Neuropharmacology of 3-isobutylmethylxanthine: effects on central noradrenergic systems in vivo.

We have previously shown that administration of 3-isobutyl-1-methylxanthine (IBMX) to rats causes an increase in levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) by a clonidine-reversible mechanism (J. Neurochem. 40: 246-251, 1983). Further investigations have revealed that IBMX administration (100 mumol/kg i.p.) stimulates noradrenergic tyrosine hydroxylation in vivo (measured after decarboxylase inhibition), an effect also reversed by the alpha-2 agonist clonidine. Consistent with previous electrophysiological data, IBMX also accelerates the disappearance of NE after inhibition of tyrosine-3-monooxygenase. When axons of the NE-dorsal bundle are mechanically severed, the effect of IBMX on MHPG is not attenuated, in contrast to the effects of the alpha-2 antagonist yohimbine which are blocked by axotomy. Administration of the adenosine agonist, 2-chloroadenosine (8 or 17 mumol/kg i.p.) or diazepam (35 mumol/kg) did not prevent the increase in MHPG caused by IBMX. The data, discussed in terms of enhanced noradrenergic activity, adenosine antagonism and phosphodiesterase inhibition, show that administration of methylxanthines (compounds known to produce anxiety and opiate withdrawal-like behaviors) results in increased biochemical activity of noradrenergic neurons in the rat.