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University of Ottawa Institute of Mental Health Research, Ottawa, Ontario, Canada (B.P.G, M.E.M., P.B.); and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada (P.B.)
Received for publication April 18, 2008.
Accepted for publication August 14, 2008.
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Abstract |
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2-adrenoceptors, respectively. Complementing these autoreceptor-mediated inhibitory feedbacks, anatomical and functional studies have established a role for noradrenergic inputs in regulating dopaminergic activity, and reciprocally. In the present study, a microiontophoretic approach was used to characterize the postsynaptic catecholamine heteroreceptors involved in such regulations. In the VTA, the application of DA and NE significantly reduced the firing activity of DA neurons. In addition to a role for D2-like receptors in the inhibitory effects of both catecholamines, it was demonstrated that the 2-adrenoceptor antagonist idazoxan dampened the DA- and NE-induced attenuations of DA neuronal activity, indicating that both of these receptors are involved in the responsiveness of VTA DA neurons to catecholamines. In the LC, the effectiveness of iontophoretically applied NE and DA to suppress NE neuronal firing was blocked by idazoxan but not by the D2-like receptor antagonist raclopride, which suggested that only 2-adrenoceptors were involved. In the dorsal hippocampus, a forebrain region having a sparse dopaminergic innervation but receiving a dense noradrenergic input, the suppressant effects of DA and NE on pyramidal neurons were attenuated by idazoxan but not by raclopride. The suppressant effect of DA was prolonged by administration of the selective NE reuptake inhibitor desipramine and, to lesser extent, of the selective DA reuptake inhibitor 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)-piperazine (GBR12909), suggesting that both the NE and DA transporters were involved in DA uptake in the hippocampus. These findings might help in designing new antidepressant strategies aimed at enhancing DA and NE neurotransmission.
). Several subtypes of -adrenergic receptors have been identified in the VTA (Lee et al., 1998), raising the possibility that NE inputs play a role in modulating DA neuronal activity. Consistent with this assumption, it was recently demonstrated that a selective lesion of LC NE neurons increases the mean firing activity of DA neurons by 70% and their burst activity by almost 50%, thus revealing a net inhibitory effect of NE in the VTA (Guiard et al., 2008). In contrast, it had been reported that the systemic administration of the selective NE reuptake inhibitor reboxetine enhanced the burst firing activity of DA neurons in the VTA, but without any apparent effect on their mean firing rate (Linnér et al., 2001). In earlier attempts at characterizing the mechanism of action of NE in the VTA, it has also been shown that the systemic administration of the 1-adrenoceptor antagonist prazosin dose-dependently decreased the burst firing of DA neurons (Grenhoff and Svensson, 1993), apparently supporting an excitatory action of NE in the VTA. However, the selective 2-adrenoceptor antagonist idazoxan increased both the firing rate and bursting activity of VTA DA neurons (Grenhoff and Svensson, 1993), thereby suggesting a complex regulation of DA neuronal activity by NE inputs. As for the local application of NE in the VTA, it usually reduced the spontaneous firing of DA neurons (Aghajanian and Bunney, 1977a,b; White and Wang, 1984a,b), suggesting that a postsynaptic inhibitory element sensitive to NE does exist in the VTA. However, whether NE exerts its effects in the VTA via -adrenergic and/or dopaminergic receptors remained an unresolved issue.
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). Moreover, in rodents, although only a small percentage of its VTA-derived afferents seem to be dopaminergic (Swanson, 1982), DA receptors mainly of the D2-like subtype have been identified in the LC (Yokoyama et al., 1994). Lesion experiments have shed some light on the nature of the effects of DA in the LC. The selective lesion of VTA DA neurons increased by 33% the mean firing rate of LC NE neurons discharging in a single spike mode and by almost 60% that of LC neurons displaying both single spike and busting activities (Guiard et al., 2008), revealing an inhibitory influence of DA inputs. In agreement with these findings, pharmacological studies have indicated that the systemic administration of the nonselective DA receptor agonist (+)-3-PP dose-dependently reduced the firing rate of LC NE neurons, whereas this effect was partially antagonized by the 2-adrenoceptor antagonist yohimbine but not the D2-like receptor antagonist haloperidol (Elam et al., 1986). These results stand in contrast with data showing that the systemic administration of haloperidol enhances the firing rate of LC NE neurons, indicating the existence of a tonically active dopamine input that modulates the firing pattern of LC NE neurons (Piercey et al., 1994; Nilsson et al., 2005). The iontophoretic application of DA in the LC has been shown to inhibit the electrical activity of NE neurons (Cedarbaum and Aghajanian, 1977; Elam et al., 1986). However, the lack or weak effect of the systemic administration of D2/D3 receptor agonists, such as pramipexole or apomorphine, on the firing rate of LC NE neurons (Cedarbaum and Aghajanian, 1977; Chernoloz et al., 2008) has not allowed the identification of the postsynaptic receptor(s) that mediate DA effects in the LC.
