3-Methoxytyramine Formation Following Monoamine Oxidase Inhibition Is a Poor Index of Dendritic Dopamine Release in the Substantia Nigra

Abstract: This study was undertaken, using microdialysis, to compare the extracellular concentration of 3-methoxytyramine and dopamine in dialysate from the striatum and substantia nigra, after pargyline (75 mg/kg), after pargyline plus amphetamine (3 mg/kg), and after pargyline plus reserpine (5 mg/kg) administration. Treatment with pargyline alone increased the extracellular dopamine concentration by 70% in the striatum and by 140% in the substantia nigra and induced in both regions a time-dependent accumulation of 3-methoxytyramine. The addition of d-amphetamine to pargyline increased the extracellular dopamine concentration, compared with pargyline-treated controls, to the same extent in both the substantia nigra (maximally by 360%) and the striatum (maximally by 400%), but the concomitant increase of 3-methoxytyramine accumulation in the dialysate was relatively smaller in the substantia nigra compared with the striatum. Reserpine treatment decreased the extracellular dopamine concentration in both regions below the detection level (<10% of basal value). When pargyline was added to reserpine, the striatal extracellular dopamine concentration increased to 50% of pargyline-treated controls and the striatal 3-methoxytyramine accumulation was less than in pargyline-treated controls. However, in the substantia nigra, the addition of pargyline to reserpine resulted in dopamine concentrations as high as after pargyline only and the 3-methoxytyramine accumulation was not changed compared with pargyline-treated controls. In summary, our results indicate that dopamine in the substantia nigra is released from reserpine-sensitive storage sites and that pargyline-induced 3-methoxytyramine accumulation is a poor indicator of the local dopamine release. The latter observation may be explained by the fact that the dopamine-metabolizing enzyme, catechol-O-methyltransferase, is located inter alia in the dopamine-containing cell bodies/dendrites in the substantia nigra, in contrast to the situation in the terminals in the striatum where catechol-O-methyltransferase is located only in nondopaminergic cells.     

Characterization and Pharmacological Responsiveness of Dopamine Release Recorded by Microdialysis in the Substantia Nigra of Conscious Rats

The extracellular concentration of dopamine (DA) and 3,4-dihydroxyphenylacetic acid in the substantia nigra (SN) and striatum was estimated by microdialysis. The dialysate content of DA from the SN was recorded during infusion of a DA uptake blocker (nomifensine; 5 mumol/L) dissolved in the perfusion fluid. Perfusion of tetrodotoxin (1 mumol/L) produced a virtually complete disappearance of nigral and striatal DA release. Dendritic as well as terminal release of DA was inhibited for several hours when the nerve impulse flow in dopaminergic neurons was blocked by systemic administration of gamma-butyrolactone (750 mg/kg, i.p.). The systemic administration (0.3 mg/kg, i.p.) as well as infusion (1 mumol/L) of the D2 agonist (-)-N-0437 [2-(n-propyl-N-2-thienylethylamino)-5-hydroxytetralin] produced a significant decrease in the release of DA in both the striatum and the SN. DA levels were recorded in the striatum both with and without addition of nomifensine to the perfusion fluid. The decrease in the striatum after (-)-N-0437 was suppressed in the presence of nomifensine. Infusion (1 mumol/L) as well as systemic administration (40 mg/kg) of sulpiride caused a similar increase in the release of striatal DA; this increase was, in both experiments, potentiated by nomifensine coinfusion. Sulpiride administration induced a small increase in the release of nigral DA. Infusion of (-)-N-0437 or (-)-sulpiride into the nigra caused a moderate decrease and increase, respectively, of striatal DA level.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential regulation of somatodendritic and nerve terminal dopamine release by serotonergic innervation of substantia nigra

Nigrostriatal dopaminergic neurons release dopamine from dendrites in substantia nigra and axon terminals in striatum. The cellular mechanisms for somatodendritic and axonal dopamine release are similar, but somatodendritic and nerve terminal dopamine release may not always occur in parallel. The current studies used in vivo microdialysis to simultaneously measure changes in dendritic and nerve terminal dopamine efflux in substantia nigra and ipsilateral striatum respectively, following intranigral application of various drugs by reverse dialysis through the nigral probe. The serotonin releasers (+/-)-fenfluramine (100 micro m) and (+)-fenfluramine (100 micro m) significantly increased dendritic dopamine efflux without affecting extracellular dopamine in striatum. The non-selective serotonin receptor agonist 1-(m-chlorophenyl)-piperazine (100 micro m) elicited a similar pattern of dopamine release in substantia nigra and striatum. NMDA (33 micro m) produced an increase in nigral dopamine of a similar magnitude to mCPP or either fenfluramine drug. However, NMDA also induced a concurrent increase in striatal dopamine. The D2 agonist quinpirole (100 micro m) had a parallel inhibitory effect on dopamine release from dendritic and terminal sites as well. Taken together, these data suggest that serotonergic afferents to substantia nigra may evoke dendritic dopamine release through a mechanism that is uncoupled from the impulse-dependent control of nerve terminal dopamine release.     

