Accumbal noradrenaline that contributes to the alpha-adrenoceptor-mediated release of dopamine from reserpine-sensitive storage vesicles in the nucleus accumbens is derived from alpha-methyl-para-tyrosine-sensitive pools.

Alpha-adrenoceptors in the nucleus accumbens are known to inhibit accumbal dopamine release from reserpine-sensitive pools. The aim of this study was to test our previously reported hypothesis that accumbal noradrenaline that controls the dopamine release from these storage vesicles is derived from alpha-methyl-para-tyrosine-sensitive pools. The sensitivity of accumbal alpha-adrenoceptors to noradrenergic agents depends on the amount of noradrenaline that is available in the synapse. In case the synaptic noradrenaline levels decrease, the conformation of alpha-adrenoceptors changes into a state that makes these receptors more sensitive to its agonists. The effects of alpha-methyl-para-tyrosine, respectively reserpine, on the alpha-adrenoceptor-agonist-induced changes of accumbal dopamine release were investigated. Alpha-methyl-para-tyrosine, but not reserpine, made accumbal postsynaptic alpha-adrenoceptors more sensitive to phenylephrine. These results indicate that noradrenaline that inhibits the release of dopamine from reserpine-sensitive storage vesicles, via stimulation of accumbal postsynaptic alpha-adrenoceptors, is derived from alpha-methyl-para-tyrosine-sensitive pools. The clinical impact of these data is discussed.

Genetic background, nature of event, and time of exposure to event direct the phenotypic expression of a particular genotype. A study with apomorphine-(un)susceptible Wistar rats.

The aim of this study was to investigate the differential long-term after-effects on the apomorphine-susceptibility in the apomorphine-susceptible (APO-SUS) and apomorphine-unsusceptible (APO-UNSUS) rats of either a saline injection (a mild stressor) or a clonidine-injection (a moderate stressor) applied around the onset of the stress-hypo-responsive-period (SHRP) on postnatal day (PND) 2, 4, 6 or 9. The present study shows that an injection of saline on PND 2 decreases the apomorphine-induced gnawing score in adult APO-SUS rats, but increases this score in adult APO-UNSUS rats; clonidine given on this day has no effect. An injection of saline on PND 4 decreases the apomorphine score in adult APO-SUS rats, but has no effect in adult APO-UNSUS rats. An injection of clonidine on PND 4 counteracts the long-term after-effects of a saline injection on this PND in adult APO-SUS rats, but has no effect in adult APO-UNSUS rats. Finally, an injection of clonidine on PND 9 has no effect on the apomorphine score in adult APO-SUS rats, but increases this score in adult APO-UNSUS rats; saline given on this day has no effect. It is concluded that the long-term after-effects of early postnatal stressors depend on the interrelationship between, rather than the separate impact of, the genetic background of the rat, the nature of the event, and time of exposure to the event, thereby implying that these factors direct the phenotypic expression of a particular genotype at adult age.

Mesolimbic alpha-, but not beta-adrenoceptors control the accumbal release of dopamine that is derived from reserpine-sensitive storage vesicles.

Mesolimbic beta-, but not alpha-adrenoceptors control the accumbal release of dopamine that is derived from alpha-methyl-para-tyrosine-sensitive pools of newly synthesized neurotransmitter. The aim of this study was to investigate which of these adrenoceptors control the accumbal release of dopamine that is derived from reserpine-sensitive pools of previously stored neurotransmitter. Rats, that were divided in low-responders and high-responders to novelty, were pretreated with 1 mg/kg of reserpine before the alpha-adrenergic-agent phentolamine or the beta-adrenergic-agent isoproterenol was locally applied into the nucleus accumbens. The original finding that phentolamine and isoproterenol increased accumbal dopamine levels in low-responders and high-responders was replicated. Reserpine reduced the phentolamine-induced increase of accumbal dopamine in both types of rat. However, phentolamine could still increase accumbal dopamine levels in reserpine-treated high-responders, but not anymore in reserpine-treated low-responders. Reserpine did not reduce the isoproterenol-induced increase of accumbal dopamine in any type of rat. This study demonstrates that mesolimbic alpha-, but not beta-adrenoceptors control the accumbal release of dopamine that is derived from reserpine-sensitive storage vesicles. In addition, these data confirm our previous finding that dopamine can still be released from storage vesicles of reserpinized high-responders, but not of reserpinized low-responders. The collected data underline our notion that alpha- and beta-adrenergic drugs may have therapeutic effects in patients suffering from diseases in which accumbal dopamine is involved.

Differential contribution of storage pools to the extracellular amount of accumbal dopamine in high and low responders to novelty: effects of reserpine.

The present study examined the effects of reserpine on the extracellular concentration of accumbal dopamine in high responders (HR) and low responders (LR) to novelty rats. Reserpine reduced the baseline concentration of extracellular accumbal dopamine more in HR than in LR, indicating that the dopamine release is more dependent on reserpine-sensitive storage vesicles in non-challenged HR than in non-challenged LR. In addition, reserpine reduced the novelty-induced increase of the extracellular concentration of accumbal dopamine in LR, but not in HR, indicating that the dopamine release in response to novelty depends on reserpine-sensitive storage vesicles only in LR, not in HR. Our data clearly demonstrate that HR and LR differ in the characteristics of those monoaminergic storage vesicles that mediate accumbal dopamine release.

Bilateral nigral 6-hydroxydopamine lesions increase the amount of extracellular dopamine in the nucleus accumbens.

The goal of the present study was to provide neurochemical evidence for a shift in the functional balance between the nigrostriatal and mesolimbic pathway in favour of the mesolimbic pathway by investigating the effects of a partial, nigral, bilateral 6-hydroxydopamine lesion on basal and novelty-induced extracellular dopamine release in the accumbens of Low responder rats to novelty (LR). Low responders were chosen because the above-mentioned shift was seen in LR rats, but not in rats that have a high response to novelty (HR). About 1 microg/microl of 6-hydroxydopamine was injected bilaterally into the substantia nigra pars compacta and a guide cannula was placed into the right accumbens. Changes in extracellular dopamine in response to novelty, a new cage, were measured using a microdialysis probe inserted into the accumbens. The lesion size was determined by quantification of tyrosine hydroxylase immunoreactivity of the substantia nigra and the ventral tegmental area. This revealed that the lesion partly destroyed the dopaminergic cells of the nigrostriatal pathway, thereby relatively sparing the dopaminergic cells of the mesolimbic pathway. The lesion significantly increased the amount of extracellular dopamine in the accumbens during both basal and novelty conditions. We suggest that the experimentally induced neuronal death in the substantia nigra pars compacta with subsequent removal of lateral inhibition of adjacent neurons underlies the observed changes in the amount of extracellular dopamine in the accumbens.