TRANSIENT LOSS OF DOPAMINE AUTORECEPTOR CONTROL IN THE PRESENCE OF HIGHLY POTENT DOPAMINE AGONISTS

The concentrations of endogenous ligands generally remain in a bounded range around a basal level, a manifestation of control. The dopaminer gic system is an excellent example of a control system in which a nega tive feedback signal is associated with receptor occupancy of a D2-lik e dopamine autoreceptor. A consequence of the control theory is that a utoreceptor occupancy by an agonist results in dopamine levels below t he basal, whereas similar stimulation by a dopamine competitive antago nist results in an increase of dopamine to levels above the basal. The se consequences of control theory were tested and verified in the rat striatum by infusing graded doses of either the agonist, quinpirole, o r the antagonist, sulpiride, into the rat striatum via a microdialysis probe and sampling dopamine and metabolite levels at various times af ter the start of infusion. Control was maintained even at the very hig hest doses of these compounds, i.e., striatal dopamine concentration r ose in response to the antagonist and fell in response to the agonist. In contrast, administration of each of two high affinity dopamine ago nists, 7-OH-DPAT and PPHT showed dose-dependent control only up to cer tain doses. Above these doses the dopamine concentration actually incr eased to levels well above basal, an indication of loss of control. Th ese findings suggest that the control of this endogenous ligand does n ot extend to the very highest levels of autoreceptor occupancy.