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IS-4. PHARMACOLOGICAL CONTROL OF AGGRESSION: FROM ANIMAL STUDIES TO HUMANS.

Organizer: Cherek, Don R.
Department of Psychiatry and Behavioral Science, University of Texas Health Science, USA.

Symposium Abstract:

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

Numerous 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-HT_1a 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-HT_1a 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-HT_1a or _1b agonists, or local administration of a 5-HT_1a or GABA_A 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.

IS-4.2.-Effect of serotonin- and GABAergic compounds on apomorphine-induced aggressive behaviour in male rats

Allikmets, 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-HT_1A agonist buspirone suppressed aggressiveness but gepirone and 8-OH-DPAT did not have significant effect. 5-HT_2A agonist DOI (1-3 mg/kg) shortened the latency and increased the intensity of aggressive attacks. Antagonists of 5-HT_2A 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. GABA_B 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-HT_1A, 5-HT_2A and GABA receptors are modulating the APO-induced aggressive behaviour. 5-HT_1A agonists have some antiaggressive and 5-HT_2A agonists proaggressive effect.

IS-4.3.-Evaluation of the Effects of Serotonergic and GABAergic Drugs on Human Aggression and Impulsivity.

Cherek,  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.

IS-4.4.-Evidence for a modulating role of 5-HT in clinical aggression

Bond, A.
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 learning disabilities.