There are large individual differences among humans and animals in behavioral, physiological and toxicological responses to drugs of abuse. Many of these individual differences in behavioral responses to drugs display substantial genetic components. Transgenic animals provide means for approaching several interrelated goals: 1)Ascertainment of biochemical and behavioral consequences of the introduction of or disruption of specific genes; 2)Ascertainment of the consequences of over- or under-expressing candidate genes identified in human studies; 3) Elucidation of gene elements yielding cell-type specific expression and trans-synaptic gene regulation; 4) Studying influences of interactions between variants at different genomic loci; 5)Elucidating haplotype-specific levels of expression differences in vivo, expecially when currently-available cultured cell models are not optimal. Influences of human allelic variations and dopamine systems in mechanisms of reward, reinforcement and learning have led to continuing focus on these systems during this year. In continuing studies of combined transporter and transporter/receptor knockouts, we have obtained novel data concerning the relationship between expression of each of these gene products at normal levels and drug-induced behavioral changes. In studies of variations at candidate gene loci determined from human studies, we have identified striking effects of cocaine reward in mice with altered levels of expression of BDNF and NrCAM. We have provided evidence for monoaminergic involvement in mechanisms of sleep/wake regulation in mice that parallels the evidence for apparent monoamine transporter in narcolepsy. Initial results of in vivo studies of two common haplotypes of the DAT gene's 5' flanking region provide evidence for brain-region specific patterns of expression driven by these promoter sequences.