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16 mars 2006
Eur J Pharmacol
Behavioral effects of quipazine in the cat
Trulson ME, Brandstetter JW, Crisp T, Jacobs BL
Drinking sucrose or saccharin enhances sensitivity of rats to quinpirole-induced yawning. Serafine KM


Administration of quipazine to cats elicits a number of behaviors, such as limb flicking abortive grooming, investigatory behavior and hallucinatory-like behavior, which we have previously proposed as an animal behavioral model for studying the actions of LSD and related hallucinogens. While recent studies have indicated that these model behaviors may not be totally specific for hallucinogenic drugs, the model can still be useful for studying drug action. Quipazine (0.5-5.0 mg/kg i.p.) produced significant increases in limb flicking, abortive grooming, investigatory behavior, hallucinatory-like behavior grooming, head and body shakes, staring and yawning. These behavioral changes persisted for 1-6 h, depending on the dose of quipazine employed. Administration of quipazine (5.0 mg/kg per day) for 5 consecutive days produced no significant tolerance effect on any of these model behaviors. These quipazine induced behavioral changes were potentiated by pretreatment with apomorphine, and partially blocked by pretreatment with haloperidol. Quipazine-induced behavioral changes were potentiated by prior serotonin depletion with p-chlorophenylalanine, and completely blocked by pretreatment with a monoamine oxidase inhibitor or the serotonin precursor, L-5-hydroxytryptophan. These quipazine-induced behavioral changes were also blocked by pretreatment with the serotonin receptor blockers, cinnanserin, methysergide or cyproheptadine. The mechanism of action of quipazine, as well as the neuropharmacology of the limb flick model, is discussed in the content of these studies with serotonergic and dopaminergic drugs.
1. Introduction 
Several recent studies have investigated the behavioral and neurochemical effects of quipazine. This compound was originally reported to act as a serotonin agonist in various smooth muscle preparations; however, recent studies have indicated that quipazine can also act as an antagonist to serotonin in certain ganglionic and smooth muscle preparations. Quipazine has been reported to have multiple effects on the central serotonergic system, including a direct stimulation of serotonin receptors, inhibition of serotonin reuptake and inhibition of monoamine oxidase, as well as decreasing the rate of synthesis and turnover of serotonin. These latter effects are considered to be secondary to a primary action of increasing the functional activity in the central serotonergic system by direct receptor activation. In addition to its multiple effects on the serotonergic system, quipazine has also been reported to produce significant effects on central dopamine, norepmephrine and acetylcholine, but at least some of these effects may be secondary changes due to interactions among the various neurotransmitter systems.
Behavioral studies have revealed that quipazine induces head twitches in mice, elicits a 'serotonin syndrome' consisting of head weaving, forepaw treading, hindlimb abduction, etc., in rats, 'limbjerks' in monkeys, and antagonizes tonic immobility in birds. Finally, quipazine has been shown to transfer to lysergic acid diethylamide (LSD) and other hallucinogens in a number of drug discrimination tasks. Interestingly, serotonin has been implicated in the mediation of all of these behavioral processes.
Several years ago we introduced an animal behavioral model for studying the actions of LSD and related hallucinogenes, which were believed to act via an inactivation of central serotonergic neurotransmission. The primary components of this model are limb flicking and abortive grooming, behaviors which are very rarely seen in saline-treated cats but occur with a high frequency after administration of LSD and other hallucinogens such as psilocin, mescaline, 2,5dimethoxy- 4- methylamphetamine (DOM), and N,N - dimethyltryptamine (DM1). Furthermore, these model behaviors can be elicited by doses of hallucinogens within the human range, and they parallel the major parameters of the drugs' action in humans, such as the duration of the behavioral changes and the development of tolerance. Since the introduction of this model, it has been used by a number of laboratories to study the actions of various hallucinogens, as well as to evaluate the effects of drugs which might modulate the action of known hallucinogens. However, recent studies have questioned whether these behaviors are elicited exclusively by hallucinogens, and whether they are specifically attributable to decreased central serotonergic functio. In spite of these apparent shortcomings, we believe that this behavioral syndrome in the cat will continue to be useful in studying drug action.
Since a number of the studies with quipazine described above indicated that this compound may possess hallucinogenic properties, in the present study we examined the behavioral effects of quipazine in our cat model and compared them with those produced by LSD.
4. Discussion
The present data demonstrate that administration of quipazine to cats elicits a number of unique behaviors, such as limb flicking, abortive grooming, investigatory and hallucinatory-like behavior, which we have previously proposed as an animal behavior model for studying the actions of LSD and related hallucinogens. Recent investigations (described below), however, have questioned whether these behaviors are specific to hallucinogens and are attributable to decreased central serotonergic neurotransmission.