In rats, the dorsal hippocampus receives a dense noradrenergic and sparse dopaminergic innervation arising from the LC (Jones and Moore, 1977) and the VTA (Swanson and Hartman, 1975; Scatton et al., 1980), respectively. In addition, because a significant decrease in hippocampal DA levels had been reported when most of the noradrenergic neurons were lesioned (Bischoff et al., 1979), it is possible that in this brain region, DA not only subserves a neurotransmitter role in dopaminergic neurons but is also present as the precursor of NE in noradrenergic neurons. Indeed, it had been proposed that approximately 40% of hippocampal DA is confined in this population of neurons (Bischoff et al., 1979). Radioligand binding studies have revealed the presence of 1-, 2-, β1-, and β2-adrenoceptors (Crutcher and Davis, 1980) and in D2-like receptors (Bischoff et al., 1986; Bruinink and Bischoff, 1993) in the hippocampus, suggesting a role of both catecholamines in the modulation of CA3 pyramidal neurons. Therefore, in vivo electrophysiological evidence demonstrated that NE generally decreased pyramidal neuronal activity, but both excitation and biphasic responses have also been observed. Whereas the inhibitory effects of iontophoretic application of NE on rat dorsal hippocampus result from the activation of 2-adrenoceptors (Curet and de Montigny, 1988a,b), it had been shown that the excitatory effects are mediated by β-adrenoceptors (Mueller et al., 1982; Curet and de Montigny, 1988). The existence of DA-sensitive receptor sites in the hippocampus was first suggested from observations that the local application of DA decreases the firing rate of CA3 pyramidal neurons (Segal et al., 1973; Benardo and Prince, 1982). Despite these results, little is known about the role of DA in the hippocampus and the nature of the receptors mediating its electrophysiological effects.
The present study was therefore aimed at characterizing the effects of microiontophoretically applied NE and DA in the VTA, LC, and the dorsal hippocampus. This technique has the advantage of limiting the zone of possible drug-receptor interactions to the discrete area of application and, as a result, to allow the identification of postsynaptic receptor(s) mediating the response to catecholamines.
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Materials and Methods |
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In Vivo Microiontophoresis. Rats were anesthetized with chloral hydrate (400 mg/kg i.p.) and placed into a stereotaxic frame. The extracellular recordings of the DA, NE, and pyramidal neurons in the VTA, LC, and CA3 region of the hippocampus, respectively, were carried out using multibarreled glass micropipettes (ASI Instruments, Warren, MI). Five-barreled glass micropipettes preloaded with fiberglass strands to promote capillary filling were pulled in the conventional manner. The central barrel used for extracellular unitary recording was filled with 2 M NaCl solution. One side barrel, filled with 2 M NaCl solution, was used for automatic current balancing. The other side barrels were filled with three of the following drug solutions: dopamine (DA-HCl, 0.1 M in 0.2 M NaCl, pH 4), norepinephrine (l-NE-HCl, 0.01 M in 0.2 M NaCl, pH 4), quinpirole-HCl (0.05 M in 0.2 M NaCl, pH 4), raclopride-tartrate (0.025 M in 0.2 M NaCl, pH 4), idazoxan-HCl (0.05 M in 0.2 M NaCl, pH 4), and quisqualate (0.0015 M in 0.2 M NaCl, pH 8). All drugs were ejected as cations and retained with currents of -10 to -8 nA, except for quisqualate, which was ejected as an anion and retained with a current of +5 nA. The impedances of the central barrel were 2 to 5 M
in the LC and hippocampus and 6 to 8 M in the VTA. The impedances of the balance barrel and side barrels were 20 to 30 and 50 to 100 M, respectively. Haloperidol (200 µg/kg), desipramine (2, 4, and 6 mg/kg), and GBR12909 (7.5 mg/kg i.v.) were administered intravenously. All drugs were purchased from Sigma (St. Louis, MO).
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Recording of LC NE Neurons. The five-barreled glass micropipettes were positioned using the following coordinates (from lambda): AP, -1.0 to -1.2 mm; L, 1.0 to 1.3 mm; and V, 5 to 7 mm. Spontaneously active NE neurons were identified using the following criteria: regular firing rate (0.5-5.0 Hz) and positive action potential of long duration (0.8-1.2 ms) exhibiting a brisk excitatory response to a nociceptive pinch of the contralateral hind paw. The mesencephalic fifth nucleus neurons were first located by a response to lower jaw depression, and then the electrode was lowered medially to record LC NE neurons.
Recording of Pyramidal Neurons in the CA3 Region of Dorsal Hippocampus. The five-barreled glass micropipettes were positioned using the following coordinates (from bregma): AP, 3.8 to 4.5 mm; L, 4 to 4.2 mm; and V, 3 to 4.5 mm. Pyramidal neurons stimulated with quisqualate were identified by their high amplitude (0.5-1.2 mV), high frequency (13-15 Hz) and long duration (0.6-1.0 ms) action potential, and their characteristic "complex spike" discharge.
