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Volume 16, Number 23, Issue of December 1, 1996 pp. 7566-7573
Copyright ©1996 Society for Neuroscience

Differential Actions of Serotonin, Mediated by 5-HT1B and 5-HT2C Receptors, on GABA-Mediated Synaptic Input to Rat Substantia Nigra Pars Reticulata Neurons In Vitro

Ian M. Stanford and Michael G. Lacey

Department of Pharmacology, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom

ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
FOOTNOTES
REFERENCES

ABSTRACT

The ability of serotonin to modulate GABA-mediated synaptic input to substantia nigra pars reticulata (SNr) neurons was investigated with the use of whole-cell patch-clamp recording from slices of rat midbrain. Fast evoked GABAA receptor-mediated synaptic currents (IPSCs) were attenuated reversibly ~60% by serotonin, which also caused an inward current with reversal potential of -25 mV. This inward current was blocked by the 5-HT2 receptor antagonist ritanserin, whereas the IPSC depression was blocked by the 5-HT1B receptor antagonist pindolol. The amplitude ratio of IPSC pairs (50 msec interpulse interval) was enhanced by serotonin (in ritanserin) and also by the GABAB receptor agonist baclofen (which also depressed the IPSC), consistent with a presynaptic site of action in both cases. In contrast, spontaneous tetrodotoxin-sensitive GABAA synaptic currents (sIPSCs) were increased in frequency by serotonin (an action that was sensitive to ritanserin, but not pindolol) but reduced in frequency by baclofen. SNr neurons therefore receive inhibitory synaptic input mediated by GABAA receptors from at least two distinct sources. One, probably originating from the striatum, may be depressed via presynaptic 5-HT1B and GABAB receptors. The second is likely to arise from axon collaterals of SNr neurons themselves and is facilitated by an increase in firing via postsynaptic, somatodendritic 5-HT2C receptor activation, but it is depressed by GABAB receptor activation. Thus, serotonin can both depolarize and disinhibit SNr neurons via 5-HT2C and 5-HT1B receptors, respectively, but excitation may be limited by GABA released from axon collaterals.

Key words: serotonin; substantia nigra pars reticulata; GABAA IPSPs; presynaptic receptors; baclofen; basal ganglia

INTRODUCTION

The substantia nigra (SN) comprises two principal sets of projection neurons, both of which play important roles in the circuitry of the basal ganglia and thereby may influence critically the control of voluntary movement (Alexander and Crutcher, 1990). Although the dopamine-containing neurons of the substantia nigra pars compacta (SNc) have been the focus of much attention from cellular physiologists and pharmacologists in recent years (for review, see Kalivas, 1993; Lacey, 1993), the GABA-containing cells of the substantia nigra pars reticulata (SNr) have been comparatively neglected. However the SNr, together with the internal globus pallidus, constitutes a principal relay for basal ganglia output (Alexander and Crutcher, 1990; Chevalier and Deniau, 1990; Parent and Hazrati, 1995) and plays a clear role in movement initiation (Scheel-Kruger et al., 1977; Kilpatrick et al., 1982) by virtue of its influence on the thalamocortical pathway (Parent and Hazrati, 1995). Moreover, the SNr also gates propagation of generalized seizures (Gale, 1986; Depaulis et al., 1994) mediated by projections to the superior colliculus (Garant and Gale, 1987), which often arise from axonal branches of the same cells that innervate the thalamus (Deniau et al., 1978).

