Functional interactions between dopamine, serotonin and norepinephrine neurons: an in-vivo electrophysiological study in rats with monoaminergic lesions

International Journal of Neuropsychopharmacology, Page 1 of 15. Copyright f 2008 CINP Functional interactions between dopamine, serotonin and norepinephrine neurons:an in-vivo electrophysiological studyin rats with monoaminergic lesions Bruno P. Guiard1, Mostafa El Mansari1, Zul Merali1,2 and Pierre Blier1,2 1 Institute of Mental Health Research, University of Ottawa, Ottawa, Ontario, Canada2 Department of Cellular and Molecular Medicine, Faculty of Medicine ; Ottawa Health Research Institute, University of Ottawa,Ottawa, Ontario, Canada Anatomical studies have established the existence of reciprocal relationships between the main populationof monoamine, serotonin (5-HT), norepinephrine (NE) and dopamine (DA) neurons in the brain. Thepresent study was thus conducted to examine the firing activity of 5-HT and NE neurons in DA-depletedrats, as well as the firing activity of DA neurons in 5-HT- or NE-depleted rats. The selective lesion of DAneurons elicited by 6-hydroxydopamine (6-OHDA) decreased the spontaneous firing activity of dorsalraphe (DR) nucleus 5-HT neurons by 60 %, thus revealing the excitatory effect of the DA input on these5-HT neurons. In contrast, the selective lesion of 5-HT neurons produced by 5,7-dihydroxytryptamine(5,7-DHT) enhanced by 36 % the firing activity of VTA DA neurons, thereby indicating an inhibitory effectof the 5-HT input on these DA neurons. With regard to the reciprocal interaction between DA and NEneurons, it was observed that the selective loss of DA neurons achieved by the intra-ventral tegmental area(VTA) injection of 6-OHDA increased the firing activity of a subset of locus coeruleus (LC) NE neurons by47 %. The selective loss of NE neurons in response to the intra-LC injection of 6-OHDA enhanced the firingactivity of VTA DA neurons by 70 %, demonstrating a net inhibitory role of the NE input on VTA DAneurons. These findings have important consequences for antidepressant treatments aimed at enhancingsimultaneously 5-HT, NE and DA transmission. Indeed, based on the understanding of such interactions,it may be possible to develop strategies to improve the effectiveness of antidepressant drugs by preventingcounter-productive negative feedback actions.
Received 12 August 2007 ; Reviewed 17 October 2007 ; Revised 21 November 2007 ; Accepted 5 December 2007 Key words : Antidepressants, dopamine, firing activity, norepinephrine, serotonin.
synthesis inhibition (Dremencov et al., 2007 ; Haddjeriet al., 1997 ; Reader et al., 1986). When NE neurons are There are reciprocal projections between the major lesioned, dorsal raphe (DR) 5-HT neurons discharge groups of serotonin (5-hydroxytryptamine ; 5-HT) and erratically at a low rate, but only for the first few days norepinephrine (NE) neurons in the brain (Aston- (Svensson et al., 1975). Although the loss of brain Jones et al., 1991 ; Kaehler et al., 1999). The physio- monoamine neurons does not necessarily reflect the logical importance of such connections is evidenced by pathophysiology of mood disorders, such an exper- alterations in neuronal activity in lesion experiments.
imental approach can be initially used to establish the When 5-HT neurons are lesioned, the firing rate of net excitatory and/or inhibitory nature of a specific locus coeruleus (LC) NE neurons is enhanced in a sus- neurotransmitter at post-synaptic level. As an example tained fashion by about 70 %, as is the case with 5-HT of the clinical relevance of monoaminergic projections,selective 5-HT reuptake inhibition produces a marked Address for correspondence : Dr B. P. Guiard, Ph.D., Institute of inhibition of the spontaneous firing rate of LC NE Mental Health Research (IMHR), 1145 Carling Avenue, University of neurons (Dremencov et al., 2007 ; Seager et al., 2004, Ottawa, Ottawa, K1Z 7K4, Ontario, Canada.
2005 ; Szabo et al., 2000). Low doses of atypical anti- Tel. : +01 (613)-722-6521 (ext. 6732) Fax : +01 (613)-792-3935E-mail : bguiard@rohcg.on.ca psychotics, which are now recognized as an effective augmentation strategy in non-psychotic selective and Esposito, 1995). However, electrical stimulation serotonin reuptake inhibitor (SSRI)-resistant depressed of the DR produces two different types of response patients, reverse this inhibitory action via blockade of in the VTA. Some DA neurons exhibit an inhibition- 5-HT2A receptors (Berman et al., 2007 ; Dremencov excitation response while others show an initial et al., 2007, Gharabawi et al., 2006a,b ; Rapaport et al., excitation followed by an inhibition (Gervais and It is well documented that dopamine (DA) neurons Descending pathways from the VTA also innervate of the ventral tegmental area (VTA), giving rise to the the LC (Ornstein et al., 1987). In-vivo recordings mesolimbic/cortical DA system, send projections to showed that direct iontophoretic application of DA in the DR (Kale´n et al., 1988) and the LC (Beckstead et al., the LC of anaesthetized rats, suppresses the firing 1979), while in turn, receiving important inputs from activity of NE neurons (Elam et al., 1986), while sys- the latter nuclei (Herve´ et al., 1987). It therefore ap- temic injection of the selective D2 antagonist halo- pears crucial to examine the reciprocal interactions of peridol enhances it (Piercey et al., 1994). In turn, these three types of neurons to understand the effects functional studies indicate that LC NE neurons of medications acting on monoaminergic systems.