Assessment of Neuronal Responsiveness. In each brain region (i.e., the VTA, LC, and dorsal hippocampus), a current-response curve was obtained by determining for each current the number of spikes suppressed during the 50-s drug ejection period. Two others parameters were used to assess neuronal responsiveness to microiontophoretic application: 1) the number of spikes suppressed per nanoampere, obtained by dividing the number of spikes suppressed from the beginning of the ejection period by the current used (in nanoamperes); and 2) the RT50 value (in seconds), which represents the time required for the firing activity to recover by 50% from the cessation of the microiontophoretic application. In the present study, the RT50 value was used to provide an index of the capacity of NE terminals in the dorsal hippocampus to remove NE or DA from the synaptic cleft in presence or not of intravenous cumulative doses of the selective NE reuptake inhibitor desipramine (from 2 to 6 mg/kg by adding 2 mg/kg after each injection) or of the selective DA reuptake inhibitor GBR12909 (7.5 mg/kg). The doses of desipramine and GBR12909 were chosen on the basis of their capacity to significantly block the NE and DA transporters, respectively (Curet and de Montigny, 1988; Einhorn et al., 1988).
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), even at high ejection currents, a complete suppression of VTA-DA neuronal activity was usually not observed. The iontophoretic application of the D2-like receptor agonist quinpirole also reduced the firing activity of all VTA DA neurons recorded in a current-dependent manner (10-40 nA; Fig. 1A), consistent with the well documented inhibitory role of D2-like receptor subtype on this population of neurons. It is noteworthy that the inhibition of the firing rate of VTA DA neurons was more pronounced after the iontophoretic application of DA than NE or quinpirole (Fig. 1, B and C). Complementing the latter results, it was observed that the iontophoretic application of the D2-like receptor antagonist raclopride (40 nA) blocked the suppressant effects of both DA and quinpirole on VTA DA neuronal activity (Fig. 2, A-C). For some neurons, the systemic administration of the D2-like receptor antagonist haloperidol also prevented the suppressant effect of DA and NE (n = 3). It is noteworthy that raclopride applied by microiontophoresis increased the spontaneous firing rate of VTA DA neurons (4.7 ± 0.7 versus 6.3 ± 0.6 Hz before and after its ejection, respectively; n = 5, P < 0.05). It thus seems that the inhibitory effect of DA was mediated by D2-like receptors. However, the iontophoretic application of raclopride did not allow the complete blockade of the electrophysiological effects of DA, raising the possibility that other(s) receptor(s) might be involved in the inhibitory action of both pharmacological agents.
The iontophoretic application of the 2-adrenoceptor antagonist idazoxan was used to test whether the effects of DA could be mediated, at least in part, by a nondopaminergic mechanism. The suppressant effect of DA was partially blocked by idazoxan (Fig. 3, A and B), whereas this drug per se did not affect the spontaneous firing of VTA DA neurons (3.9 ± 0.7 versus 4.1 ± 0.8 Hz, before and after its ejection; n = 5, P > 0.05). The suppressant effect of NE was also blocked by idazoxan in the VTA (Fig. 3, A and C).
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2-adrenergic autoreceptors in the LC, the iontophoretic application of idazoxan blocked the suppressant effect of NE on NE neuronal activity (Fig. 5, A and B). The fact that similar results were obtained with DA suggests that DA may also activate 2-adrenergic autoreceptors to exert an inhibitory effect on LC NE neurons (Fig. 5, A and C). Despite its blocking activity on both NE and DA, idazoxan did not affect by itself the spontaneous firing of NE neurons (2.1 ± 0.3 versus 2.3 ± 0.4 Hz, before and after its local application, respectively; n = 7, P > 0.05).
Pharmacological Characterization of the Effects of Iontophoretically Applied NE and DA on Pyramidal Neurons of the CA3 Region of the Dorsal Hippocampus. The CA3 region of the dorsal hippocampus was chosen to further establish the possibility that DA could act via -adrenergic receptors because of it has sparse DA projections. The firing activity of dorsal hippocampus pyramidal CA3 neurons was activated by quisqualate to 14.3 ± 0.7 Hz (n = 29). All CA3 neurons responded to a marked and current-dependent inhibition to iontophoretically applied DA (5-80 nA) and NE (5-30 nA), whereas the D2-like receptor agonist quinpirole (5-80 nA) had no effect (Fig. 6A). The suppressant effect of DA on these pyramidal CA3 neurons was not blocked by the iontophoretic application of raclopride (Fig. 6, B and D) or by the systemic injection administration of haloperidol (Figs. 6E) but was significantly attenuated by idazoxan (Fig. 7, A and B).
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2-adrenoceptors, the putative involvement of D2-like receptor in this response was examined. No modification of the suppressant effect of microiontophoretically applied NE was detected in presence of raclopride or haloperidol, thereby confirming the lack of regulation of pyramidal CA3 neurons by D2 receptors in the hippocampus (Fig. 8, A-C). Finally, the spontaneous firing activity of CA3 pyramidal neurons remained unchanged after the local application of raclopride (17.3 ± 2.1 versus 13.4 ± 2.4 Hz, before and after its application, respectively; n = 8, P > 0.05) or of idazoxan (13.4 ± 4.2 versus 13.7 ± 4.9 Hz, before and after its application, respectively; n = 5, P > 0.05).
