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)
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 ?g.kg-1, 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 mg.kg-1, 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 mg.kg-1, sc) did not affect any of
the responses evoked by the serotonin.
Quipazine (5 mg.kg-1, 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.