Comparison of Serotonin and Dopamine Release in Substantia Nigra and Ventral Tegmental Area: Region and Species Differences

Abstract: In this study, we compare the electrically evoked, somatodendritic release of dopamine (DA) with axonal release of serotonin (5-HT) in the substantia nigra (SN) and ventral tegmental area (VTA) in vitro by using fast-scan cyclic voltammetry with carbon-fibre microelectrodes. Furthermore, we have examined transmitter release in these regions in guinea-pig compared with rat. Somatodendritic DA was released, as shown previously, in guinea-pig VTA, SN pars compacta (SNc), and occasionally in SN pars reticulata (SNr). 5-HT was rarely released, except in SNr, where nonetheless it only contributed to <30% of amine signals. In rat midbrain, somatodendritic DA release was evoked to a similar extent as in guinea-pig. However, a clear species difference was apparent; i.e., 5-HT and DA were detected equally in rat SNc, whereas in rat SNr, 5-HT was the predominant transmitter detected. Nevertheless, electrically evoked extracellular concentrations of 5-HT in SNc and SNr were, respectively, seven- and fourfold less than DA in SNc. 5-HT release was low in all regions in neonatal rat slices before the maturation of 5-HT terminals. Hence, axonal 5-HT transmission in midbrain exhibits both species and site selectivity. Moreover, whereas somatodendritic DA release is conventionally regarded as modest compared with axon terminal release in striatum, somatodendritic DA release can result in significantly greater extracellular levels than a transmitter released from axon terminals in the same locality.     

Amphetamine Promotes Neostriatal Ascorbate Release via a Nigro-Thalamo-Cortico-Neostriatal Loop

Abstract: In the neostriatum, amphetamine and other dopamine agonists elevate the extracellular level of ascorbate, which is known to modulate neostriatal function. Although both D₁ and D₂ receptors have been linked to neostriatal ascorbate release, ample evidence suggests it is controlled by areas outside the neostriatum. The present series of experiments used selective lesions and intracerebral drug infusions to probe the involvement of the ventromedial thalamus and substantia nigra pars reticulata. Our results implicate both of these sites in amphetamine-induced increases in the release of neostriatal ascorbate. Thus, whereas unilateral electrolytic lesions of the substantia nigra pars reticulata completely abolished the ability of systemic amphetamine (2.5 mg/kg) to increase extracellular ascorbate in ipsilateral neostriatum, intranigral infusions of this drug (10 and 30 µg/µl) elevated neostriatal ascorbate release. This infusion effect, moreover, was blocked by electrolytic lesions of the ipsilateral ventromedial thalamus, which receives input from the substantia nigra pars reticulata and projects to the cerebral cortex. These results, combined with previous evidence implicating cortical projections to neostriatum as the source of extracellular ascorbate, suggest that neostriatal ascorbate release is regulated, at least in part, by a nigro-thalamo-cortico-neostriatal pathway.     

Reserpine pretreatment prevents increases in extracellular striatal dopamine following L-DOPA administration in rats with nigrostriatal denervation

The influence of L-DOPA and reserpine on extracellular dopamine (DA) levels in the striatum of intact and dopaminergic denervated rats was studied using the brain microdialysis technique. In intact rats, reserpine (5 mg/kg s.c.) reduced extracellular DA levels to 4% of basal values. L-DOPA (50 mg/kg i.p.) had no effect on extracellular DA levels in reserpine-pretreated rats. In rats with 6-hydroxydopamine-induced lesion of the nigrostriatal dopaminergic system, basal levels of extracellular DA were low but markedly increased by L-DOPA (50 mg/kg i.p.). In 6-hydroxydopamine-lesioned rats, pretreatment with reserpine (5 mg/kg s.c.) diminished L-DOPA (50 mg/kg i.p.)-induced increases in extracellular DA levels to 16% of those obtained in denervated animals not pretreated with reserpine (p<0.01). These results suggest that in the intact striatum, extracellular DA stems mainly from vesicular storage sites and that in the striatum with dopaminergic denervation, a large part of the L-DOPA-derived extracellular DA is also derived from a vesicular pool that is released by an exocytosis mechanism.     