modulate DA neurons of the VTA. For instance, the In particular, there is growing interest for DA in the electrical stimulation of the LC as well as the systemic field of mood disorders, since drugs that enhance its administration of the selective NE reuptake inhibitor transmission are clinically effective on their own. For reboxetine, both increase NE levels in the VTA, pro- example, the selective D2/D3 agonist pramipexole, ducing excitation of DA neurons (Grenhoff et al., 1993 ; customarily used in the treatment of Parkinson’s dis- Linner et al., 2001). In contrast, the local application ease (PD), was shown to be effective in depression of NE in the VTA was shown to inhibit the electrical as a monotherapy (Barone et al., 2006 ; Corrigan et al., activity of DA neurons (Aghajanian and Bunney, 1977 ; 2000), as well as an augmentation strategy for SSRI- Grenhoff et al., 1995 ; White and Wang, 1984).
resistant patients (Goldberg et al., 2004 ; Lattanzi et al., In order to further elucidate the interactions be- 2002). Conversely, degeneration of DA neurons in PD tween DA, 5-HT and NE neurons, the firing activity of patients typically leads to anhedonia and loss of 5-HT and NE neurons was examined in DA-depleted motivation, two symptoms frequently associated with rats, as well as the firing activity of DA neurons in depression (Harro and Oreland, 2001). More import- antly, the prevalence of depression can reach 50 % inPD patients (McDonald et al., 2003). Taken together, these observations suggest that an attenuation of DAtransmission could participate in the pathogenesis of mood disorders, possibly in part through interactions Male Sprague–Dawley rats (Charles River, St Constant, with the 5-HT and/or the NE system(s).
QC, Canada) weighing 250–300 g, were used for the There is consistent evidence regarding the dopa- experiments. They were housed individually and kept minergic regulation of DR 5-HT neurons. Infusion of under standard laboratory conditions (12 : 12 h light/ the DA agonist apomorphine in the rat DR stimulates dark cycle with free access to food and water). All the firing rate of 5-HT neurons and the local release of animals were handled according to the guidelines of 5-HT, while these effects are partially prevented by the the Canadian Council on Animal Care (CCAC) and selective D2 receptor antagonist raclopride (Ferre and protocols in this study were approved by the local Artigas, 1993 ; Martin-Ruiz et al., 2001). The hypothesis Animal Care Committee (Ottawa Health Research that DA interacts with 5-HT neurons, mainly through activation of D2 receptors is also supported by the de-polarizing action of quinpirole, and its blockade with the D2 receptor antagonist haloperidol, in rat 5-HTneurons recorded in vitro (Aman et al., 2006 ; Haj- Rats were anaesthetized with a mixture 1 : 1 by volume Dahmane, 2001). The exact nature of the effect of 5-HT of xylazine (20 mg/ml) and ketamine (100 mg/ml) on VTA DA neuron activity remains unclear, in that and placed into a stereotaxic frame with atraumatic both inhibitory and excitatory roles for 5-HT have ear bars. To study interactions between 5-HT and DA been observed. Acute intravenous administration of neurons, rats were administered intracerebroven- SSRIs, which probably enhances extracellular 5-HT triculary (i.c.v., unilateral) with 5,7-dihydroxytrypt- levels in the VTA, induces a small decrease in the firing amine (5,7-DHT : 200 mg free base in 10 ml of 0.9 % NaCl rate of VTA DA neurons (Di Mascio et al., 1998 ; Prisco and 0.1 % ascorbic acid) or 6-hydroxydopamine Interactions between monoaminergic neurons (6-OHDA : 120 mg free base in 10 ml of 0.9 % NaCl and 0.1 % ascorbic acid) as previously described (Reader The single-barrelled glass micropipettes were pos- and Gauthier, 1984). The following stereotaxic co- itioned using the following coordinates (in mm from ordinates (in mm from bregma) : AP x0.9, L+1.5, V lambda) : AP+1.0 to 1.2, L 0¡0.1, V 5–7. The presumed 3.7 were used to reach the lateral ventricle. The flow 5-HT neurons were then identified using the following rate injection was 1 ml/min and after completion of the criteria : a slow (0.5–2.5 Hz) and regular firing rate and i.c.v. infusion of neurotoxins or vehicle, the syringe long-duration (2–5 ms) bi- or triphasic extracellular was left in place for 15 min to allow sufficient diffusion waveform (Aghajanian and Vandermaelen, 1982).
before its withdrawal. One hour before the i.c.v. in-jection, animals lesioned with 5,7-DHT were pre- treated with the selective NE reuptake inhibitordesipramine (25 mg/kg i.p.) and the selective DA The single-barrelled glass micropipettes were pos- reuptake inhibitor GBR12909 (25 mg/kg i.p.) to pre- itioned using the following coordinates (in mm from vent loss of NE and DA neurons, respectively. Those Bregma) : AP x6 to x5.4, L 1 to 0.6, V 7–9. The pre- lesioned with 6-OHDA were pre-treated with desipra- sumed DA neurons were identified according to the mine (25 mg/kg i.p.) and the SSRI fluoxetine (10 mg/ well-established electrophysiological properties in kg i.p.) to prevent loss of NE and 5-HT neurons.