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Inhibitory Action of Iontophoretically Applied DA on CA3 Pyramidal Neurons in the Presence of the Selective NE Reuptake Inhibitor Desipramine or the Selective DA Reuptake Inhibitor GBR12909. The recovery time, from the suppression of hippocampus pyramidal neuron firing activity after microiontophoretic application of NE or DA, was assessed by determining RT50 values before and after the short-term intravenous administration of desipramine or GBR12909. In agreement with previous data, cumulative doses of desipramine (2, 4, and 6 mg/kg i.v.) did not significantly modify the firing activity of CA3 pyramidal neurons. After the administration of desipramine (2 mg/kg i.v.), the RT50 values were significantly increased after the application of NE and DA (Fig. 9, A-C). Cumulative injections of desipramine (4 and 6 mg/kg) further increased RT50 values for both monoamines, whereas GBR12909 (7.5 mg/kg i.v.) decreased the firing activity of pyramidal neurons by 42%. A small but significant increase in the RT50 value of DA but not NE was obtained after the short-term administration of GBR12909 (Fig. 9, D-F).
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2-adrenoceptor antagonist idazoxan. In the LC and dorsal hippocampus, the suppressant effect of both catecholamines was only attenuated by idazoxan.
In the VTA, the suppressant effect of both DA and quinpirole on DA neurons and their blockade by the D2-like receptor antagonist raclopride further support the involvement of D2 receptor in the DA response. The observation that piperoxane, a nonselective -adrenoceptor antagonist, also attenuates the inhibitory effects of DA (Freedman and Aghajanian, 1984) suggested actions on this class of receptors also. Indeed, the present study showed that the local application of the selective 2-adrenoceptor antagonist idazoxan attenuated the suppressant effect of DA on VTA DA neurons. Such an effect could not be attributed to a nonselective action of idazoxan because this compound has no affinity for DA receptors. Competition experiments in the rat cortex have shown that idazoxan has at least 1000-fold lower affinity for D2 receptors than for 2-adrenoceptors (Ki values, >10 µM and 8 nM, respectively) (Doxey et al., 1983; Neve et al., 1990). It thus seems that in addition to the stimulation of D2 receptors, DA also inhibits the firing activity of DA neurons by acting upon 2-adrenoceptors. Although functional studies previously emphasized such an unselective property of DA in the central nervous system (Cornil et al., 2008), the role of 2-adrenoceptors in a direct regulation of DA neurons themselves remained debatable, especially because, in rat brain, the affinity of DA for 2-adrenoceptors is approximately 3- to 7-fold lower than that of NE (Boyajian et al., 1987). Moreover, despite the expression of 2-adrenoceptors on DA neurons in the VTA (Lee et al., 1998), it was reported that the microiontophoretic application of clonidine (20-120 nA) has no depressant effect on VTA DA neuronal activity (White and Wang, 1984a,b; Aghajanian and Bunney, 1977a,b). The apparent discrepancy between the microiontophoretic effects of clonidine and DA may be explained by the capacity of DA to bind and activate both D2 and 2-adrenoceptors. Indeed, the stimulation of both types of receptors by DA could be important for generating a robust inhibitory effect in the VTA. It is interesting that the systemic administration of low doses of clonidine, which probably activate presynaptic 2-adrenoceptors, does not modify the mean firing rate of VTA DA neurons but decreases their bursting activity (Gobbi et al., 2001; Georges and Aston-Jones, 2003). In contrast, higher doses of clonidine increase both the firing rate and bursting activity of VTA DA neurons (Gobbi et al., 2001). These findings are paradoxical in the light of the present data, but it is possible that systemic administration of adrenergic agonists involves long-loop feedback mechanisms that are not activated with local application. Another possibility is a blunting of the effect of locally applied clonidine by its concomitant binding to postsynaptic 1-adrenoceptors (Anden et al., 1976), whose activation stimulates VTA DA neurons (Grenhoff and Svensson, 1993; Grenhoff et al., 1993, 1995).
The iontophoretic application of NE also reduced the firing activity of DA neurons. Previous reports have indicated that the inhibition of VTA DA neuronal activity induced by local application of NE may be prevented by the D2-like receptor antagonist sulpiride (Aghajanian and Bunney, 1977a,b; White and Wang, 1984a,b), but we show here that idazoxan also has the capacity of preventing the effects of NE. Taken together, these results indicate that NE and DA can activate D2 and 2-receptors in the VTA to inhibit DA neuronal activity.
