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PHARMACOLOGICAL CONTROL OF
AGGRESSION: FROM ANIMAL STUDIES TO HUMANS.
Cherek, Don R.
Department of Psychiatry and Behavioral Science, University of Texas Health Science, USA.
This symposium will present data supporting a major
role for serotonin and possibly GABA in the regulation of aggressive behavior in
animals and humans and demonstrate consistency in studies conducted across and
animal and human subjects. Studies with mice high or low in aggressive behavior
indicate that more sensitivity in the postsynaptic 5-HT system among the high
aggressive mice. Also, systemic and localized administration of 5-HT1a and GABA-A
agonists inhibited aggressive behavior. Data will be presented from rodents
studying aggressive behavior induced by apomorphine which is suppressed by
5-HT1a agonists and GABA agonists. Human
laboratory studies will present data that indicates that 5-HT releasing agent d-fenfuramine
and the GABA-B agonist baclofen selective decrease aggressive behavior. Lastly,
clinical and laboratory studies will be reviewed which support a role for 5-HT
in regulation and control of human aggression.
Clinical trials of potentially useful drugs to alter and comtrol human
aggression are lacking
IS-4.1.-TRAIT VERSUS STATE AGGRESSION IN RATS AND MICE: DIFFERENTIAL
INVOLVEMENT OF SEROTONERGIC NEUROTRANSMISSION
van der Vegt, B.J., Koolhaas, J.M.
and de Boer, S.F.
Department of Animal Physiology, University of Groningen, Haren, The Netherlands
experiments have shown an inverse relationship between brain serotonergic (5-HT)
neurotransmission and aggression, in humans and in animals. This lead to the
so-called 5-HT deficiency hypothesis of aggression. This hypothesis is based on
aggression as a trait characteristic, but it is questionable whether it can be
extrapolated to aggression as a state. Therefore, in the studies presented here,
a distinction is made between the individual propensity to express aggression,
as a trait characteristic, and the actual display of aggressive behaviour as a
state phenomenon. In mice, selectively bred for high or low levels of
aggression, there is an upregulation of postsynaptic 5-HT1a receptors
in the aggressive individuals, both in the number of receptors and in mRNA
expression. In a randomly bred strain of rats, with a large inter-individual
variation in aggressiveness, such a difference in number of receptors could not
be shown. However, in a functional challenge test, i.e. the hypothermic response
after administration of a 5-HT1a agonist, the response was strongest
in the aggressive individuals, both in rats and mice. These findings show that
the postsynaptic part of the 5-HT system is more sensitive in aggressive
individuals than in non-aggressive ones. This may be a compensatory upregulation
due to a lower basal 5-HT neurotransmission in these aggressive individuals,
which is in accordance with the 5-HT deficiency hypothesis. With regard to the
act of aggressive behaviour itself, the effects of systemic administration of
5-HT1a or 1b agonists, or local administration of a 5-HT1a
or GABAA agonist in the dorsal raphe nucleus were studied. Inhibition
of 5-HT neurons by these means lead to inhibition of aggression. This points to
an activation of the 5-HT system when aggressive behaviour is actually
performed. From these findings the hypothesis is raised that high aggressiveness
as a trait characteristic is associated with a low 5-HT neurotransmission, while
aggressive behaviour itself is correlated with an increase in 5-HT transmission.
of serotonin- and GABAergic compounds on apomorphine-induced aggressive
behaviour in male rats
L., Skrebuhhova-Malmros, T., Pruus, K. and Matto, V.
Department of Pharmacology, University of Tartu, 50090, Tartu, Estonia
Repeated treatment with low doses (0.5-1 mg/kg s.c.
1-2 weeks) of apomorphine (APO), an unselective dopamine agonist on pre- and
postsynaptic receptors, is inducing spontaneous aggressive behaviour in male
rats. This pathology of behaviour has been proposed to be an equivalent to
affective or psychotic aggressive behaviour in humans. The APO-aggressiveness is
effectively antagonised by D1 and D2 receptor blockers,
neuroleptics, opiates and intensified by adren- and dopaminergic agonists
(direct and indirect). In our experiments on male Wistar rats we analysed the
effect of 5-HT receptors’ agonists and antagonists and GABA agonists, also
different antidepressants on APO-aggressiveness. Both serotonin- and GABAergic
mechanisms are involved in different pathologies of affective behaviour –
anxiety, depression, dysthymia, impulsivity, panic and sleep disorders etc.