vivo : a typical triphasic action potential with a marked Control rats (sham-operated) were subjected to the negative deflection ; a characteristic long duration same procedure and received the corresponding pre- (>2.5 ms) often with an inflection or ‘notch ’ on the treatments 1 h before the unilateral injection of 10 ml rising phase ; a slow spontaneous firing rate (0.5–5 Hz) with an irregular single spiking pattern with slow To study interactions between central NE and DA bursting activity (characterized by spike-amplitude neurons, rats received a bilateral injection of 6-OHDA decrement) (Grace and Bunney, 1983). As previously (5 mg free base in 0.5 ml of 0.9 % NaCl and 0.1 % ascor- described, a criterion of duration (>1.1 ms from the bic acid) into the LC or VTA to limit the diffusion of start of the action potential to the negative trough) was the neurotoxin throughout the brain and consequently produce a more selective deafferentation (Reader, 1982). This is of particular interest since intracerebralinjection of 6-OHDA may deplete both NE and DA The single-barrelled glass micropipettes were pos- levels (Reader and Gauthier, 1984). The following co- itioned using the following coordinates (in mm from ordinates were used : AP x1.1, L 1.1, V 5.5 for the LC lambda) : AP x1.0 to x1.2, L 1.0–1.3, V 5–7. Spon- (in mm from lambda) and AP – 5.8, L 0.7, V 8.5 for the taneously active NE neurons were identified using the VTA (in mm from bregma). Rats that received intra- following criteria : regular firing rate (0.5–5.0 Hz) and LC 6-OHDA were pre-treated, 1 h before, with fluoxe- positive action potential of long duration (0.8–1.2 ms) tine (10 mg/kg i.p.) and GBR12909 (25 mg/kg i.p.) and exhibiting a brisk excitatory response to a nociceptive those that received intra-VTA 6-OHDA, were ad- pinch of the contralateral hind paw (Aghajanian and ministered fluoxetine (10 mg/kg i.p.) and desipramine Vandermaelen, 1982). The compression lasted y1 s (25 mg/kg i.p.). It is noteworthy that intracerebral with equal pressure being applied to the paw of rats ; administration of 6-OHDA was reported to be more once the opposite sides of the forceps made contact effective in depleting NE than the systemic treatment with each other, the forceps were then released. Of with DSP4 (Lookingland et al., 1986).
interest, it has also been reported that the numberof elicited bursts is largely independent of paw-compression intensity.
Ten days after the injection of the neurotoxins, ratswere anaesthetized with chloral hydrate (400 mg/kg The firing patterns of DA and NE neurons (both i.p.) and placed into a stereotaxic frame. The extra- displaying a bursting activity) were analysed by spike- cellular recordings of the 5-HT, DA and NE neurons in interval burst analysis following the criteria estab- the DR, VTA and LC, were performed using single- lished by Grace and Bunney (1984). The onset of a barrelled glass micropipettes (R&D Scientific Glass, burst was defined as the occurrence of two spikes Spencerville, MD, USA) preloaded with a 2 M NaCl with an inter-spike interval shorter than 0.08 s. The solution. Their impedance typically ranged between termination of bursts was defined as an inter-spike interval (ISI) of o0.16 s. The detailed analysis of ISI for DA, NE and also 5-HT neurons in sham-operated and lesioned rats is provided in Supplementary material Neurochemical analyses of the neurotoxic lesions Rats treated with the i.c.v. injection of 6-OHDA dis- Biochemical analysis of brain monoamine levels played a 70 % reduction of DA levels in the striatum The effectiveness and selectivity of the neurochemical (Table 1a). In the DA neuron-lesioned rats, no changes lesions was confirmed by measuring 5-HT, NE and DA in 5-HT levels were detected in the frontal cortex concentrations at specific brain sites. The frontal cortex (Table 1a), the hippocampus and the striatum (data and striatum (including the nucleus accumbens) were not shown) compared to sham-operated rats. More- chosen to determine the extent of 5-HT and DA de- over, no changes in NE levels were reported in these pletion, respectively, as preferential serotonergic and post-synaptic structures (Table 1a, and data not dopaminergic projections from the DR and the VTA.
shown) with the exception of the frontal cortex The hippocampus was selected to examine NE con- (0.13¡0.02 ng/mg vs. 0.22¡0.01 ng/mg in lesioned centration since it has been repeatedly shown to have and sham-operated rats, respectively ; p<0.05), sug- high levels of this monoamine (Dailly et al., 2006).
