In neuropsychiatric disorders, serotonergic dysfunction may contribute to negative affect in alcoholism and major depression, while dysfunction of central dopaminergic neurotransmission has been associated with motivational disorders in addiction and schizophrenia. Animal experiments revealed that 1) neurodevelopmentally early social isolation stress exposure is associated with altered serotonin turnover and transporters and 2), neurodevelopmentally early lesion of the temporolimbic cortex is associated with increased striatal dopamine release. In human studies, dopamine and serotonin transporters and receptors interact with central processing of reward-indicating and affectively positive and negative stimuli, and specific alterations in these interactions can be observed in schizophrenic, alcoholics and affective disorders. Monoamine effects on central processing of emotionally salient stimuli are genetically influenced, and besides single gene effect, gene-gene interactions have been postulated. Additive gene-gene effects are often assumed but difficult to test in behavioral genetics due to the small explained behavioral variance. Processing of unpleasant stimuli in the amygdala has been associated with a functional polymorphism (val158-met) in the catechol-O-methyltransferase (COMT) gene and independently with a functional polymorphism in the regulatory region of the serotonin transporter (5-HTT) gene. 5-HTT function may also be affected by a recently detected A/G exchange in the long allele (insertion) of the 5-HTT regulatory region. In individuals with more COMT met158 alleles and with more s or lG alleles of the 5-HTT regulatory region, aversive stimuli elicited greater neuronal activity in the bilateral amygdalae and hippocampi. These genotype effects were additive on amygdala and hippocampus activation by aversive versus neutral stimuli, indicating that COMT val158-met and 5-HTT genotype were additively associated with increased processing of aversive stimuli in the amygdalae. Functional brain imaging may be used to assess the interaction of multiple genotypes on neuronal activation in neuropsychiatric disorders.