessation of drug treatment. These novel behavioral changes, which were accompanied by increased behavioral responsiveness to acutely administered AP and amphetamine, were correlated with increased levels of dopamine, homovanillic acid, and 3,4-dihydroxyphenylacetic acid in the striatum but not the nucleus accumbens. This novel behavioral syndrome appears to reflect a rebound increase in dopaminergic mechanisms in striatum following their chronic suppression by low levels of AP.

Behavioral CRs elicited by a lithium- or an amphetamine-paired contextual test chamber

The behavioral CRs elicited by a drug-paired contextual cue in rats were measured in a series of experiments. The first three experiments measured the pattern of CRs elicited by a lithiumand an amphetamine-paired CS chamber. The final experiment measured the pattern of URs elicited by lithium or amphetamine when administered in the same chamber. The suppression of grooming-related activities (body washing, face washing, and/or scratching) appeared as a nonspecific effect of both drug USs that was capable of becoming conditioned to the contextual chamber cue. A number of other behaviors differed among conditions, which provides evidence that contextual cue-drug associations are drug-specific. Of the behaviors that differed between the two US drug conditions, lithium CRs showed evidence of behavioral activation (enhanced rearing and limb flicking), but amphetamine CRs showed evidence of behavioral suppression (line crossing, rearing, and shaking). The UR patterns shared some similar and some dissimilar elements of the CR patterns elicited by the CS chamber for both lithium and amphetamine; in fact, by the activity and rearing measures, the URs and CRs were opposite in direction. The results exclusively supported neither stimulus substitution nor conditioned compensatory response accounts of Pavlovian conditioning; instead, each process appears to have accounted for different components of the overall CR pattern.

Tolerance to the behavioral effects of bromocriptine in cats.

Repeated daily administration of LSD and related hallucinogens produces tolerance to their behavioral effects. The objective was to test whether repeated administration of bromocriptine (BC) produced behavioral tolerance. Experiments began after 4 weeks of habituation and baseline measurements. Cats were then injected daily with BC (10 mg/kg i.p.) for 7 days. The frequency of 40 different behaviors and neurological signs were scored for 60 min after one h post-injection. There was a rapid tolerance to the 'emergent' behavior induced by BC. In the case of hallucinatory-like behavior/escape, tolerance to a second dose of BC one day after a first dose was virtually complete. A substantial tolerance to BC effects such as abortive grooming, increased investigatory-play behavior and grooming occurred within one day. The decrease in sleep produced by BC was absent at the fourth day. Limb flicks and body shakes decreased but persisted until the seventh day. There was also tolerance to emotional behavior (irritability, rage, threat, flight) but motor effects (circling, ataxia, hypokinesia) remained throughout the week. Autonomic reactions were unaffected by BC. The results indicated that the psychotomimetic effects (but not the motor or autonomic) of BC showed rapid and long-lasting tolerance. These studies suggest that BC-induced alterations in cats parallel parameters of action of hallucinogens in humans.

Long-lasting behavioral effects of bromocriptine in cats.

The objective was to determine the behavioral effects and duration of action of bromocriptine (BC) doses from 6 to 60 mg/kg i.p. Cats were housed in large outdoors cages designed for prolonged observation using an ethological approach. Baseline behavior was measured after a 3 month period of habituation. The frequency of 12 behaviors was then scored continuously over 12 h following BC administration. Cats were also observed for one h at 24, 30, 36 and 48 h post-drug. The behavioral effects of BC were remarkably similar to those of LSD and psilocybin but lasted much longer. Treated cats showed hallucinatory-like and escape behavior. Abnormal involuntary movements such as limb flicks, abortive grooming, and head and body shakes were also evoked with a dose-dependent frequency. Lower doses (6-20) produced generalized arousal, but larger doses (30-60) resulted in a decrease in arousal. After 30 mg/kg, hallucinatory-like behavior and general activity (rubbing, treading, kneading) were high at 48 h post-drug, but there were no longer abnormal movements. Behavioral suppression followed the 60 mg/kg dose and peak effects were at 96 h post-injection. This model may prove useful to further study the neural basis of the psychoactive effects of BC.