gesting that desipramine does not effectively protect Immediately after electrophysiological experiments NE terminals within the latter region. The lesion of sham-operated rats and lesioned rats were sacrified, 5-HT neurons induced by the i.c.v. injection of 5,7- the brain removed and stored at x80 xC. The frontal DHT significantly reduced the levels of 5-HT in the cortex, hippocampus and striatum were dissected as frontal cortex by 87 %. The selectivity of the 5,7-DHT previously described (Chenu et al., 2006). Each separ- lesion was confirmed from the observations that the ate brain area was placed in an Eppendorf tube with concentrations of NE and DA were not different be- tween lesioned and sham-operated rats in the frontal an internal standard, dihydroxybenzylamine), homo- cortex, hippocampus and striatum (Table 1a, and data genized using ultrasound and centrifuged at 8000 g for 15 min. The supernatant was analysed for monoamine The lesion of VTA DA neurons elicited by local content using high-performance liquid chromato- injection of 6-OHDA produced a significant reduction in DA levels (48 %) in the striatum (Table 1b). In-terestingly, the depletion of VTA DA neurons pro- duced a similar degree of depletion (50 %) in the frontalcortex of lesioned rats compared to sham-operated Electrophysiological data were expressed as mean¡ rats (0.08¡0.02 ng/mg vs. 0.19¡0.03 ng/mg ; p<0.01).
S.E.M of the firing rate, number of single spikes, number 5-HT and NE levels were unchanged in the frontal of bursts and single spikes per burst. Statistical com- cortex, hippocampus and striatum of rats that received parisons among DR, VTA and LC of sham-operated the intra-VTA injection of 6-OHDA with respect to the and lesioned rats were performed using two-tailed sham-operated animals (Table 1b, and data not Student’s t tests. The means (number¡S.E.M) of neurons shown). The lesion of LC NE neurons achieved by recorded per track in sham-operated and lesioned rats local injection of 6-OHDA significantly decreased the were also compared using a two-tailed Student’s t test.
level of NE in the hippocampus by 66 % (Table 1b).
For the lesioning studies, each neurotransmitter peak 5-HT and DA levels were not different between sham- from the HPLC was converted into values represent- operated and lesioned rats in the frontal cortex, hippo- ing ng/mg wet weight tissue based on external campus and striatum (Table 1b, and data not shown).
neurotransmitter standards of that day. A Student’st test was used to analyse between-group differences.
Effect of DA neuron lesion on the firing activity of 5-HTneurons in the DR Desipramine hydrochloride, GBR12909 and the neuro-toxins (5,7-DHT creatinine sulphate, 6-OHDA hydro- The mean number of DR 5-HT neurons recorded per bromide) were purchased from Sigma-Aldrich (St track was not significantly different between sham- Louis, MO, USA). Fluoxetine was purchased from operated (n=24 tracks) and DA neuron-lesioned rats Medisca Pharmaceutic Inc. (Montreal, Canada) and (n=22 tracks, Table 2). The mean firing frequency idazoxan from Sigma/RBI (Oakville, ON, Canada). All of DR 5-HT neurons in DA neuron-lesioned rats was neurotoxins were dissolved before experiments and significantly decreased by 60 % compared to sham- protected from light during the injection.
Interactions between monoaminergic neurons Table 1. Effect of monoaminergic neurons lesion on the extent of 5-HT, NE and DA levels in the frontal cortex,hippocampus and striatum (a) Intracerebroventricular injections of neurotoxinsSham-operated rats (b) In-situ injections of neurotoxinsSham-operated rats VTA, Ventral tegmental area ; LC, locus coeruleus.
Values are expressed as the mean¡S.E.M. (ng/mg wet tissue) of each monoamine in sham-operated rats and lesioned rats, 10 dafter the injection of vehicle or the neurotoxin. One hour before the administration of the neurotoxin, fluoxetine, desipramineand/or GBR12909 were administered to protect the 5-HT, NE and DA, respectively and enhance the selectivity of the lesion.
* p<0.05 and ** p<0.01 relative the corresponding group of sham-operated rats.
Table 2. Electrophysiological characteristics of monoaminergic neurons in sham-operated and lesioned rats DR, Dorsal raphe ; VTA, ventral tegmental area ; LC, locus coeruleus.
* p<0.05, ** p<0.01 and *** p<0.001 relative the corresponding group of sham-operated rats.
Effect of 5-HT neuron lesion on the firing activity of DA sham-operated (n=49 tracks) and 5-HT neuron- lesioned rats (n=61 tracks, Table 2). In rats with their5-HT neurons lesioned, the mean firing frequency of The mean number of VTA DA neurons recorded VTA DA neurons was significantly increased by 36 % per track was not significantly different between compared to sham-operated rats (Figure 2c). In order Figure 1. Effect of dopaminergic lesion with6-hydroxydopamine (6-OHDA) on the electrophysiologic Figure 2. Effect of serotonergic lesion with 5,7- activity of 5-HT neurons in the dorsal raphe (DR).
dihydroxytryptamine (5,7-DHT) on the electrophysiological Examples of typical recordings of DR 5-HT neurons obtained activity of DA neurons in the ventral tegmental area (VTA).
in (a) a sham-operated rat and (b) a DA neuron-lesioned Examples of typical recordings of VTA DA neurons obtained rat. (c) Mean¡S.E.M. of frequency (Hz) of 5-HT neurons in (a) a sham-operated rat and (b) a 5-HT neuron-lesioned rat, recorded in the DR of sham-operated rats (n=5) each asterisk indicates a burst. (c) Mean¡S.E.M. of frequency (grey histogram) and 6-OHDA-treated rats (n=6) (Hz) of DA neurons. Number of single spikes/min (d), (white histogram). *** p<0.001 indicates significantly bursts/min (e), and single spikes/burst (f), recorded in the different from sham-operated rats. The numbers within the VTA of sham-operated rats (n=7) (grey histogram) and histograms indicate the number of neurons recorded.