Of all these behavioral effects, the limb flick has proven to be the most sensitive and reliable index of drug action in previous studies. The limb flick is the best behavioral index because it is very rarely seen in saline-treated animals and occurs with a high frequency following drug administration. Furthermore, it is a behavior that is very easy to observe and quantify. In the present study, the limb flick showed the highest percentage increase in frequency of occurrence following quipazine administration, and persisted after all other quipazine-induced behavioral changes had subsided at all dose levels of the drug.
Chronic administration of quipazine (5.0 mg/kg per day for 5 consecutive days) produced no significant tolerance effect on any of the behavioral measures in the present study. However, there was a tendency for many of the behaviors to decrease in frequency of occurrence across days and, therefore, it may be possible to demonstrate a significant tolerance effect to quipazine following its repeated administration if the appropriate pretreatment regimen (dose and duration of drug administration) could be determined. It is noteworthy, however, that the present findings are in sharp contrast to the nearly complete tolerance that develops to LSD following a single injection. These results are apparently not due to differences in the half-life of the drugs, since the behavioral effects of quipazine (5 mg/kg) persist longer than those following LSD (10 gig/kg) at doses employed in tolerance studies.
Our previous studies have indicated that the magnitude of the behavioral changes observed in the present experiments is modulated by the dopammergic system. Drugs such as LSD and DOM, which possess dopaminergic agonist properties in addition to their serotonergic effects, produce much larger behavioral changes than drugs such as DMT and psilocin, which are virtually devoid of direct dopaminergic actions at the doses employed in these studies. Our present studies with quipazine strongly support the hypothesis of a dopaminergic involvement in eliciting these behaviors. Pretreatment with apomorphine, a directacting dopamine agonist, greatly potentiated many of the behavioral effects of quipazine, while pretreatment with haloperidol, a dopamine receptor blocker, attenuated many of the quipazine-induced behavioral changes. However, these latter effects may be due to a general depressant action of the neuroleptic, since quipazine is reported to have negligible dopaminergic actions at low doses. This is supported by the fact that increasing the dose of haloperidol to 1-2 mg/kg completely blocks all quipazine-induced behavioral changes (unpublished observations). Interestingly, pretreatment with L-DOPA, the immediate precursor to dopamine, produced no significant effects on quipazine-induced behavioral changes, with the exception of an inhibition of yawning. These differences in the modulatory effects of apomorphine versus L - DOPA on quipazine induced behaviors may be due to a greater potency of apomorphine on central dopamine receptors, as opposed to the small increase in central dopamine which occurs following 10 mg/kg of L-DOPA. It is worth emphasizing that apomorphine, administered alone, produces a significant increase in the limb flick rat. This drug reportedly does not decrease central serotonergic neurotransmission. Therefore, while our original hypothesis (described below) was that decreased serotonergic transmission is necessary for eliciting limb flicks, and dopamine agonist actions increase the magnitude of the behavioral effects, the above data suggest an alternative hypothesis. That is, a dopamine agonist action may be the primary action in eliciting limb flicks, and a secondary serotonergic action may modulate the magnitude of the behavioral effects. This issue will require further study.
LSD and related hallucinogens were originally hypothesized to act via brain serotonin: an inactivation of central serotonergic neurotransmission was considered to be a necessary and sufficient condition for hallucinogenesis in humans, and for inducing limb flicks and related behaviors in cats. Although the hallucinogenic potency of PCPA in humans is controversial, serotonin depletion by PCPA has been shown to elicit limb flicks in cats. Quipazine, which is very effective in eliciting limb flicks, is generally regarded as a serotonin agonist. In view of this, it is interesting that prior depletion of serotonin by chronic PCPA administration greatly potentiates the behavioral effects of quipazine. This finding is consistent with previous studies which reported that PCPA pretreatment potentiates quipazine-induced hyperactivity in rats. One explanation of these results would be that chronic serotonin depletion via PCPA administration induces supersensitivity at postsynaptic serotonin receptors. However, several investigations of this issue have demonstrated a lack of development of supersensitivity following chronic PCPA administration. Another explanation, which has been suggested by other investigators, is that partial serotonin depletion allows easier access of quipazine to postsynaptic serotonin receptor sites, so that the drug is more effective as a direct serotonin agonist. Limb flicks and related behaviors are apparently not elicited simply by enhanced activity at postsynaptic serotonin receptors because administration of L-5HTP, monoamine oxidase inhibitors, or serotonin reuptake blockers do not elicit these behaviors. Indeed, pretreatment with L 5HTP or a monoamine oxidase inhibitor to increase synaptic serotonin was found to block quipazine-induced behavioral changes in the present study. On the other hand, pretreatment with serotonin receptor blockers was found to block quipazine-induced behavioral changes as well. These latter findings agree well with recent studies by Marini and Sheard (1981) who found that pretreatment with methysergide blocked the behavioral effects of LSD in cats.