The substantia nigra receives innervation arising from the serotonin (5-hydroxytryptamine; 5-HT)-containing neurons of the dorsal raphe nucleus (Fibiger and Miller, 1977; Corvaja et al., 1993), and its functional role has been explored by several investigators, again with the main focus on dopamine neurons. However, the neurons of the SNr have been implicated in the contralateral turning (Oberlander et al., 1981; Kilpatrick et al., 1982) and stereotyped chewing behavior (Liminga et al., 1993) caused by intranigral serotonin application and also the anticonvulsant action of intranigral fluoxetine (the selective serotonin reuptake inhibitor; Pasini et al., 1992). Although in vivo experimentation has suggested an inhibitory action of serotonin on SNr neurons (Dray et al., 1976; Oberlander et al., 1981; Kilpatrick et al., 1982), we have demonstrated recently that serotonin can depolarize and excite rat SNr neurons in midbrain slices by a direct action on 5-HT2C-like receptors (Rick et al., 1995). However, three serotonin receptor subtypes in the rat SN clearly have been identified by radioligand binding studies: 5-HT1B, 5-HT2C (Pazos and Palacios, 1985), and 5-HT4 (Grossman et al., 1993). We have hypothesized that additional actions of serotonin in the SNr, possibly mediated by receptors other than 5-HT2C, may contribute to its overall effect in vivo (Rick et al., 1995), and here we explore the modulation by serotonin of synaptic input to SNr neurons mediated by GABA. We show that serotonin acts on presynaptic 5-HT1B receptors to depress evoked GABA-mediated synaptic input to SNr neurons. Furthermore, activation of the postsynaptic 5-HT2C receptors promotes spontaneous synaptic activation of GABAA receptors, probably mediated by axon collaterals. These actions of serotonin are compared with those of the GABAB receptor agonist baclofen, which also acts both pre- and postsynaptically.

Some of these findings have been described previously in abstract form (Stanford and Lacey, 1995a).

MATERIALS AND METHODS

Whole-cell patch-clamp recordings were made from parasagittal slices (300 µm thick) of rat (Wistar) midbrain obtained from animals 9-12 d old. Slices were prepared as described previously (Stanford and Lacey, 1995b). Slices were maintained in a recording chamber (0.75 ml) and perfused continuously at 2-3 ml/min with artificial cerebrospinal fluid (aCSF) containing (in mM): NaCl 126, KCl 2.5, NaH2PO4 1.2, MgCl2 1.3, CaCl2 2.4, and glucose 10 buffered to pH 7.4 with Na2HCO3 (26 mM) and maintained at 33-35°C. Recordings were made with borosilicate glass pipettes (3-5 MOmega resistance) containing (in mM): K-gluconate 125, NaCl 10, CaCl2 1.0, MgCl2 2.0, BAPTA 10, HEPES 10, GTP 0.3, and Mg-ATP 2.0, adjusted to pH 7.25 with KOH (final K+ concentration 165 mM). Cs-gluconate was substituted for K-gluconate in some experiments.

Individual neurons of the substantia nigra pars reticulata were visualized with a differential interference contrast (Nomarski) optical system (Zeiss Axioscop FS microscope, Oberkochen, Germany) with a 40× water immersion objective. Recording pipettes were advanced while under positive pressure toward individual cells in the slice, and, on contact, tight seals of 10-20 GOmega were made by applying negative pressure. Then the membrane patch was ruptured by suction, and membrane current and potential were monitored with an Axopatch 1B patch-clamp amplifier (Axon Instruments, Foster City, CA). Whole-cell access resistances were in the range of 10-30 MOmega before electronic compensation by 65-80%. After initial determination in current-clamp mode, the compensated access resistance was monitored continuously in voltage clamp by measuring the size of the capacitance transient in response to a 5 mV hyperpolarizing step (Stuart et al., 1993) and checked intermittently in current clamp. Experiments were abandoned if the access resistance changed by >20%. Membrane potentials were corrected with respect to the null potential measured at the end of recording.

Synaptic events were evoked by focal bipolar stimulation of the slice 300-600 µm rostral to the recording site. Single shock stimulations (0.5 msec, 0.5-3 mA) were made at 30 sec intervals by a constant current stimulation unit (AMPI Isoflex, Israel). Voltage steps were generated by pCLAMP software (Axon Instruments); the resulting membrane currents, as well as those resulting from synaptic activation, were stored to computer disk and a DAT recorder for subsequent analysis and display on a chart recorder (Gould Easygraph, Hainault, UK). Numerical data derived from experimental manipulations on synaptic currents were quantified from the mean of five consecutive single events. All numerical data are expressed as mean ± SD unless otherwise stated.

Drugs were applied to the superfusate by exchanging the aCSF for one differing only by the addition of a known concentration of drug, with the exchange beginning after a dead time of 20-30 sec. Drugs used were 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), (-)D-2-amino-5-phosphonopentanoic acid (D-AP5), bicuculline methiodide, and picrotoxin (all from Tocris Cookson, Bristol, UK); and baclofen, tetrodotoxin (TTX), and 5-hydroxytryptamine maleate (serotonin, 5-HT; all from Sigma, St. Louis, MO). Ritanserin (10 mM stock in methanol) and pindolol (10 mM stock in 3 mM HCl) were obtained from Research Biochemicals International (Natick, MA).