Behavioral conditioned responses across multiple conditioning/testing trials elicited by lithium- and amphetamine-paired flavors

The present experiment measured the pattern of conditioned responses across 10 conditioning/testing trials which were elicited by an intraoral presentation of either a lithium- or an amphetamine-paired flavor. A nonspecific conditioned response pattern of suppressed limb flicking after five conditioning trials and of suppressed scratching after six conditioning trials was supported by both drugs. Lithium-specific increased activity level after one conditioning trial and chin rubbing after two conditioning trials were observed across conditioning/testing days. The lithium-specific conditioned responses were not the result of a stronger flavor aversion, because both lithium and amphetamine produced equivalent flavor avoidance responses across the 10 conditioning/testing trials. The results support previous research which suggests that flavor aversions produced by lithium and amphetamine are produced by different unconditioned response mechanisms.

Some behavioral effects of hallucinogens are mediated by a postsynaptic serotonergic action: Evidence from single unit studies in freely moving cats

Although central serotonergic systems appear to be linked importantly to the mechanism of action of a variety of hallucinogenic drugs, the nature of this interaction has remained unclear. In the present study, the question of whether the critical link is presynaptic or postsynaptic was examined in cats. Behaviorally inactive doses (1.0 mg/kg) of the serotonin receptor antagonists mianserin, ketanserin or metergoline effectively blocked behavior, as measured by the cat limb flick response, elicited by either LSD (50 μg/kg) or DOM (250 μg/kg) but not that resulting either from lisuride (50 μg/kg) or a high dose of apomorphine (4 mg/kg). Pretreatment with 1.0 mg/kg of mianserin, which completely attenuated LSD's behavioral effect, failed to alter LSD-induced depression of mesencephalic serotonergic neuron discharge. These results demonstrate that at least some of the behavioral effects of LSD can be blocked by pharmacological antagonism of postsynaptic serotonin receptors which leaves LSD's presynaptic synaptic effect unaffected. Thus, the behavioral and possibly psychoactive, effects of hallucinogens appear to be attributable to an action at 5HT 2 receptors, presumably located postsynaptically.

Behavioral effects of serotonergic and dopaminergic drugs in cats following chronic amphetamine administration

Chronic administration of amphetamine to cats (twice daily, in doses increasing from 5 to 15 mg/kg over a 10-day period) elicited a number of behaviors e.g. limb flicking, abortive grooming, and excessive head shaking, which were originally proposed as an animal behavioral model for studying the actions of hallucinogens that depress central serotonergic neurotransmission. This drug treatment produced large decreases (approximately 50%) in central nervous system serotonin (5HT) and its major metabolite, 5-hydroxyindoleacetic acid, and even larger decreases (approximately 90%) in the levels of dopamine (DA) and norepinephrine. Administration of the 5HT precursors L-tryptophan (25 mg/kg i.p.) or L-5-hydroxytryptophan (12.5 mg/kg i.p), a direct-acting 5HT agonist (quipazine, 1 mg/kg i.p.) or a monoamine oxidase inhibitor (tranylcypromine, 4 mg/kg i.p.) produced no significant changes in these behaviors in cats treated chronically with amphetamine. Administration of a 5HT reuptake blocker (fluoxetine, 5 mg/kg i.p.) produced a small, but significant, decrease in the frequency of occurencence of these behaviors in amphetamine-treated cats. L-Dihydroxyphenylalanine (L-DOPA, 20 mg/kg i.p.) greatly potentiated these behaviors in cats chronically treated with amphetamine, but L-DOPA was totally ineffective in eliciting these behaviors in naive animals. The behavioral effects of apomorphine (2 mg/kg i.p.) were also significantly potentiated by chronic amphetamine pretreatment. The amino acid precursor of DA, L-tyrosine (25 mg/kg i.p.), and a DA reuptake blocker, bupropion (5 mg/kg i.p.) were without significant effect on these behaviors in amphetamine-treated cats. The data suggest that these cat behaviors are elicited by an action at central DA receptors and that these receptors become supersensitive following chronic amphetamine administration. Furthermore, there may be a qualitative change in DA receptors, since L-DOPA is very effective in potentiating these behaviors in cats treated chronically with amphetamine, but is totally ineffective in naive cats.

