Ka. Miczek et al., NEUROBIOLOGICAL MECHANISMS CONTROLLING AGGRESSION - PRECLINICAL DEVELOPMENTS FOR PHARMACOTHERAPEUTIC INTERVENTIONS, Neuroscience and biobehavioral reviews, 18(1), 1994, pp. 97-110
Current pharmacotherapeutic approaches to the management of violent an
d aggressive behavior rely mostly on agents that act as receptor agoni
sts or antagonists at subtypes of brain dopaminergic, GABAergic, and s
erotonergic receptors. Ethological experimental studies in animals hav
e shown that drugs may modulate aggression by inhibiting motor activit
y, by distorting aggression-provoking or -inhibiting signals, by fragm
enting behavioral sequences or temporal patterning, or by increasing t
he rate and intensity of aggressive acts. Evidence from animal studies
points to large changes in selected brain dopamine, serotonin, and GA
BA systems during and following aggressive and defensive behavior. How
ever, the specificity of drugs that are currently used to control aggr
essive behavior through their action as agonists or antagonists at sub
types of dopamine, serotonin or GABA receptors continues to be of conc
ern. Similar to the effects of widely used traditional neuroleptics th
at nonselectively antagonize dopamine receptors, the range of behavior
s which is suppressed by either D-1 or D-2 receptor antagonists is per
vasive. At present, systemic administration of dopamine receptor antag
onists in animal preparations does not target aggression-specific mech
anisms. The GABA(A)/Benzodiazepine/Chroride ionophore receptor complex
is implicated in the aggression-heightening effects of alcohol and be
nzodiazepines. Although early reports focused on the ''taming'' effect
s of benzodiazepine anxiolytics, low doses may enhance aggression in b
oth animals and humans. Benzodiazepine antagonists block heightened ag
gression after low doses of alcohol or benzodiazepines. Agonists at ce
rtain 5-HT1 receptor subtypes such as eltoprazine are potently effecti
ve in reducing aggressive behavior of males and females of various ani
mal species under conditions that promote charging offensive-type aggr
ession, without adversely affecting nonaggressive components of the be
havioral repertoire. However, recent reports indicate that eltoprazine
and related compounds may potentiate anxiety reactions in rodents, an
d question the behavioral specificity of these substances. Opioid rece
ptor antagonists modulate primarily physiological and behavioral respo
nses of defense and submission. Defeated animals show tolerance to opi
ate analgesia and withdrawal responses upon challenge with opioid rece
ptor antagonists. Defensive and submissive vocalizations are potently
blocked by opioid peptides. Substances that target specific receptor s
ubtypes at serotonergic, GABAergic and opioidergic synapses are most p
romising for the selective modification of aggressive, defensive and s
ubmissive behavior patterns.