In the LC, prior results have already suggested a higher sensitivity for NE than DA, because a similar inhibition of NE neurons was detected after the ejection of both NE and DA but with a 10-fold lower concentration of NE than DA. The earlier observation that iontophoretically applied NE-induced inhibition of LC NE neurons is blocked by piperoxane (Cedarbaum and Aghajanian, 1977) was compatible with an involvement of -adrenoceptors. Consistent with these results, the inhibitory effects of both NE and DA here reported were antagonized by idazoxan. Although the inhibitory influence of NE through 2-adrenoceptor on LC NE neurons has been extensively studied (Svensson et al., 1975; Cedarbaum and Aghajanian, 1977), evidence that DA stimulates 2-adrenoceptors to reduce, at least in part, LC NE neuronal firing, was not clearly documented.
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), their direct activation on NE neurons after the iontophoretic application of NE or DA could not be excluded. However, the present study showed that raclopride has no effect on NE- or DA-induced inhibition of LC NE neurons at concentrations and currents found to exert a potent inhibition of VTA DA neurons (Fig. 2C). These results are consistent with the previous demonstration that the nonselective DA receptor antagonist trifluoperazine is ineffective in blocking the inhibition of LC neurons induced by both DA and NE (Cedarbaum and Aghajanian, 1977) and that the capacity of clonidine to inhibit NE neuronal firing is unaltered by haloperidol (Piercey et al., 1994). The putative lack of regulation of LC neurons by D2-like receptors is also evidenced by the observation that these NE neurons are insensitive to the local application of D2-like receptor agonists, such as (+)-3-PP, apomorphine (Aghajanian and Bunney, 1977; Elam et al., 1986), or quinpirole as shown in the present study. Altogether, these observations converge to show that only 2-adrenoceptors are involved in the inhibitory control of LC NE exerted by NE and DA, even if the systemic administration of haloperidol has been reported to enhance the firing rate of LC NE neurons (Piercey et al., 1994; Nilsson et al., 2005). Such an effect could not be related to an antagonistic activity of haloperidol on 2-adrenoceptor (U'Prichard et al., 1977), because the systemic administration of haloperidol in the present study modified neither the spontaneous firing activity of LC NE neurons nor the inhibitory actions of NE or DA. Other studies suggest an excitatory effect of haloperidol on NE neurons that may initially be driven through the local release of glutamate in the LC (Nilsson et al., 2005).
In the dorsal hippocampus, a possible role for DA had to be considered because the iontophoretic application of DA and NE inhibited the firing activity of CA3 pyramidal neurons. However, this DA-induced inhibition of firing was only partial, as if some of the DA effects were counterbalanced by an excitatory component. Given that β-adrenoceptors exert an excitatory action on hippocampus pyramidal neurons (Curet and de Montigny, 1988b), it is possible that the net biological response to DA results from opposite effects exerted on various adrenoceptors. In keeping with a weak expression of DA receptors and raclopride binding sites in the dorsal hippocampus (Dubois et al., 1986; Delis et al., 2004), it was reported that neither the iontophoretic application of raclopride nor the systemic injection of haloperidol blocked DA- or NE-induced inhibition in the dorsal hippocampus. Although haloperidol is known to bind and antagonize both D2 and 1-receptors (Cohen and Lipinski, 1986), the possibility that it blocked the adrenoceptors in the present study can be excluded, because the administration of the selective 1-adrenoceptor antagonist prazosin reduced the effect of NE in a dose-dependent manner (Curet and de Montigny, 1988a) and was here devoid of antagonistic activity. In contrast, the inhibitory action of DA was partially blocked by idazoxan at concentrations that usually antagonize the inhibitory effects of NE or clonidine on CA3 pyramidal neurons (Curet and de Montigny, 1988a). The involvement of postsynaptic 2-adrenoceptors in the electrophysiological response to DA, as described above in VTA and LC, was strongly supported by the latter results. To better understand the physiological importance of such a property, the possibility that NE neurons themselves could be the main source of DA in the hippocampus was addressed. The observation that the selective NE reuptake inhibitor desipramine prolonged the inhibitory effects of microiontophoretic applied DA strongly suggested that the clearance of DA in the hippocampus is mediated, at least in part, by the NE transporter (NET). This is consistent with previous data showing that DA has a greater affinity for the NET than the DA transporter (DAT) itself (Giros et al., 1994) and that DA reuptake by NE terminals occurs in brain regions in which DAT expression is minimal (e.g., the frontal cortex), intermediate, or maximal (e.g., nucleus accumbens shell and the bed nucleus, respectively) (Bymaster et al., 2002; Morón et al., 2002; Carboni and Silvagni, 2004). Recent experiments have proposed that DA may be coreleased with NE from noradrenergic terminals in several cortical areas (Devoto et al., 2004). Although it is not clear whether this feature might be related to a previous nonspecific uptake of DA by NE terminals, it is proposed here that DA is taken up by the NET in the hippocampus (Fig. 9), as reported previously in the frontal cortex (Bymaster et al., 2002). It is interesting that the selective DA reuptake inhibitor GBR12909 also produced a small but significant increase in the RT50 value of iontophoretically applied DA, which could hardly be ascribed to a nonselective binding of GBR12909 to the NET because the RT50 value of NE was not altered in this experiment. Thus, in the dorsal hippocampus, DA uptake could be mediated by distinct transport systems. The involvement of DAT was somewhat unexpected because in brain regions in which DAT is weakly expressed, as in the hippocampus (Delis et al., 2004; Dahlin et al., 2007), a limited role of DAT in removing DA from the extracellular space has been reported (Morón et al., 2002). An alternative mechanism could be that residual DA uptake was mediated by the recently cloned and characterized polyspecific cation-monoamine transporters organic cation transporters (2 and 3) or plasma membrane monoamine transporter. Indeed, these transporters are expressed in the rat hippocampus (Dahlin et al., 2007), but high concentrations of GBR12909 are necessary to block their activity (Morón et al., 2002). In view of these results and of the high ratio NET/DAT in hippocampus, it seems likely that, in this brain region, DA is captured by NET before it reaches other transport sites.