GABAA Receptors in the Pars Compacta and GABAB Receptors in the Pars Reticulata of Rat Substantia Nigra Modulate the Striatal Dopamine Release

The nigral GABAergic regulation of striatal dopamine release was investigated using voltammetry in freely moving rats. The local administration of muscimol (1 nM) in the substantia nigra pars compacta, but not in the substantia nigra pars reticulata, increased the striatal dopamine release. In contrast, the administration of baclofen (10 nM) in the substantia nigra pars reticulata, but not in the substantia nigra pars compacta, produced a decrease of the striatal dopamine release. Opposite effects were respectively observed after administration of GABA_A and GABA_B antagonists. These data lead us to suggest a differential presynaptic GABAergic control of the dopaminergic neurotransmission through GABA_A receptors in the substantia nigra pars compacta, and GABA_B receptors in the substantia nigra pars reticulata.     

Serotonin Agonists Reduce Dopamine Synthesis in the Striatum Only when the Impulse Flow of Nigro-Striatal Neurons Is Intact

The effects of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) and m-chlorophenylpiperazine (CPP), two 5-hydroxytryptamine (5-HT, serotonin) agonists, on the accumulation of 3,4-dihydroxyphenylalanine (DOPA] were studied in the striatum of rats treated with gamma-butyrolactone (GBL). Unlike 2 mg/kg i.p. apomorphine, neither 5 mg/kg i.p. 5-MeO-DMT nor 2.5 mg/kg i.p. CPP significantly reduced the GBL-induced increase in DOPA accumulation in the striatum. 5-MeO-DMT and CPP significantly reduced DOPA accumulation in animals that had received the aromatic amino acid decarboxylase inhibitor Ro 4-4602 but not GBL. 5-HT (10 micrograms in 0.5 microliter) injected in the substantia nigra, pars compacta, like GBL, significantly increased Ro 4-4602-induced accumulation of DOPA in the striatum. The data indicate that 5-HT agonists can reduce 3,4-dihydroxyphenylethylamine (DA, dopamine) synthesis in the striatum of rats only when the impulse flow of DA neurons is intact. An indirect effect through mechanisms controlling DA synthesis in the striatum, for instance cholinergic and GABA-ergic neurons, is suggested.     

Changes in function and ultrastructure of striatal dopaminergic terminals that regenerate following partial lesions of the SNpc

Following partial substantia nigra lesions, remaining dopaminergic neurones sprout, returning terminal density in the dorsal striatum to normal by 16 weeks. This suggests regeneration and maintenance of terminal density is regulated to release appropriate levels of dopamine. This study examined the structure and function of these reinnervated terminals, defining characteristics of dopamine uptake and release, density and affinity of the dopamine transporter (DAT) and ultrastructural morphology of dopamine terminals in the reinnervated dorsal striatum. Finally, rotational behaviour of animals in response to amphetamine was examined 4 and 16 weeks after substantia nigra pars compacta (SNpc) lesions. Dopamine transport was markedly reduced 16 weeks after lesioning along with reduced density and affinity of DAT. Rate of dopamine release and peak concentration, measured electrochemically, was similar in lesioned and control animals, while clearance was prolonged after lesioning. Ultrastructurally, terminals after lesioning were morphologically distinct, having increased bouton size, vesicle number and mitochondria, and more proximal contacts on post-synaptic cells. After 4 weeks, tendency to rotate in response to amphetamine was proportional to lesion size. By 16 weeks, rotational behaviour returned to near normal in animals where lesions were less than 70%, although some animals demonstrated unusual rotational patterns at the beginning and end of the amphetamine effect. Together, these changes indicate that sprouted terminals are well compensated for dopamine release but that transport mechanisms are functionally impaired. We discuss these results in terms of implications for dyskinesia and other behavioural states.     

