title: Is the release of dopamine from medial prefrontal cortex modulated by presynaptic receptors? Comparison with nigrostriatal and mesolimbic terminals.
abstract: Results obtained from our in vitro studies employing superfused slices obtained from three functionally different brain regions rich in DA axon terminals were discussed. Striking qualitative and quantitative similarities were found for the modulation of DA release from the nucleus caudate and the OT of the rabbit. However, the PFC DA terminals showed important differences from the nigrostriatal and mesolimbic DA terminals. Although release modulatory D2 DA autoreceptors could also be demonstrated in superfused slices of the PFC, our results suggest that the cortical nerve terminals may have a lower number of functional autoreceptors or a reduced efficiency of coupling between receptors and inhibition of release. Either possibility could explain (a) the poor inhibitory efficacy of the agonists, (b) the small facilitatory effect of the antagonists, (c) the disproportionate increase in transmitter overflow produced by neuronal uptake inhibitors, and (d) the lack of synergism between uptake inhibitors and DA antagonists. When the efficacy of the autoreceptor mechanisms was evaluated at stimulation frequencies comparable to the in vivo firing rates reported for each of the three neuronal groups, it was found that DA release from the striatum and the OT was tightly modulated by presynaptic D2 DA receptors; whereas release from PFC was not. We propose that the autoreceptor-mediated control of DA release from PFC may not function in vivo, even though modulation of release by presynaptic D2 DA receptors from PFC terminals could be demonstrated under specific experimental conditions in vitro. However, it is envisaged that if in vivo firing rate of the PFC DA neurons is reduced, the inhibitory actions of DA agonists on DA release may be regained. From these and other studies it is apparent that drug effects on autoreceptors are highly dependent on the rate and duration of stimulation applied to a specific neuronal group. We propose that the basal status of activity of a specific neuronal target could determine the type and magnitude of the effect produced by a therapeutic agent acting at release modulatory receptors. The neuronal activity (firing rate and pattern) may be affected by physiological status, disease, and by current or previous drug treatments. The mechanisms by which PFC DA terminals release a larger proportion of their storage pool compared to other mesotelencephalic DA terminals is unknown and may represent a compensatory mechanism to the continuous rapid firing rates at which these neurons are exposed in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Division of Pharmacology, Pharmacy Faculty, Central University of Venezuela, Caracas.
authors.forename: L X
authors.initials: LX
authors.lastname: Cubeddu
authors.forename: I S
authors.initials: IS
authors.lastname: Hoffmann
authors.forename: R K
authors.initials: RK
authors.lastname: Talmaciu
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D005625:Frontal Lobe / Q000378:metabolism*; D066298:In Vitro Techniques; D008032:Limbic System / Q000378:metabolism*; D009411:Nerve Endings / Q000378:metabolism; D009830:Olfactory Bulb / Q000378:metabolism; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011817:Rabbits; D011954:Receptors, Dopamine / Q000502:physiology; D017448:Receptors, Dopamine D2; D017981:Receptors, Neurotransmitter / Q000502:physiology*; D013378:Substantia Nigra / Q000378:metabolism*
chemical_list: D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D017981:Receptors, Neurotransmitter; D015240:Phorbol 12,13-Dibutyrate; D004298:Dopamine