In summary, the present findings showed that, depending on the brain structure studied, DA and NE activate D2 and/or 2-adrenoceptors to exert inhibitory postsynaptic effects (Fig. 10). This is in agreement with previous studies showing the in vivo and in vitro stereoselective interactions of DA with 2-adrenoceptors (Zhang et al., 2004; Cornil et al., 2008) and NE with D2-like receptors (Newman-Tancredi et al., 1997; Wedemeyer et al., 2007). The fact that DA can act in concert with the NE system to strengthen the intensity of postsynaptic noradrenergic responses may have important implications in the treatment of mood disorders.
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Footnotes |
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ABBREVIATIONS: DA, dopamine; CA, field of the hippocampus; DAT, dopamine transporter; GBR12909, 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine; NE, norepinephrine; NET, norepinephrine transporter; LC, locus ceruleus; RT, recovery time; VTA, ventral tegmental area; (+)-3-PP, 3-(3-hydroxyphenyl)-N-n-propylpiperidine.
Address correspondence to: Dr. Pierre Blier, University of Ottawa Institute of Mental Health Research, 1145 Carling Avenue, Ottawa, K1Z 7K4, Ontario, Canada. E-mail: pblier{at}rohcg.on.ca
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References |
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Aghajanian GK and Bunney BS (1977b) Pharmacological characterization of dopamine "autoreceptors" by microiontophoretic single-cell recording studies. Adv Biochem Psychopharmacol 16: 433-438.[Medline]
Andén NE, Grabowska M, and Strömbom U (1976) Different alpha-adrenoreceptors in the central nervous system mediating biochemical and functional effects of clonidine and receptor blocking agents. Naunyn Schmiedebergs Arch Pharmacol 292: 43-52.[CrossRef][Medline]
Benardo LS and Prince DA (1982) Dopamine action on hippocampal pyramidal cells. J Neurosci 2: 415-423.[Abstract]
Bischoff S, Heinrich M, Sonntag JM, and Krauss J (1986) The D-1 dopamine receptor antagonist SCH 23390 also interacts potently with brain serotonin (5-HT2) receptors. Eur J Pharmacol 129: 367-370.[CrossRef][Medline]
Bischoff S, Scatton B, and Korf J (1979) Biochemical evidence for a transmitter role of dopamine in the rat hippocampus. Brain Res 165: 161-165.[CrossRef][Medline]
Boyajian CL, Loughlin SE, and Leslie FM (1987) Anatomical evidence for -2 adrenoceptor heterogeneity: differential autoradiographic distributions of [3H]-rauwolscine and [3H]idazoxan in rat brain. J Pharmacol Exp Ther 241: 1079-1091.
Bruinink A and Bischoff S (1993) Dopamine D2 receptors are unevenly distributed in the rat hippocampus and are modulated differently than in striatum. Eur J Pharmacol 245: 157-164.[CrossRef][Medline]
Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, and Perry KW (2002) Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology 27: 699-711.[CrossRef][Medline]
Carboni E and Silvagni A (2004) Dopamine reuptake by norepinephrine neurons: exception or rule? Crit Rev Neurobiol 16: 121-128.[CrossRef][Medline]
Cedarbaum JM and Aghajanian GK (1977) Catecholamine receptors on locus coeruleus neurons: pharmacological characterization. Eur J Pharmacol 44: 375-385.[CrossRef][Medline]
Chernoloz O, Mansari ME, and Blier P (2008) Sustained administration of pramipexole modifies the spontaneous firing rate of dopamine, norepinephrine, and serotonin neurons in the rat brain. Neuropsychopharmacology, in press.