Effects of Daily Cocaine and Morphine Treatment on Somatodendritic and Terminal Field Dopamine Release

Daily injections of cocaine or morphine into rodents produces behavioral sensitization such that the last daily injection results in a greater motor stimulant effect than the first injection. To evaluate a role for brain dopamine in behavioral sensitization to cocaine and morphine, tissue slices from the ventromedial mesencephalon (containing dopamine cell bodies), the nucleus accumbens, and striatum (dopamine terminal fields) were obtained from rats pretreated with daily cocaine, morphine, or saline 2-3 weeks earlier. When the tissue slices were depolarized by increasing potassium concentration in the superfusate, the release of endogenous dopamine from the ventromedial mesencephalon of cocaine- and morphine-pretreated rats was significantly decreased. In contrast, the release of dopamine from the nucleus accumbens and striatum was either unaltered or slightly enhanced in rats pretreated with cocaine and morphine. When dopamine was released by amphetamine, a significant decrease in dopamine release from the ventromedial mesencephalon of cocaine-pretreated rats was measured. No other significant changes were measured after amphetamine-induced release. It is postulated that the decrease in dopamine release from the ventromedial mesencephalon of cocaine- and morphine-sensitized rats results in less somatodendritic autoreceptor stimulation, and thereby produces an increase in dopamine neuronal activity.     

The Anxiogenic β-Carboline FG 7142 Selectively Increases Dopamine Release in Rat Prefrontal Cortex as Measured by Microdialysis

The effect of the anxiogenic beta-carboline methyl-beta-carboline-3-carboxyamide (FG 7142) on dopamine release in prefrontal cortex and striatum in the awake freely moving rat was determined using the technique of microdialysis. FG 7142 (25 mg/kg, i.p.) caused a time-dependent increase in dopamine release in prefrontal cortex which was statistically significantly greater than the response to vehicle administration. Dopamine release in striatum was unaltered by FG 7142. Pretreatment of animals with the benzodiazepine antagonist Ro 15-1788 (30 mg/kg, i.p., 15 min prior to FG 7142 administration) completely abolished the increase in dopamine release caused by FG 7142 in prefrontal cortex. These data indicate that the anxiogenic benzodiazepine inverse agonist FG 7142 can selectively increase dopamine release in prefrontal cortex, and that this effect appears to be mediated via the gamma-aminobutyric acid/benzodiazepine receptor complex.     

Apomorphine Does Not Alter Amphetamine-Induced Dopamine Release Measured in Striatal Dialysates

Amphetamine facilitates the release of dopamine from nerve terminals, but the mechanisms underlying this effect have not been fully delineated. The present experiments were designed to test the extent to which amphetamine-induced dopamine release is dependent on impulse flow and autoreceptor function in dopaminergic neurons. Rats were pretreated with a low dose of apomorphine (0.05 mg/kg) to inhibit dopamine neuronal activity, and the striatal dopaminergic response to amphetamine (0.5 mg/kg) was assessed by in vivo dialysis in freely moving animals. Consistent with previous results, apomorphine alone substantially decreased, whereas amphetamine increased, striatal dialysate dopamine concentrations. However, whereas apomorphine pretreatment decreased the locomotor response to amphetamine, the amphetamine-induced increase in dialysate dopamine was unaffected. These results indicate that amphetamine-facilitated dopamine release is independent of neuronal firing and autoreceptor regulation, consistent with the putative accelerative exchange-diffusion mechanism of amphetamine-induced dopamine release. Other possible mechanisms underlying the inhibitory effects of apomorphine on amphetamine locomotor activation are discussed.     

Different Effects of Opiate Withdrawal on Dopamine Turnover,Uptake, and Release in the Striatum and Nucleus Accumbens

The purpose of these experiments was to further characterize changes in dopaminergic function that follow withdrawal from chronic opiate treatment. Withdrawal after treatment to a maximum dose of 120 mg/kg of morphine did not alter dopamine concentrations in the substantia nigra, ventral tegmental area, striatum, or nucleus accumbens; but did decrease concentrations of DOPAC and the ratio of DOPAC to dopamine in the lateral striatum and nucleus accumbens. Uptake of tritiated dopamine was diminished for withdrawn slices obtained from the striatum with no effect observed for tissue from the nucleus accumbens. Deficits of in vitro release of tritiated dopamine also occurred following withdrawal, with the nucleus accumbens being sensitive to dependence produced by a lower dose of morphine. In conclusion, opiate withdrawal produces a complex pattern of effects on dopaminergic function that is specific for the striatum and nucleus accumbens.     