Tolerance develops to LSD while the drug is exerting its maximal behavioral effects: Implications for the neural bases of tolerance

Tolerance to a test dose of 50 mg/kg of LSD occurred within 0.5–1.0 h following an initial dose of 10 mg/kg of the drug, using limb flicking and abortive grooming as behavioral indices in the cat. These findings represent an example of very rapidly developing drug tolerance using a behavioral index. These data are discussed within the context of hypotheses concerning the neurochemical bases of tolerance to LSD.

Antagonism of a behavioral effect of LSD and lisuride in the cat.

These experiments investigated the role of serotonin 5-HT) and dopamine (DA) receptors in the limb-flick (LF) response elicited by the hallucinogenic ergot LSD and its nonhallucinogenic structural congener lisuride. Pretreatment with either the 5-HT antagonist pizotifen (BC-105) or the DA antagonist haloperidol significantly attenuated LF elicited by either LSD or lisuride. Thus, the LF model failed to differentiate the neuropharmacological actions of LSD and lisuride. Cocaine also prevented LSD- and lisuride-elicited LF simply by reducing the activity of cats (response competition) suggesting the need for caution in interpreting 'antagonism' of the LF response.

Lack of synergism and cross tolerance between tactile stimulus- and LSD-induced limb flicking in the cat

The hypotheses that LSD-induced limb flicking, as well as tolerance to this behavioral effect following repeated drug administration, are due to alterations in somatosensory thresholds were tested by examining the rate of limb flicking to LSD alone, saline plus water on the limbs, or LSD plus water on the limbs, and by comparing the limb flick rate with water on the limbs in drug tolerant versus non-tolerant conditions. Cats exhibited the same rate of limb flicking in response to water on the limbs regardless of whether they were pretreated with saline of LSD. Furthermore, there was no significant difference in the tactile stimulus-induced rate of limb flicking in the tolerant versus non-tolerant states. These data suggest that LSD-induced limb flicking is not simply a function of drug-induced altered somatosensory thresholds, but is apparently reflective of more complex neural processes.

Nonconsummatory and consummatory behavioral CRs elicited by lithium- and amphetamine-paired flavors

Various behavioral CRs elicited by saccharin solution previously paired with either lithium or amphetamine were measured in a series of four experiments. With one conditioning trial, lithium (Experiment 1), but not amphetamine (Experiment 2), produced nonconsummatory behavioral evidence of conditioning in the form of chin-rub CRs; both drugs, however, produced strong flavor aversions. With 3 conditioning trials, lithium- and amphetamine-paired flavors elicited a pattern of agitated activity, characterized by increased general activity, rearing duration, and body temperature, when the flavor was forcibly presented through an intraoral cannula (Experiment 3). When the flavor was presented in a single-bottle test (Experiment 4), 3 conditioning trials produced a similar pattern of agitated activity characterized by increased general activity, rearing (duration and frequency), stretching (duration and frequency), and limb flicking. Although both drugs supported the pattern of increased agitation-related CRs, only the lithium-paired flavors elicited chin-rub CRs (Experiments 1, 3, and 4). The difference between the drug conditions was not the result of a greater saccharin aversion in the lithium-conditioned group than in the amphetamine-conditioned group (Experiment 4). The results are related to findings that suggest that flavor aversions are mediated by a shift in the hedonic properties of the drug-paired flavors.

Raphe unit activity in freely moving cats: Effects of quipazine

Quipazine produced a dose-dependent decrease in the discharge rate of serotonin-containing neurons in the dorsal raphe nucleus of freely-moving cats. This ranged from a 10% decrease at 0.5 mg/kg, (i.p.), to a virtually complete depression of activity at 5.0 mg/kg. The effects of quipazine on raphe units occurred with a short latency (5–10 min) and its duration of action was dose-dependent and lasted from 1 to 6 hr. The degree of depression of raphe unit activity was directly related to the frequency of occurrence of a number of behaviors such as limb flicking and abortive grooming. There was a close temporal correlation between the depression of raphe unit activity and the occurrence of these behaviors. These data reveal that quipazine produces behavioral and raphe unit changes similar to those observed after administration of hallucinogens with an indole nucleus.