Cohen BM and Lipinski JF (1986) In vivo potencies of antipsychotic drugs in blocking alpha 1 noradrenergic and dopamine D2 receptors: implications for drug mechanisms of action. Life Sci 39: 2571-2580.[CrossRef][Medline]
Cornil CA, Castelino CB, and Ball GF (2008) Dopamine binds to alpha2-adrenergic receptors in the song control system of zebra finches (Taeniopygia guttata). J Chem Neuroanat 35: 202-215.[Medline]
Crutcher KA and Davis JN (1980) Hippocampal alpha- and beta-adrenergic receptors: comparison of [3H]dihydroalprenolol and [3H]WB 4101 binding with noradrenergic innervation in the rat. Brain Res 182: 107-117.[CrossRef][Medline]
Curet O and de Montigny C (1988a) Electrophysiological characterization of adrenoceptors in the rat dorsal hippocampus. I. Receptors mediating the effect of microiontophoretically applied norepinephrine. Brain Res 475: 35-46.[CrossRef][Medline]
Curet O and de Montigny C (1988b) Electrophysiological characterization of adrenoceptors in the rat dorsal hippocampus. II. Receptors mediating the effect of microiontophoretically applied norepinephrine. Brain Res 475: 47-57.[CrossRef][Medline]
Dahlin A, Xia L, Kong W, Hevner R, and Wang J (2007) Expression and immunolocalization of the plasma membrane monoamine transporter in the brain. Neuroscience 146: 1193-1211.[CrossRef][Medline]
Delis F, Mitsacos A, and Giompres P (2004) Dopamine receptor and transporter levels are altered in the brain of Purkinje cell degeneration mutant mice. Neuroscience 125: 255-268.[CrossRef][Medline]
Devoto P, Flore G, Pira L, Longu G, and Gessa GL (2004) Mirtazapine-induced corelease of dopamine and noradrenaline from noradrenergic neurons in the medial prefrontal and occipital cortex. Eur J Pharmacol 487: 105-111.[CrossRef][Medline]
Doxey JC, Roach AG, and Smith CF (1983) Studies on RX 781094: a selective, potent and specific antagonist of alpha 2-adrenoceptors. Br J Pharmacol 78: 489-505.[Medline]
Dubois A, Savasta M, Curet O, and Scatton B (1986) Autoradiographic distribution of the D1 agonist [3H]SKF 38393, in the rat brain and spinal cord. Comparison with the distribution of D2 dopamine receptors. Neuroscience 19: 125-137.[CrossRef][Medline]
Einhorn LC, Johansen PA, and White FJ (1988) Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: studies in the ventral tegmental area. J Neurosci 8: 100-112.[Abstract]
Elam M, Clark D, and Svensson TH (1986) Electrophysiological effects of the enantiomers of 3-PPP on neurons in the locus coeruleus of the rat. Neuropharmacology 25: 1003-1008.[CrossRef][Medline]
Freedman JE and Aghajanian GK (1984) Idazoxan (RX 781094) selectively antagonizes alpha 2-adrenoceptors on rat central neurons. Eur J Pharmacol 105: 265-272.[CrossRef][Medline]
Georges F and Aston-Jones G (2003) Prolonged activation of mesolimbic dopaminergic neurons by morphine withdrawal following clonidine: participation of imidazoline and norepinephrine receptors. Neuropsychopharmacology 28: 1140-1149.[Medline]
Giros B, Wang YM, Suter S, McLeskey SB, Pifl C, and Caron MG (1994) Delineation of discrete domains for substrate, cocaine, and tricyclic antidepressant interactions using chimeric dopamine-norepinephrine transporters. J Biol Chem 269: 15985-15988.
Gobbi G, Muntoni AL, Gessa GL, and Diana M (2001) Clonidine fails to modify dopaminergic neuronal activity during morphine withdrawal. Psychopharmacology (Berl) 158: 1-6.[CrossRef][Medline]
Grenhoff J and Svensson TH (1993) Prazosin modulates the firing pattern of dopamine neurons in rat ventral tegmental area. Eur J Pharmacol 233: 79-84.[CrossRef][Medline]
Grenhoff J, Nisell M, Ferré S, Aston-Jones G, and Svensson TH (1993) Noradrenergic modulation of midbrain dopamine cell firing elicited by stimulation of the locus coeruleus in the rat. J Neural Transm Gen Sect 93: 11-25.[CrossRef][Medline]
Grenhoff J, North RA, and Johnson SW (1995) Alpha 1-adrenergic effects on dopamine neurons recorded intracellularly in the rat midbrain slice. Eur J Neurosci 7: 1707-1713.[CrossRef][Medline]
Guiard BP, El Mansari M, Merali Z, and Blier P (2008) Functional interactions between dopamine, serotonin and norepinephrine neurons: an in-vivo electrophysiological study in rats with monoaminergic lesions. Int J Neuropsychopharmacol 11: 625-639.[Medline]
Jones BE and Moore RY (1977) Ascending projections of the locus coeruleus in the rat. II. Autoradiographic study. Brain Res 127: 25-53.[Medline]
Lee A, Wissekerke AE, Rosin DL, and Lynch KR (1998) Localization of alpha2C-adrenergic receptor immunoreactivity in catecholaminergic neurons in the rat central nervous system. Neuroscience 84: 1085-1096.[CrossRef][Medline]
Linnér L, Endersz H, Ohman D, Bengtsson F, Schalling M, and Svensson TH (2001) Reboxetine modulates the firing pattern of dopamine cells in the ventral tegmental area and selectively increases dopamine availability in the prefrontal cortex. J Pharmacol Exp Ther 297: 540-546.