5,7-DHT-treated rats (n=7) (white histogram). * p<0.05,** p<0.01 and *** p<0.001 indicates significantly differentfrom sham-operated rats. The numbers within the histograms to determine whether this increase was due to indicate the number of neurons recorded.
an alteration of single spike and/or burst activity, amore detailed analysis was performed. The meannumber of single spikes/min did not quite reach tracks) than in VTA-lesioned rats (n=36 tracks, the pre-determined level of statistical significance Table 2). The mean firing frequency of all spontaneous in depleted rats compared to sham-operated rats active LC NE neurons was significantly increased by (Figure 2d). However, the number of bursts/min and 47 % in VTA-lesioned rats compared to sham-operated of single spikes per burst was significantly increased in rats with 5-HT neurons lesioned (Figure 2e, f).
(Dremencov et al., 2007), it was found that 77 % of NEcells discharged only in single-spike mode while the Effect of DA neuron lesion on the firing activity of NE rest displayed bursting activity. These percentages were not affected by the lesion of VTA DA neurons The mean number of NE neurons recorded per track since 71 % and 29 % of LC NE neurons exhibited a was significantly higher in sham-operated rats (n=10 single spike and bursting activity, respectively. The Interactions between monoaminergic neurons Table 3. Effect of VTA DA neuron lesion on the sensory-evoked firing activity of LC NE neurons VTA, Ventral tegmental area ; LC, locus coeruleus.
* p<0.05 and ** p<0.01, relative the sham-operated group of rats.
mean firing frequency of NE cells discharging with a significant difference between depleted rats and sham- single spike pattern, was significantly increased by operated rats was detected in the mean number of 33 % in VTA DA neuron-lesioned rats compared to single spikes/min (Figure 5d). However, the number sham-operated rats (Figure 3c). In addition, among the of bursts/min and single spikes per burst were sig- LC NE cells displaying a bursting activity, the mean nificantly increased in LC NE neuron-lesioned rats firing frequency of LC NE neurons was increased by compared to sham-operated rats (Figure 5e, f ).
59 % in VTA DA neuron-lesioned rats compared tosham-operated (Figure 4c). No significant differencewas detected between both groups of rats in the mean number of single spikes/min ; while the number of The present electrophysiological study showed that bursts/min and single spikes per burst were signifi- lesioning 5-HT and NE neurons increased the firing cantly increased in VTA-lesioned rats (Figure 4e, f ).
activity of VTA DA neurons. Conversely, lesioning In addition, it has been observed that the percentage DA neurons decreased DR 5-HT neuronal firing but of neurons displaying a sensory-evoked burst firing is significantly increased in VTA DA neuron-lesionedrats compared to sham-operated rats, while no differ-ences were detected in the number of spikes per burst Reciprocal interactions between DA and 5-HT In VTA-lesioned rats, pre-treatment with the selec- The lesion of DA neurons by i.c.v. administration of tive a2-adrenoreceptor antagonist idazoxan (1 mg/kg 6-OHDA produced a profound and selective decrease i.v.) did not increase the mean number of NE neurons in brain DA levels (Table 1). In these experimental recorded per track compared with the corresponding conditions, the discharge rate of DR 5-HT neurons group of VTA DA neuron-lesioned rats receiving no was reduced by 60 % indicating that DA input exerts pre-treatment (0.7¡0.1, n=12 tracks vs. 0.6¡0.1, n=61 a tonic excitatory effect on 5-HT neurons in intact brain.