RESULTS

Substantia nigra pars reticulata neurons

The cells included in this study (40 in total) exhibited spontaneous action potential firing at rates of 11.7 ± 4.6 Hz (range 5-26 Hz; n = 18) at rest in current-clamp recording mode. This property distinguishes these SNr neurons from the dopamine-containing neurons of the substantia nigra pars compacta (SNc), which generally have slower firing rates (<6 Hz; Fig. 1A) (for review, see Lacey, 1993; Stanford and Lacey, 1995b). In voltage clamp, the resting potential (at which holding current was zero) was -51.8 ± 3.4 mV (range from -45 to -58 mV; n = 23). Hyperpolarizing voltage steps of 200 msec duration from -60 mV to -140 mV did not reveal any notable membrane rectification, time-dependent or otherwise, which is a distinct and well established property of the dopamine-containing neurons of the substantia nigra (Fig. 1B). Membrane conductance over this voltage range was 2.65 ± 1.56 nS (n = 35). These properties correspond to those of previous descriptions of SNr neurons derived from intracellular recording (Nakanishi et al., 1987; Hajós and Greenfield, 1994; Stanford and Lacey, 1996); although several cells with the characteristics of dopamine neurons were encountered within the SNr during the course of these experiments, they specifically were excluded from the present study.
Fig. 1. Substantia nigra pars reticulata neurons may be discriminated from dopaminergic neurons by their basic electrophysiological properties. A, Records of membrane potential from an SNr neuron (top) and a putative dopamine neuron (bottom), recorded at resting potential. Both cells fire action potentials spontaneously (full amplitude not reproduced) at regular rates but at markedly different frequencies (SNr neuron, 25 Hz; dopamine neuron, 1.75 Hz). B, Voltage steps (200 msec) to potentials in the range -40 to -140 mV performed under voltage clamp (holding potential -60 mV) demonstrate pronounced time-dependent inward rectification on hyperpolarization (Ih) in the dopaminergic neuron (bottom records), which is virtually absent in the SNr neuron (top records). The top pair of records shows the series of voltage steps applied to the same SNr neuron as in A and the resultant membrane currents, whereas the bottom pair shows the voltage steps and currents produced in the dopamine neuron in A.
[View Larger Version of this Image (40K GIF file)]

Serotonin caused an inward current

Application of serotonin (3-10 µM) caused an inward current in 25 of the 27 cells tested at holding potentials of -50 to -80 mV, which was reversible on washout, as described previously (Rick et al., 1995). At -80 mV this current was 55.6 ± 23.3 pA, and it was 45.8 ± 16.7 pA at -50 mV (both with serotonin 10 µM). Current/voltage (I/V) plots were generated by depolarizing voltage ramps (20 mV/sec) from a holding potential of -100 mV to 0 mV in five cells, two of which were recorded with pipettes containing Cs+ instead of K+, and in the presence of TTX (1 µM). Comparison of I/V plots obtained before and during the application of serotonin showed the serotonin inward current to reverse polarity at -27 ± 6.1 mV (n = 3; K+ in pipettes) or at -33 and -21 mV, respectively (n = 2; Cs+ in pipettes, with TTX in perfusate), with mean reversal potential of -24.6 ± 5.2 mV for all five experiments, accompanied by a linear conductance increase over the whole voltage range examined (Fig. 2). The similar reversal potential obtained by using intracellular dialysis with Cs+, which would be expected to block potassium channels, suggests that the ionic basis of the serotonin inward current did not involve a change in potassium conductance. The serotonin inward current, which is considered to be mediated by 5-HT2C receptors on SNr neurons (Rick et al., 1995), was blocked by ritanserin (1 or 3 µM), the antagonist of 5-HT2-type receptors (Baxter et al., 1995), in all nine cells tested (see Fig. 3A).
Fig. 2. The serotonin inward current is voltage-independent and accompanied by a conductance increase, with a reversal potential at approximately -25 mV. A, Steady-state current/voltage plots obtained with a ramp depolarization (20 mV/sec) under voltage clamp from -100 to 0 mV before (control) and during application of serotonin (10 µM). Serotonin caused an inward current at potentials negative to -28 mV, reversing to an outward current between -28 and 0 mV. B, The serotonin current derived from A by digital subtraction is plotted against membrane potential. The current reverses polarity at -28 mV, and the conductance is essentially linear over the voltage range examined.
[View Larger Version of this Image (23K GIF file)]