Alterations in amphetamine stereotypy following acute lesions of substantia nigra

Stereotypy induced by high doses of amphetamine has been related to the ability of this drug to increase the release of dopamine in the caudate nucleus and to block its reuptake. Since amphetamine-stimulated dopamine release in the caudate is blocked by acute lesions of the nigrostriatal pathway, the mechanism by which amphetamine acts to produce stereotypy may be dependent upon intact nigrostriatal impulse flow. The present study examined the involvement of nigrostriatal impulse flow in amphetamine stereotypy by determining the effect of acute, bilateral lesions of substantia nigra pars compacta on measures of stimulant-induced stereotypy and motility. Acute nigral lesions did not significantly alter the stereotypy or motility induced by 3.0 or 6.0 mg/kg amphetamine. These results suggest that the observed behavioral effects of amphetamine do not require an intact nigrostriatal pathway, and thus may involve changes in spontaneous release or reuptake of dopamine rather than in changes in impulse-coupled dopamine release.     

Alteration of neurotensin receptors in MPTP-treated mice.

We examined the sequential changes in neurotensin receptors in the striatum and substantia nigra of mouse brains lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by receptor autoradiography, in comparison with the alterations in dopamine uptake sites. The mice received four intraperitoneal injections of MPTP (10 mg/kg) at 1-h intervals and then the brains were analyzed at 6 h and 1, 3, 7, and 21 days after the treatments. [3H]Neurotensin and [3H]mazindol were used to label neurotensin receptors and dopamine uptake sites, respectively. [3H]Neurotensin binding was significantly decreased in the striatum from 6 h to 21 days after MPTP treatment. In the substantia nigra, pars reticulata also showed a significant decrease in [3H]neurotensin binding from 3 to 21 days post-MPTP treatment. However, no significant change in [3H]neurotensin binding was observed in the pars compacta even after 21 days. On the other hand, [3H]mazindol binding was markedly decreased in the striatum and substantia nigra from 6 h to 21 days after MPTP treatment. These results indicate that neurotoxin MPTP can produce a severe decrease in neurotensin receptors and dopamine uptake sites in the striatum and substantia nigra of mice. Thus, our findings provide evidence that the dysfunction in neurotensin receptors may be involved in the degenerative processes causing Parkinson's disease.     

Effect of Chronic Estradiol and Progesterone Treatments of Ovariectomized Rats on Brain Dopamine Uptake Sites

Abstract: Dopamine released from brain nerve terminals is mainly removed from the synaptic cleft by an uptake mechanism. Despite their functional importance, modulation of the dopamine uptake sites is still not well known. Steroid hormones were shown to modulate brain dopamine transmission. The aim of this study was thus to investigate in ovariectomized rats the effects of 17β-estradiol and progesterone treatments on brain dopamine uptake sites. Treatments consisted of 17β-estradiol (10 μg/0.2 ml), progesterone (0.72 mg/0.2 ml). 17β-estradiol + progesterone, or the vehicle (0.3% gelatin in saline solution) twice daily for 2 weeks. The steroid treatments left the affinity of [³H]GBR 12935 binding to striatal homogenates unchanged (ovariectomized rats, 0.823 ± 0.028 nM), whereas the density was increased by these steroids alone or in combination to a similar extent of 16-23%. Chronic treatment of ovariectomized rats with 17β-estradiol progesterone, or their combination increased to the same extent and uniformly [³H]-GBR 12935 binding in the striatum as measured by autoradiography; the increase was similar in the substantia nigra pars compacta, whereas no steroid effect was observed in the nucleus accumbens and in the substantia nigra pars reticulata. In summary, chronic exposure to 17β-estradiol and/ or progesterone increased dopamine uptake site density in the nigrostriatal dopaminergic system, whereas the nucleus accumbens and the substantia nigra pars reticulata were unaffected.     

A Comparison of Axonal and Somatodendritic Dopamine Release Using In Vivo Dialysis

The release of endogenous dopamine from the axon terminal field in the nucleus accumbens and from the A10 dopamine cell bodies of conscious rats was measured using intracranial dialysis. Release of dopamine from both areas was calcium-dependent and markedly inhibited by the presence of the D2 agonist, quinpirole, in the dialysis buffer. However, the addition of tetrodotoxin to the buffer produced less of a decrease in dopamine in the A10 region than in the nucleus accumbens. When dopamine release was examined by substituting K+ for Na+ or by adding amphetamine to the buffer, the evoked release was significantly less in the A10 region than in the nucleus accumbens. Likewise, enhanced extracellular dopamine following blockade of reuptake by nomifensine addition to the dialysis buffer was not as great in the A10 region as in the nucleus accumbens. These data argue that, in general, axonal and somatodendritic dopamine release are regulated by similar factors, although somatodendritic release is less influenced by action potential generation and less responsive to some releasing agents.     