tracks, respectively). However, the mean firing fre- It may seem unusual that despite the marked attenu- quency of LC NE neurons after the idazoxan pre- ation of DR 5-HT neuronal firing in lesioned rats, the treatment was significantly increased (4.5¡0.3 Hz, number of DR 5-HT neurons recorded per track was n=9 neurons vs. 3.1¡0.3 Hz, n=24 neurons ; p= unchanged. However, previous electrophysiological data indicate that conditions that decrease the firingactivity of DR 5-HT neurons by about 50 % do not Effect of NE neuron lesion with 6-OHDA on the firing necessarily modify the number of neurons found per track (Blier et al., 1986). These findings are consistent The mean number of DA neurons recorded per track with previous in-vivo electrophysiological and neuro- was not significantly different between sham-operated chemical studies having shown that the systemic ad- (n=49 tracks) and LC NE neuron-lesioned rats (n=64 ministration of the non-selective DA receptor agonist tracks, Table 2). In the lesioned rats, the mean firing apomorphine, increases the firing rate of 5-HT neurons frequency of VTA DA neurons was increased by 70 % (Martin-Ruiz et al., 2001), thereby enhancing 5-HT compared to sham-operated rats (Figure 5c). No outflow in the rat DR (Ferre et al., 1994 ; Ferre and Figure 3. Effect of dopaminergic lesion with 6-hydroxydopamine (6-OHDA) on the electrophysiological activity of locus coeruleus (LC) NE neurons discharging in asingle-spike mode. Examples of typical recordings of LC NE Figure 4. Effect of dopaminergic lesion with neurons obtained in (a) a sham-operated rat and (b) a ventral 6-hydroxydopamine (6-OHDA) on the electrophysiological tegmental area (VTA) DA neuron-lesioned rat. The activity of locus coeruleus (LC) NE neurons exhibiting a characteristic increase in firing activity (without producing a single-spike and burst activity. Examples of typical burst) followed by a ‘ silence’ in response to pinch is recordings of LC NE neurons obtained in (a) a sham-operated indicated by an arrow. (c) Mean¡S.E.M. of frequency (Hz) of rat and (b) a ventral tegmental area (VTA) DA neuron- NE neurons recorded in the VTA of sham-operated rats lesioned rat, each asterisk indicates a burst. The characteristic (n=3) (grey histogram) and 6-OHDA-treated rats (n=7) increase in firing activity followed by a ‘silence’ in response (white histogram). * p<0.05 indicates significantly different to pinch is indicated by an arrow. (c) Mean¡S.E.M. of from sham-operated rats. The numbers within the histograms frequency (Hz) of NE neurons. Number of single spikes/ indicate the number of neurons recorded.
min(d), bursts/min (e), and single spikes/burst (f), recordedin the VTA of sham-operated rats (n=3) (grey histogram)and 6-OHDA-treated rats (n=7) (white histogram). * p<0.05,** p<0.01 and *** p<0.001 indicates significantly different Artigas, 1993 ; Martin-Ruiz et al., 2001). Likewise, it has from sham-operated rats. The numbers within the histograms been shown by intracellular recordings that both ap- indicate the number of neurons recorded.
plication of DA and the D2/D3 agonist quinpirole in DRslices produces a concentration-dependent membranedepolarization of 5-HT neurons (Haj-Dahmane, 2001).
These D2-like receptors are probably located on the antagonists 6,7-dinitroquinoxaline-2,3-dione and 2- 5-HT neurons themeselves, because the effects of quin- amino-5-phosphonopentanoic acid, did not prevent pirole were unaffected by tetrodotoxin (which blocks the DA-induced depolarization of DR 5-HT membrane neuronal conduction ; Haj-Dahmane, 2001). Further- (Haj-Dahmane, 2001) ruling out the possibility that more, the pharmacological inactivation of ionotropic the excitatory effects of DA involved a local release and metabotropic glutamate receptors by the selective of glutamate. It is well known that the DR is driven by a Interactions between monoaminergic neurons results indicate that the DA input exerts a direct excit- atory effect, probably via D2 receptors on DR 5-HT neurons while the influence of other non-dopaminergic The i.c.v. injection of 5,7-DHT produced a robust and selective decrease in brain 5-HT levels (Table 1) leading to a 36 % increase in the discharge rate of VTA DA neurons. This enhancement of DA neuronal ac- tivity resulted from a higher number of bursts and spikes per burst. The putative inhibitory effect of the 5-HT input on DA neurons suggested by the present study is consistent with the finding that SSRIs, which probably raise extracellular 5-HT levels in the VTA, induce a slight decrease in the firing rate of VTA DAneurons (Di Mascio et al., 1998 ; Prisco and Esposito, 1995). The inhibitory influence of the 5-HT input on DA neurons was further supported by the observation that low doses of the 5-HT1A receptor agonist 8-OHDPAT, known to attenuate the electrical activity of DR 5-HT neurons, increases the firing rate and the number of burst discharge of DA neurons in the VTA (Arborelius et al., 1993 ; Lejeune and Millan, 1998, 2000 ; Lejeune et al., 1997), and consequently DA release at the somatodendritic (Chen and Reith, 1995) and terminal levels (Ago et al., 2002 ; Arborelius et al., 1993 ; Rasmusson et al., 1994 ; Tanda et al., 1994). How- Figure 5. Effect of noradrenergic lesion with 6- ever, high doses of 8-OHDPAT which preferentially hydroxydopamine (6-OHDA) on the electrophysiological activate post-synpatic receptors, also produce in- activity of DA neurons in the ventral tegmental area (VTA).
creases in the discharge of DA neurons (Lejeune and Examples of typical recordings of VTA DA neurons obtained Millan, 1998). Consequently, the inhibitory effect of the in (a) a sham-operated rat and (b) a locus coeruleus (LC) 5-HT input on VTA DA neurons remains debatable.
NE neuron-lesioned rat, each asterisk indicating a burst.
