PMC:1134661 / 11480-18771 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/1134661","sourcedb":"PMC","sourceid":"1134661","source_url":"https://www.ncbi.nlm.nih.gov/pmc/1134661","text":"Discussion\nIn this research study on anaesthetised animals we found that extracellular basal levels of NA and DA in the mPFC and Occ were analogous to those previously detected in our lab in freely moving rats. Due to the different probe geometry, which may have affected in vivo recovery of catecholamines, comparison of data collected in the mPFC (by means of vertical probes) with data obtained from Occ (by means of horizontal probes) is not appropriate. However, considering each area separately, it appears that while in the mPFC DA and NA concentrations were of a similar magnitude, consistent with the dense dopaminergic innervation of the mPFC, in the Occ DA resulted slightly lower than NA, but higher than one could expect from the scarce, if any, dopaminergic innervation, confirming our previous observations [8].\nElectrical stimulation of the LC produced an increase in both NA and DA concentrations in the cerebral cortex of anaesthetized rats, superimposable to that previously demonstrated by our group in freely moving animals [12]. These data exclude the possibility that stress is involved in electrical stimulation induced catecholamine release.\nOur results show that single train and repetitive stimulation of the LC caused a concomitant increase not only of extracellular NA but also of DA in both the mPFC and Occ.\nBasal catecholamine levels and stimulation-induced elevations appear to be produced by a nerve-impulse mediated exocytotic process since the local perfusion of TTX dramatically reduced basal levels and totally suppressed the effect of LC stimulation in both cortices. This result exclude the possibility that the increase of extracellular DA originates from a passive leakage of cytosolic DA.\nFurthermore, LC stimulation failed to increase DA in the caudate nucleus, which argues against the possibility that midbrain DA neurons might be stimulated by current spread or transynaptically.\nNAT displays a high affinity for DA in vitro, and actively reuptakes it from extracellular space [17,18]. The coupling of NA and DA changes in the mPFC has been explained with the hypothesis that DA changes are secondary to the changes in NA competing with DA for NAT [19-21]. However, against this hypothesis is the finding that following phasic stimulation, DA remained elevated much longer than NA both in the mPFC and to a much longer extent in the OCC.\nMoreover, electrical stimulation of the LC produced an increase in DA output when NA uptake had been previously blocked by a NAT inhibitor, both in the mPFC and Occ.\nOn the other hand, our results indicate that the time course of the release of the two catecholamines may be differentially influenced by the frequency and pattern of noradrenergic activity. Thus, while NA returned to the pre-stimulus level within 20 min after either single train or repeated phasic stimulation, DA elevation persisted for a much longer time. Indeed, repeated stimulation produced a persistent elevation of basal DA both in the mPFC and, to a greater extent, in the OCC. A similar elevation of inter-stimulation levels is also observed for NA during DMI perfusion, leading to the speculation that re-uptake mechanism in vivo is more active in clearing NA than DA, especially in the Occ. In fact, when NAT is blocked by DMI, NA curve approaches the DA one that, on the contrary, displays a similar profile in the absence or in the presence of DMI. A scarce efficacy of NAT in the clearance of DA from extracellular space in the Occ has been already proposed by Valentini et al. [22].\nAnother possible explanation for the finding that the duration of DA increase in both cortices exceeded that of NA, is that LC stimulation activates DA synthesis in noradrenergic neurons in excess to that can be converted to NA, due to increase in tyrosine hydroxylase activity following nerve cell stimulation [23], and consequent possible partial saturation of DA-β-hydroxylase. However, there is no report of this type of saturation, even though evidence exists for a stimulation-induced increase in tyrosine hydroxylase with no change in DA-β-hydroxylase activity in noradrenergic neurons [24-26].\nA difficult problem is posed by the finding that DA elevation in the mPFC was of shorter duration than in the parietal cortex. It might be suggested that in the mPFC the DA transporter (DAT), other than NAT, participates in the removal of DA from extracellular space, so that DA removal from mPFC would be more efficient than in the OCC, where DAT is scarce [9,27]. The latter hypothesis is difficult to test, as the selective DAT inhibitor GBR 12909 has been demonstrated to be ineffective in raising extracellular DA levels in the mPFC [11,28] even during dopaminergic activity stimulation by means of haloperidol administration [11]. This observation has been explained with the NAT capacity to totally compensate for DAT exclusion, due to the high affinity of DA for NAT [17,18]. Anyway, this consideration does not exclude that in the mPFC DAT actively reuptakes DA into dopaminergic terminals, thus contributing to decrease extracellular DA levels. Hence, the different profiles of the curves might imply differences in clearance mechanisms for the two catecholamines. MAO A displays higher affinity for NA than for DA [29], and in the Occ DOPAC is about 10% that found in the mPFC [11], thus the possibility exists that in the Occ released DA is cleared prevalently by diffusion, instead of being metabolized to DOPAC.\nBy means of the double probe preparation, we demonstrated that the NA increase produced by LC electrical stimulation is elicited both in the mPFC and caudate nucleus, while DA increase is present in the mPFC but not in the caudate nucleus. Furthermore, when stimulating electrodes were placed outside the LC, no catecholamine increase was observed. Together, these data indicate that DA increase is not due to dopaminergic neuron activation by current spread. Moreover they exclude the possibility that the DA increase observed in the cerebral cortex is due to direct or indirect stimulation of dopaminergic neurons by NA; on the contrary, the DA decrease observed in the caudate nucleus during prolonged stimulation is consistent with an inhibitory action of NA on DA neurons, as already suggested [30,31]. Such an inhibitory action might contribute to explain why DA elevation in the mPFC was of shorter duration than in the occipital cortex: it might suggest that DA released from noradrenergic terminals was compensated in the mPFC by a reduced DA release from dopaminergic terminals. Indeed, in the caudate nucleus multiple stimulation evidenced a decrease in DA levels.\nFinally, the finding that LC stimulation produced the same elevation of DA in areas with high or low dopaminergic innervation, argues against the possibility that a robust portion of extracellular DA, at least in the occipital cortex, might originate from the scarce dopaminergic afferences in these areas.\nOn the other hand, the co-transmitter hypothesis poses the problem of whether the release of the two catecholamines may be differentially controlled. Indeed, our results indicate that the time course of the release of the two catecholamines may be differentially influenced by the frequency and pattern of noradrenergic activity.","divisions":[{"label":"title","span":{"begin":0,"end":10}},{"label":"p","span":{"begin":11,"end":826}},{"label":"p","span":{"begin":827,"end":1166}},{"label":"p","span":{"begin":1167,"end":1338}},{"label":"p","span":{"begin":1339,"end":1731}},{"label":"p","span":{"begin":1732,"end":1926}},{"label":"p","span":{"begin":1927,"end":2384}},{"label":"p","span":{"begin":2385,"end":2550}},{"label":"p","span":{"begin":2551,"end":3550}},{"label":"p","span":{"begin":3551,"end":4152}},{"label":"p","span":{"begin":4153,"end":5478}},{"label":"p","span":{"begin":5479,"end":6654}},{"label":"p","span":{"begin":6655,"end":6961}}],"tracks":[]}