The significance of a characteristic symptomatology (
hypothermia, hypoactivity, forepaw shaking, grooming, head twitches) as a potential in vivo correlate of enhanced availability of brain
adenosine cyclic 3',5'-monophosphate (cAMP) was examined in rats following systemic administration of various doses of dibutyryladenosine cAMP (
dBcAMP) or of the
phosphodiesterase (PDE) inhibitors
rolipram,
Ro 20-1724, ICI 63-197, isobutylmethylxanthine (
IBMX)
theophylline,
cartazolate, and
papaverine. The various PDE inhibitors could be assigned to three groups according to the pattern of behavioral alterations they induced.
Rolipram,
Ro 20-1724, and ICI 63-197 (group 1) caused
hypothermia, hypoactivity, forepaw shaking, grooming, and head twitches. All behavioral effects were mimicked by
dBcAMP but not dBcGMP. The order of potency and effective dosage range to induce the behavioral alterations were, in descending order,
rolipram (0.09-1453 mumol/kg IP), ICI 63-197 (0.48-119 mumol/kg IP),
Ro 20-1724 (5.6-1438 mumol/kg IP), corresponding with the recently reported efficacy of the drugs to elevate rat brain cAMP in vivo. Comparatively high doses of the alkylxanthine PDE inhibitors
IBMX and
theophylline (group 2) caused
hypothermia, forepaw shaking, grooming, and head twitches concomitantly with a decline of the motor stimulatory effect, suggesting enhanced availability of brain cAMP. The order of potency and the effective dosage range to induce the behavioral alterations were, in descending order,
IBMX (28.1-113 mumol/kg IP) and
theophylline (139-555 mumol/kg IP). The third group,
papaverine (295-1179 mumol/kg IP) and
cartazolate (21.5-345 mumol/kg IP), caused only
hypothermia and hypoactivity. The differences in the behavioral pattern of the two latter groups of compounds in comparison with
dBcAMP and the selective cAMP PDE inhibitors are discussed with regard to their additional interference with
adenosine actions besides their nonselective PDE inhibitory action.