Indeed, initial intracellular recordings showed that 5- (c) Mean¡S.E.M. of frequency (Hz) of DA neurons. Number HT depolarized 46 % of rat VTA DA neurons (Pessia of single spikes/min (d), bursts/min (e), and single et al., 1994) and stimulated the release of [3H]DA in spikes/burst (f), recorded in the VTA of sham-operated rats VTA slices (Beart and McDonald, 1982). In line with (n=6) (grey histogram) and 6-OHDA-treated rats (n=7) these results, microinfusion of 5-HT in the VTA in- (white histogram). ** p<0.01 and *** p<0.001 indicates creased DA release in projection areas such as the nu- significantly different from sham-operated rats. The numberswithin the histograms indicate the number of neurons cleus accumbens (Guan and McBride, 1989). It was also observed that the electrical stimulation of the DRproduces two different types of response in the VTA :some cells exhibit an inhibition-excitation response noradrenergic input ; therefore a lesion of DA neurons while other DA neurons show an excitation followed might alter 5-HT neuronal activity indirectly via its in- by an inhibition (Gervais and Rouillard, 2000). These teractions with NE neurons. The possibility that the results raised the possibility that the regulation of VTA i.c.v. injection of 6-OHDA destroyed NE terminals in DA neurons involves various post-synaptic 5-HT re- the DR should be considered since a reduction of NE ceptors. The 5-HT2A and 5-HT2C receptor subtypes levels has been detected in the hippocampus (Table 1, identified in the VTA (Cornea-Hebert et al., 1999 ; n.s.) and the frontal cortex (data not shown, p<0.05) in Nocjar et al., 2002) are of particular interest since their lesioned rats. However, Svensson et al. (1975) demon- pharmacological activation respectively stimulates and strated that the spontaneous firing rate of DR 5-HT suppresses, VTA DA neuronal activity (Di Giovanni neurons after 6-OHDA is unaltered suggesting that et al., 2000 ; Di Matteo et al., 2000 ; Gobert et al., 2000 ; a putative loss of NE would not have a sustained im- Millan et al., 2000 ; Pessia et al., 1994 ; Prisco et al., pact on 5-HT neuronal activity. In conclusion, these 1994) and DA release in the nucleus accumbens (De Deurwaerdere et al., 2004 ; Porras et al., 2002).
neuronal activity (Nilsson et al., 2005 ; Piercey et al., Overall, it would thus seem that the inhibitory influ- 1994). An involvement of 5-HT neurons in the disin- ence of 5-HT input plays a predominant role in hibitory effect of DA neuron lesion on NE neuronal the regulation of DA neuronal activity given that the firing should also be considered. Indeed, the decrease systemic administration of the non-selective 5-HT2 in DR 5-HT neuronal activity in response to the VTA receptor antagonist ritanserin dose-dependently in- lesion could lead to a significant reduction of 5-HT creases the burst firing and the firing rate of VTA DA release in the LC, thus contributing to the increase of neurons (Ugedo et al., 1989). Importantly, the lesion of NE neuronal firing through a lower tonic activation 5-HT neurons might have disrupted more than the of 5-HT2A receptors (Szabo and Blier, 2002). Such an serotonergic inputs to the VTA. Growing evidence indirect mechanism, as well as a removal of the direct suggests that feedback loops involving the 5-HT sys- inhibitory effect of DA in the LC, could explain the tem may control VTA DA neuronal activity. For ex- present findings that the VTA lesion increased the ample, it was proposed that the activation of 5-HT1A firing activity of some NE neurons. Despite the elev- and 5-HT2A receptor subtypes in the medial prefrontal ated discharge of LC NE neurons observed in VTA- cortex produces an excitation of VTA DA neurons lesioned rats, the number of NE neurons recorded (Bortolozzi et al., 2005 ; Diaz-Mataix et al., 2005, 2006).
was significantly reduced. Since, a partial loss of NE However, in contrast to the present study, a lower to- neurons was unlikely on the basis of the neuro- nic stimulation of these pathways in 5-HT-depleted chemical analysis (Table 1), the possibility that NE rats should have produced an attenuation of the VTA neurons were tonically inhibited by a local increase of DA neurons’ firing activity. It may also be claimed that NE levels was considered. In VTA-lesioned rats, the the excitatory effect of the DR 5-HT lesion on VTA DA systemic administration of the a2-adrenoreceptor an- neurons was indirectly mediated by NE neurons. In- tagonist idazoxan did not allow the recording of deed, it is well established that NE neurons send pro- more NE neurons. It thus seems possible that DA jections to the VTA and that a lesion of 5-HT neurons could also impinge on LC afferents, such as glutama- increases the firing activity of the LC NE neurons tergic neurons (Nilsson et al., 2005) that could in- (Haddjeri et al., 1997). This is, however, unlikely since directly participate in activating, at least in part, a the present study suggests that NE exerts a robust in- subpopulation of LC NE neurons. In line with this hibitory action on VTA DA neurons (Figure 5).
hypothesis, it was reported that the stimulation ofthe VTA can produce an activation of NE neuronalactivity (Deutch et al., 1986). It should also be men- Reciprocal interactions between DA and NE neurons tioned that the intra-VTA injection of 6-OHDA could The lesion of VTA DA neurons obtained with local have destroyed, at least partly, NE terminals in the injection of 6-OHDA resulted in a significant and VTA. Although, this possibility cannot be completely selective reduction of striatal DA levels (Table 1). This excluded, it is noteworthy that no reductions of the selective lesion also results in a 47 % increase in the NE levels were detected either in the hippocampus discharge rate of LC NE neurons suggesting that (Table 1) or in the frontal cortex or striatum of lesioned DA exerts an inhibitory action on these NE neurons.
