Alterations in adipocyte cyclic AMP concentrations in response to 100 microM forskolin and 10 microM isoproterenol over a 4 hour period were found to be similar; with each agent, a peak response was noted within 30 minutes. In general, the greater the magnitude of peak response, the more rapid the decline of cyclic AMP concentration during the ensuing 3 1/2 hours. Alpha-2 adrenergic activation, achieved with 10 microM clonidine or 10 microM epinephrine, substantially reduced the cyclic AMP concentrations in cells stimulated by 100 microM forskolin or 10 microM isoproterenol. Isoproterenol-stimulated cells appeared to be more sensitive to alpha adrenergic inhibition than did forskolin-stimulated cells. Cells preincubated for 3 hours with 100 microM forskolin were markedly less responsive to a second exposure to the diterpine. Cells exposed to forskolin for 3 hours also had a reduced response when incubated with isoproterenol; thus, desensitization to forskolin appears to be heterologous. Forskolin desensitization did not appear to be dependent on cellular ATP depletion since cells mildly stimulated during preincubation were as severely desensitized as those adipocytes strongly stimulated. Maximum desensitization required a preincubation time of 1-2 hours with either isoproterenol or forskolin.