Aggressive behaviour was measured in specially designed cages, where the animals
were put pairwise immedisately after APO injection. The time of latency and the
intensity of aggressiveness were measured. 5-HT1A agonist buspirone
suppressed aggressiveness but gepirone and 8-OH-DPAT did not have significant
effect. 5-HT2A agonist DOI (1-3 mg/kg) shortened the latency and
increased the intensity of aggressive attacks. Antagonists of 5-HT2A
receptors ketanserin (2.5-5 mg/kg) and ritanserin (5 mg/kg) moderately increased
the latency but had no effect on the intensity of aggressiveness. Risperidone
(0.1-0.3 mg/kg) an atypical neuroleptic drug with high potency of 5-HT2
and D2 blocking activity suppressed aggressiveness completely. 5-HT2
antagonist quipazine attenuated APO-aggressiveness significantly. 5-HT3
antagonists MDL-72222 (4 mg/kg) and tropisetron (0.1-0.3 mg/kg) increased the
latency of aggressiveness but ondansetron was ineffective. GABAB
receptor agonists phenibut (100 mg/kg) and baclofen (2-8 mg/kg) had suppressive
effect on aggressiveness. Also benzodiazepines
(indirect GABA agonists) suppressed APO-aggressiveness. Noradrenergic
antidepressants desipramine and maprotiline facilitated the APO-aggressiveness,
serotoninergic antidepressants fluoxetine and citalopram had some suppressive
effect only in high doses (40 mg/kg), but their antiaggressive effect was
increased in combination with serotoninopotentiating drugs. Serotoninergic
antidepressants trazodone (5-20 mg/kg) antagonized APO-aggressiveness. The
results indicate that 5-HT1A, 5-HT2A and GABA receptors
are modulating the APO-induced aggressive behaviour. 5-HT1A agonists
have some antiaggressive and 5-HT2A agonists proaggressive effect.
of the Effects of Serotonergic and GABAergic Drugs on Human Aggression and
D.R. and Lane, S.D.
Department of Psychiatry and Behavioral Science, University of Texas-Houston Health Science Center, USA
Laboratory procedures were used to determine the
effects of different types of serotonergic agents and a GABAergic drug on human
aggressive and impulsive responding. The
Point Subtraction Aggression Paradigm (PSAP) was used to measure human
aggressive, escape and monetary responding. The PSAP procedure involved subjects
responding for monetary rewards, and exposing subjects to provocations
(subtractions of their earnings) and recording aggressive responses (money
subtracted from other fictitious person) and escape responses (protecting their
earnings from the other person). Impulsivity was measured using a delayed reward
procedure with adjusting delay intervals, a procedure used initially with
animals. Subjects chose immediate smaller rewards (impulsive option) and larger
rewards after longer delays (non-impulsive option).
Initial experiments with serotonin releaser, d,l-fenfluramine found a
dose-related decrease in aggressive and impulsive responding and no effects on
escape and monetary responding among adult male antisocials.
In an additional study, we determined the effects of d-fenfluramine on
male parolees with and without a history of childhood conduct disorder (CD).
D-fenfluramine reduced aggressive responding significantly in CD subjects
but not in controls; escape responding was reduced in both groups; impulsive
responding was not significantly decreased and there were no effects on monetary
responding. These decreases in
aggressive responding could not be attributed to sedative effects of
fenfluramine since (1) to reductions in monetary
responding was observed, and (2) no changes in reaction times in the impulsivity
were noted. Newer studies involve
the chronic administration of paroxetine (Paxil) a serotonin reuptake inhibitor,
on aggressive and impulsive responding. Concurrent placebo subjects are
currently participating to clarify time-related changes, which were observed
during chronic paroxetine treatment. Initial studies with a GABA-B agonist, baclofen, indicate
selective dose-related decreases in aggressive responding among CD subjects.
Consistency of these results with animal studies presented in this symposium
will be discussed.
for a modulating role of 5-HT in clinical aggression
Section of Clinical Psychopharmacology, Institute of Psychiatry, King College London, UK.
Many strands of evidence, including post-mortem
studies, CSF examination and neuroendocrine challenge studies, now support the
existence of an inverse relationship between central serotonergic activity and
impulsive aggressive behavior in humans. Most of the research has been
correlational and has sought to demonstrate relationships between a history of
aggressive behavior or trait measures of hostility and various markers of
serotonergic function. Neuroendocrine challenge studies using drugs with
different serotonergic actions have shown endocrine responses to be reduced in
aggressive individuals and to inversely correlate to scores on different
measures of aggression in the healthy population. Similar results have been
found for both a non-selective serotonin releasing agent such as fenfluramine
and for 5-HT1a agonists such as buspirone and ipsapirone.
There is thus some preliminary evidence in humans to support animal work,
indicating that impaired 5-HT1a receptor function is associated with increased
aggressiveness. However, in correlational studies, it is difficult to
disentangle the possible influences of other variables. Experimental methods are
therefor an important complementary research strategy. The technique of
tryptophan depletion or enhancement can be used to study acute alterations of
serotonergic neurotransmission on aggressive feelings and behavior.
A number of studies have now shown that tryptophan depletion increases
the probability of affective aggression in predisposed individuals while
enhancement has the opposite effect. Tryptophan has also been added to other
drug treatments in an attempt to control aggressive behavior in psychiatric
patients. There are few controlled studies of the treatment of aggressive
behavior with serotonergic drugs. This is partly because the propensity for
aggressive behavior runs across different diagnoses for which particular drugs
are indicated. However, many of the currently used drugs do have effects on the
serotonergic system and this may contribute to their efficacy. Specific
serotonergic compounds can be divided into agonists and uptake inhibitors.
There is some evidence from case reports and small studies that both
buspirone and various serotonin re-uptake inhibitors are effective in treating
symptoms of impulsivity and irritability as well as in reducing aggressive or
self-injurious behavior in patients with borderline personality disorder or