The fact that serotonin depletion via PCPA administration and serotonin receptor blockade produce opposite effects on quipazine-induced behaviors may seem inconsistent. However, it has recently been demonstrated that there are two types of central serotonin receptors which subserve different physiological functions, i.e. serotonin exerts an inhibitory synaptic action on one type of receptor and an excitatory action on the other. Serotonin receptor blockers antagonize only the excitatory synaptic actions of serotonin, while PCPA apparently depletes serotonin throughout the CNS. Therefore, the significance of the opposite effects of PCPA and serotonin receptor blockers on quipazine-induced behaviors cannot be assessed in the absence of knowledge of the neuronal substrate which mediates these behaviors.
In our original studies, we tested a wide variety of psychoactive drugs for their behavioral effects in cats and found that certain behaviors such as limb flicking and abortive grooming were elicited only by LSD and related drugs which produce hallucinations in humans. Quipazine may fit this pattern, since some studies with humans indicate that this drug possesses hallucinogenic properties. Other investigators, however, found no evidence for hallucinogenic activity of quipazine. It is important to note that moderate to high doses of quipazine were not tested in these human studies, due to the onset of dysphoric effects such as nausea. Therefore, the hallucinogenic potency of quipazine is unclear.
There have recently been some apparent exceptions to the general rule that these behaviors are elicited only by hallucinogenic drugs. First, recent studies have found that lisuride, an ergot derivative structurally related to LSD, is very effective in eliciting these behaviors in cats. This drug has rarely been reported to produce hallucinations after acute administration to humans. Secondly, pilocarpine, a muscarinic cholinergic agonist which does not decrease central serotonergic transmission, has been found to be effective in eliciting these behaviors in cats. While pilocarpine does not possess hallucinogenic properties similar to those of LSD and related compounds, it does have some hallucinogenic potency. And thirdly, apomorphine, an apparently non-hallucinogenic drug which does not decrease serotonergic neurotransmission, has also been found to elicit limb flicks in cats. It is important to point out, however, that the above-mentioned drugs produce dysphoric effects at moderate to high doses in humans and, therefore, cannot be tested at doses comparable to those used in cats.
In conclusion, the limb flick and related behaviors may not be elicited exclusively by hallucinogenic drugs that depress central serotonergic neurotransmission. However, we believe that this behavioral syndrome in the cat will continue to be useful in studying the parameters and mechanisms of action of hallucinogenic drugs.

Behavioral and neuropharmacological evidence that serotonin crosses the blood-brain barrier in Coturnix japonica (Galliformes; Aves)
Braz. J. Biol., 67(1): 167-171, 2007
Polo, PA., Reis, RO., Cedraz-Mercez, PL., Cavalcante-Lima, HR., Olivares, EL., Medeiros, MA., Côrtes, WS. and Reis, LC.
Departamento de Ciências Fisiológicas, Instituto de Biologia, UFRuralRJ, CEP 23890-000, Seropédica, RJ, Brazil
This study was carried out aiming to reach behavioral and neuropharmacological evidence of the permeability of the blood-brain barrier (BBB) to serotonin systemically administered in quails. Serotonin injected by a parenteral route (250-1000 ?, sc) elicited a sequence of behavioral events concerned with a sleeping-like state. Sleeping-like behaviors began with feather bristling, rapid oral movements, blinking and finally crouching and closure of the eyes. Previous administration of 5-HT2C antagonist, LY53857 (3, sc) reduced the episodes of feather bristling and rapid oral movements significantly but without altering the frequency of blinking and closure of the eyes. Treatment with the 5-HT2A/2C antagonist, ketanserin (3, sc) did not affect any of the responses evoked by the serotonin. Quipazine (5, sc) a 5-HT2A/2C/3 agonist induced intense hypomotility, long periods of yawning-like and sleeping-like states. Previous ketanserin suppressed gaping responses and reduced hypomotility, rapid oral movements and bristling but was ineffective for remaining responses induced by quipazine. Results showed that unlike mammals, serotonin permeates the BBB and activates hypnogenic mechanisms in quails. Studies using serotoninergic agonist and antagonists have disclosed that among the actions of the serotonin, feather bristling, rapid oral movements and yawning-like state originated from activation of 5-HT2 receptors while blinking and closure of the eyes possibly require other subtypes of receptors.