Acute stressing procedures cause a shortlasting increase in the levels of guanosie 3',5'-monophosphate (cGMP) in mouse brain without significantly influencing the concentrations of adenosine 3'-5'-monophosphate (cAMP). Animals were pretreated with various centrally acting drugs before being stressed in order to study the involvement of specific neurotransmitters in the stress-induced rise of cGMP levels. Centrally depressant drugs affecting different synaptic mechanisms, such as chlorpromazine, reserpine, haloperidol, diazepam, and pentobarbital, inhibited the cCMP increase elicited by stress. Pretreatment with atropine, diphenhydramine, antazoline, cyproheptadine, phentolamine, bunitrolol, and indomethacin had no significant effect. Clonidine and both the (-)- and (+)-isomers of propranolol inhibited the stress-induced cGMP increase in a dose-related manner. Our results suggest that norepinephrine, serotonin, acetylcholine, or prostaglandins are not involved in the elevation of cGMP levels elicited by acute stress. Participation of other neurotransmitter(s), such as dopamine or GABA, cannot be excluded.