Morón JA, Brockington A, Wise RA, Rocha BA, and Hope BT (2002) Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines. J Neurosci 22: 389-395.
Mueller AL, Palmer MR, Hoffer BJ, and Dunwiddie TV (1982) Hippocampal noradrenergic responses in vivo and in vitro. Characterization of alpha and beta components. Naunyn Schmiedebergs Arch Pharmacol 318: 259-266.[CrossRef][Medline]
Neve KA, Henningsen RA, Kinzie JM, De Paulis T, Schmidt DE, Kessler RM, and Janowsky A (1990) Sodium-dependent isomerization of Dopamine D-2 receptors characterized using [125I]epidepride, a high-affinity substituted benzamide ligand. J Pharmacol Exp Ther 252: 1108-1116.
Newman-Tancredi A, Audinot-Bouchez V, Gobert A, and Millan MJ (1997) Noradrenaline and adrenaline are high affinity agonists at dopamine D4 receptors. Eur J Pharmacol 319: 379-383.[CrossRef][Medline]
Nilsson LK, Schwieler L, Engberg G, Linderholm KR, and Erhardt S (2005) Activation of noradrenergic locus coeruleus neurons by clozapine and haloperidol: involvement of glutamatergic mechanisms. Int J Neuropsychopharmacol 8: 329-339.[CrossRef][Medline]
Ornstein K, Milon H, McRae-Degueurce A, Alvarez C, Berger B, and Würzner HP (1987) Biochemical and radioautographic evidence for dopaminergic afferents of the locus coeruleus originating in the ventral tegmental area. J Neural Transm 70: 183-191.[CrossRef][Medline]
Piercey MF, Smith MW, and Lum-Ragan JT (1994) Excitation of noradrenergic cell firing by 5-hydroxytryptamine1A agonists correlates with dopamine antagonist properties. J Pharmacol Exp Ther 268: 1297-1303.
Scatton B, Simon H, Le Moal M, and Bischoff S (1980) Origin of dopaminergic innervation of the rat hippocampal formation. Neurosci Lett 18: 125-131.[CrossRef][Medline]
Segal M, Pickel V, and Bloom F (1973) The projections of the nucleus locus coeruleus: an autoradiographic study. Life Sci 13: 817-821.[CrossRef][Medline]
Simon H, Le Moal M, Stinus L, and Calas A (1979) Anatomical relationships between the ventral mesencephalic tegmentum—a 10 region and the locus coeruleus as demonstrated by anterograde and retrograde tracing techniques. J Neural Transm 44: 77-86.[CrossRef][Medline]
Svensson TH, Bunney BS, and Aghajanian GK (1975) Inhibition of both noradrenergic and serotonergic neurons in brain by the alpha-adrenergic agonist clonidine. Brain Res 92: 291-306.[CrossRef][Medline]
Swanson LW and Hartman BK (1975) The central adrenergic system. An immunofluorescence study of the location of cell bodies and their efferent connections in the rat utilizing dopamine-beta-hydroxylase as a marker. J Comp Neurol 163: 467-505.[CrossRef][Medline]
Swanson LW (1982) The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat. Brain Res Bull 9: 321-353.[CrossRef][Medline]
U'Prichard DC, Greenberg DA, and Snyder SH (1977) Binding characteristics of a radiolabeled agonist and antagonist at central nervous system noradrenergic receptors. Mol Pharmacol 13: 454-473.
Wedemeyer C, Goutman JD, Avale ME, Franchini LF, Rubinstein M, and Calvo DJ (2007) Functional activation by central monoamines of human dopamine D4 receptor polymorphic variants coupled to GIRK channels in Xenopus oocytes. Eur J Pharmacol 562: 165-173.[CrossRef][Medline]
White FJ and Wang RY (1984a) A10 dopamine neurons: role of autoreceptors in determining firing rate and sensitivity to dopamine agonists. Life Sci 34: 1161-1170.[CrossRef][Medline]
White FJ and Wang RY (1984b) Pharmacological characterization of dopamine autoreceptors in the rat ventral tegmental area: microiontophoretic studies. J Pharmacol Exp Ther 231: 275-280.
Yokoyama C, Okamura H, Nakajima T, Taguchi J, and Ibata Y (1994) Autoradiographic distribution of [3H]YM-09151-2, a high-affinity and selective antagonist ligand for the dopamine D2 receptor group, in the rat brain and spinal cord. J Comp Neurol 344: 121-136.[CrossRef][Medline]
Zhang WP, Ouyang M, and Thomas SA (2004) Potency of catecholamines and other L-tyrosine derivatives at the cloned mouse adrenergic receptors. Neuropharmacology 47: 438-449.[CrossRef][Medline]
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