Delayed Treatment with Arundic Acid Reduces the MPTP-induced Neurotoxicity in Mice

The authors investigated the protective effects of a novel astrocyte-modulating agent, arundic acid, in a 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine (MPTP) mouse model of Parkinson’s disease. Male mice received four intraperitoneal (i.p.) injections of MPTP (20 mg/kg) at 2 h intervals. The content of dopamine and its metabolites in the striatum was reduced markedly 7 days after MPTP treatment. The delayed treatment with arundic acid (30 mg/kg, i.p.) administered 3, 4, 5 and 6 days after MPTP treatment did not affect the depletion of dopamine and its metabolites in the striatum. Our immunohistochemical study with anti-tyrosine hydroxylase antibody, anti-neuronal nuclei antibody, anti-glial fibrillary acidic protein antibody, anti-S100β antibody and anti-nestin antibody showed that the delayed treatment with arundic acid had a protective effect against MPTP-induced neuronal damage in the striatum and the substantia nigra of mice. Furthermore, this agent ameliorated the severe reductions in number of isolectin reactive microglia in the striatum and the substantia nigra 7 days after MPTP treatment. These results demonstrate that the inhibition of S100β synthesis in astrocytes may be the major component of the beneficial effect of arundic acid. Thus, our present findings provide that the therapeutic strategies targeted to astrocytic modulation with arundic acid offers a great potential for restoring the functional capacity of the surviving dopaminergic neurons in individuals affected with Parkinson’s disease.     

Acute Effects of Typical and Atypical Antipsychotic Drugs on the Release of Dopamine from Prefrontal Cortex, Nucleus Accumbens, and Striatum of the Rat: An In Vivo Microdialysis Study

In vivo microdialysis has been used to study the acute effects of antipsychotic drugs on the extracellular level of dopamine from the nucleus accumbens, striatum, and prefrontal cortex of the rat. (-)-Sulpiride (20, 50, and 100 mg/kg i.v.) and haloperidol (0.1 and 0.5 mg/kg i.v.) enhanced the outflow of dopamine in the striatum and nucleus accumbens. In the medial prefrontal cortex, (-)-sulpiride at all doses tested did not significantly affect the extracellular level of dopamine. The effect of haloperidol was also attenuated in the medial prefrontal cortex; 0.1 mg/kg did not increase the outflow of dopamine and the effect of 0.5 mg/kg haloperidol was of shorter duration in the prefrontal cortex than that observed in striatum and nucleus accumbens. The atypical antipsychotic drug clozapine (5 and 10 mg/kg) increased the extracellular concentration of dopamine in all three regions. In contrast to the effects of sulpiride and haloperidol, that of clozapine in the medial prefrontal cortex was profound. These data suggest that different classes of antipsychotic drugs may have distinct effects on the release of dopamine from the nigrostriatal, mesolimbic, and mesocortical terminals.     

Somatodendritic α2-Adrenoceptors in the Locus Coeruleus Are Involved in the In Vivo Modulation of Cortical Noradrenaline Release by the Antidepressant Desipramine

Abstract: The effect of the antidepressant and selective noradrenaline reuptake blocker desipramine (DMI) on noradrenergic transmission was evaluated in vivo by dual-probe microdialysis. DMI (1, 3, and 10 mg/kg, i.p.) dose-dependently increased extracellular levels of noradrenaline (NA) in the locus coeruleus (LC) area. In the cingulate cortex (Cg), DMI (3 and 10 mg/kg, i.p.) also increased NA dialysate, but at the lowest dose (1 mg/kg, i.p.) it decreased NA levels. When the α₂-adrenoceptor antagonist RX821002 (1 µ M ) was perfused in the LC, DMI (1 mg/kg, i.p.) no longer decreased but rather increased NA dialysate in the Cg. In electrophysiological experiments, DMI (1 mg/kg, i.p.) inhibited the firing activity of LC neurons by a mechanism reversed by RX821002. Local DMI (0.01–100 µ M ) into the LC increased concentration-dependently NA levels in the LC and simultaneously decreased NA levels in the Cg. This decrease was abolished by local RX821002 administration into the LC. The results demonstrate in vivo that DMI inhibits NA reuptake at somatodendritic and nerve terminal levels of noradrenergic cells. The increased NA dialysate in the LC inhibits noradrenergic activity, which in part counteracts the effects of DMI on the Cg. The modulation of cortical NA release by activity of DMI at the somatodendritic level is mediated through α₂-adrenoceptors located in the LC.