5,7-DHT lesions of the serotonin (5HT) system in rat brain that decreased tissue levels of 5HT 50-60% had no effect on extracellular levels as assessed with microdialysis. Over a 90% decrease in tissue levels was necessary in order to decrease EC 5HT. It appears that presynaptic compensatory changes take place in 5-HT neurons following lesioning similar to those seen in the dopaminergic system. An antisense phosphothioate oligonucleotide directed at rat tyramine hydroxylase mRNA injected into the median raphe nucleus produced anxiogenic effects without altering tissue 5HT, dopamine (DA), or norepinephrine. More subtle alterations in 5HT function may underlie the behavioral effects observed. In unanesthetized rats, systemic administration of caffeine increased locomotor activity without having any effect on n. accumbens DA. It seems that the behavioral effects of caffeine are not dependent on the facilitation of DA overflow in the n. accumbens. Systemically administered corticosterone (CORT) increased frontal cortex norepinephrine and decreased n. accumbens DA. Tolerance developed to the effects of CORT on norepinephrine but not DA following chronic administration. Decreases in forebrain DA function by acute and chronic CORT may be relevant for understanding behavioral depression seen following environmental stress which elevates CORT. 5,7-DHT lesions of the serotonin (5HT) system in rat brain that decreased tissue levels of 5HT 50-60% had no effect on extracellular levels as assessed with microdialysis. Over a 90% decrease in tissue levels was necessary in order to decrease EC 5HT. It appears that presynaptic compensatory changes take place in 5-HT neurons following lesioning similar to those seen in the dopaminergic system. An antisense phosphothioate oligonucleotide directed at rat tyramine hydroxylase mRNA injected into the median raphe nucleus produced anxiogenic effects without altering tissue 5HT, dopamine (DA), or norepinephrine. More subtle alterations in 5HT function may underlie the behavioral effects observed. In unanesthetized rats, systemic administration of caffeine increased locomotor activity without having any effect on n. accumbens DA. It seems that the behavioral effects of caffeine are not dependent on the facilitation of DA overflow in the n. accumbens. Systemically administered corticosterone (CORT) increased frontal cortex norepinephrine and decreased n. accumbens DA. Tolerance developed to the effects of CORT on norepinephrine but not DA following chronic administration. Decreases in forebrain DA function by acute and chronic CORT may be relevant for understanding behavioral depression seen following environmental stress which elevates CORT.