By means of the dopamine (DA) agonist radio ligand 3H-N-propyinorapomorphine (3H-NPA) the effects of cholecystokinin-8 (CCK-8) have been evaluated in vitro on the binding characteristics of the DA agonist sites in membrane preparations from the subcortical limbic forebrain containing mainly nucleus accumbens and tuberculum olfactorium. It was shown that CCK-8 (10−8 M) can produce a 40% increase in the KD value of the 3H-NPA binding sites and a significant I0% increase in the Bmax values of these sites. It is therefore suggested that there exist marked receptor-receptor interactions between the CCK-8 binding sites and DA agonist binding sites in the limbic forebrain. On the basis of these findings and in view of the fact that CCK peptides are comodulators in certain types of mesolimbic DNA neurons but cannot modulate DA release in these DNA synapses) the hypothesis is introduced that the presence of DA comodulators such as CCK-8 in the DA synapses makes possible a heterostatic regulation of the synapse. Thus, by means of receptor-receptor interactions, peptide comodulators may change the set point of the main transmission line without inducing homeostatic feedback responses on synthesis and release of the main transmitter, opening up a new way to modulate chemical transmission in general.

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