rats (data not shown). Consequently, the present find- Although the majority of LC NE neurons discharge ings suggest that DA exerts a direct inhibitory action spontaneously in a single-spike mode (Dawe et al., on some LC NE neurons through D2 receptors as well 2001 ; Dremencov et al., 2007), about 30 % of NE as an indirect activation involving other neuronal neurons exhibit both single and burst patterns of spontaneous firing. In the later population of NE The lesion of LC induced by the local injection of neurons, VTA lesion also elevated the mean discharge 6-OHDA resulted in a significant and selective re- rate as the result of a significant increase in the number duction of brain NE levels (Table 1). This lesion in- of bursts and spikes per burst. The putative inhibitory creased the discharge rate of VTA DA neurons by 70 % influence of DA input upon LC NE neurons is in line owing to a significant higher number of bursts and with the observation that direct iontophoretic appli- action potentials per burst. This finding was consistent cation of DA suppresses the firing rate of NE neurons with those of earlier studies having shown that (Elam et al., 1986). Similarly, in-vivo extracellular re- the systemic administration of low doses of the a2- cordings have demonstrated an involvement of D adrenoreceptor agonist clonidine, which attenuates ceptors in this inhibitory effect, since the systemic overall NE transmission (Haddjeri and Blier, 2000 ; administration of antipsychotic drugs, including the Haddjeri et al., 1998 ; Szabo and Blier, 2001), also in- creases the firing activity of VTA DA neurons 2 receptor antagonist haloperidol, increased LC NE Interactions between monoaminergic neurons (Georges and Aston-Jones, 2003 ; Gobbi et al., 2001 ; VTA DA neurons, it seems highly unlikely that the Millan et al., 2000). Taken together, these data strongly decrease in burst firing activity in LC NE-lesioned rats suggest that NE inputs exert an inhibitory influence altered those pathways. However, it is more conceiv- on spontaneous VTA DA neuronal activity. In line able that the depletion of NE reduces the electrical with this assumption, initial electrophysiological activity of LDT GABAergic neurons projecting to the studies have demonstrated that the microiontophoretic VTA. These hypotheses will be of interest to address application of NE in the VTA reduces the firing of in future investigations. Nevertheless, so far a direct DA neurons while this effect is blocked by the non- attenuation of post-synaptic D2 receptor stimulation selective a1/2-adrenoreceptor antagonist piperoxane seems a more plausible hypothesis to explain the (White and Wang, 1984). Thus far, it has been shown increase in DA neuronal activity observed in LC- that the stimulation of a1-adrenoceptors exerts a direct excitatory influence on VTA DA neurons and an The present lesion experiments emphasize the com- indirect inhibitory effect by activating GABA inter- plex regulation of 5-HT, NE and DA neuronal firing neurons (Grenhoff et al., 1995 ; Steffensen et al., 1998).
activity. Further electrophysiological studies in com- Thus, an attenuation of GABA release in the VTA, bination with local or systemic administration of could support the observation reported herein that DA pharmacological agents will be useful in clarifying the neuronal activity is enhanced in LC-lesioned rats.
pharmacological bases for these interactions in vivo.
With regard to a2-adrenoceptors, it has been demon- Indeed, a better knowledge of such interactions could strated that the local application of clonidine in the provide important information for improving the VTA does not inhibit DA neurons (Aghajanian and treatment of depression, more specifically for pharma- Bunney, 1977) ruling out the possibility that the cotherapies aimed at enhancing simultaneously DA, inhibitory effects of NE involved post-synaptic a2- NE and 5-HT transmission without triggering counter- adrenoceptors. However, divergent results have also productive negative feedback actions. It is noteworthy been reported. For example, the systemic adminis- that the most of the traditional antidepressant drugs tration of idazoxan or selective NE reuptake inhibitors, tend to increase the endogenous monoaminergic which raise extracellular NE levels in the VTA has tone whereas the present study is based on the effect been shown to increase the burst firing activity of DA of the removal of this tone. However, those lesioning neurons in the VTA (Grenhoff and Svensson, 1989, experiments may initiate novel treatment approaches 1993 ; Linner et al., 2001 ; Shi et al., 2000). Clearly, fur- whose clinical utility remains to be demonstrated.
ther studies are needed to determine the complexmechanism by which the NE input regulates VTA DA neuronal activity. In particular, it would be relevantto address the issue of the selectivity of NE since the Supplementary material accompanies this paper on inhibitory effect of NE was found to be prevented the Journal’s website (http://journals.cambridge.org).
by the iontophoretic application of the D2 receptorantagonist sulpiride (White and Wang, 1984). Indirect mechanisms might also be involved in the effect ofLC NE neuron depletion on VTA DA neuronal This study was supported by the Canadian Institutes activity. The laterodorsal tegmentum (LTD), an ad- for Health Research grant (G6152147) and salary sup- jacent region to the LC that projects heavily to the port from the University of Ottawa Institute of VTA (Forster and Blaha, 2000 ; Oakman et al., 1995 ; Mental Health Research to B.G, M.E., Z.M. and P.B., Omelchenko and Sesack, 2005) is mainly concerned.
as well as a Research Chair in Psychopharmacology Indeed, inputs to the VTA that arrive from the LTD from the Canadian Government to P.B.
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