Fig. 3. Serotonin depresses the evoked IPSC. Although the serotonin inward current is blocked by the 5-HT2 antagonist ritanserin, the depression of the IPSC by serotonin is blocked by the 5-HT1B antagonist pindolol. A, Serotonin (3 µM; filled bars) causes an inward current and also reversibly depresses the IPSC amplitude (transient outward currents evoked every 30 sec). In the presence of ritanserin (3 µM; open bar) serotonin still depresses the IPSC, but the inward current is blocked. Shown is a continuous record of membrane current, except for a 13 min break where indicated, from cell clamped at -50 mV. CNQX (10 µM) and D-AP5 (50 µM) are present throughout. B, Left, Plot of time course of experiment from another cell: serotonin (3 µM) reversibly depresses the evoked IPSC (ii) but was ineffective in the presence of pindolol (3 µM; iv). Right, Single records from this experiment, at times indicated on the plot, showing the IPSC preceded by current resulting from -5 mV test step. The cell was voltage-clamped at -50 mV in the continued presence of ritanserin (3 µM) as well as CNQX (10 µM) and D-AP5 (50 µM).
[View Larger Version of this Image (24K GIF file)]

Depression of evoked GABAA IPSCs by serotonin

Focal stimulation 300-600 µm rostral to the recorded cell evoked fast synaptic currents that, in the presence of glutamate receptor antagonists CNQX (10 µM) and D-AP5 (50 µM), were blocked by TTX (1 µM; n = 2) and also the GABAA receptor antagonists picrotoxin (50 µM; n = 3) and bicuculline (10 µM; n = 4). These IPSCs were outward at -50 mV, becoming inward at potentials negative to -65 mV, close to the predicted Cl- equilibrium potential, all of which are consistent with mediation by GABAA receptors.

Serotonin reduced reversibly the amplitude of these evoked IPSCs by 54.2 ± 23.8% (3 µM serotonin; n = 11) and 60.0 ± 22.5% (10 µM serotonin; n = 11; Fig. 3). Unlike the serotonin inward current, this effect was resistant to ritanserin (3 µM; n = 7; Fig. 3) but was blocked by pindolol (3 µM), the antagonist of 5-HT1B receptors (Hoyer, 1989), in six of eight cells tested (Fig. 3B). In contrast, pindolol (3 µM) was without effect on the serotonin inward current in both cells tested.

Baclofen caused an outward current and a depression of GABAA IPSCs

The GABAB receptor agonist baclofen has been shown previously to inhibit extracellularly recorded single-unit SNr cell firing in vitro (Rick and Lacey, 1994). In the present study 30 µM baclofen caused a small outward current (33 ± 7.5 p at -50 mV; n = 3), whereas 3 µM baclofen was without effect. However, at the lower concentration of 3 µM, baclofen reduced reversibly the amplitude of the evoked GABAA IPSC by 77.7 ± 9.9% (n = 6; Fig. 4).
Fig. 4. Both serotonin and baclofen enhance the paired-pulse IPSC ratio. A, Superimposed records from two different cells showing the effects of serotonin (3 µM; left) and baclofen (3 µM; right), relative to control in each case, on successive IPSCs evoked with the same stimulus at an interpulse interval of 50 msec. In control conditions, paired-pulse facilitation was observed in which the second IPSC was larger than the first. Both serotonin and baclofen reduced IPSC amplitude, but the second IPSC of the pair was reduced to a lesser extent than the first. Shown are IPSCs preceded by current resulting from +5 mV test step. Holding potential is -50 mV. Ritanserin (3 µM), CNQX (10 µM), and D-AP5 (50 µM) were present throughout. B, Same data as in A, but records in the presence of serotonin and baclofen are rescaled digitally so that the first IPSC of the pair is of similar amplitude to control. The second IPSC is clearly larger relative to control in the presence of both serotonin and baclofen, indicating that the depression of the IPSC (in A) by serotonin and baclofen occurs at a presynaptic locus.
[View Larger Version of this Image (19K GIF file)]

Depression of the GABAA IPSC by serotonin and baclofen was attributable to presynaptic actions

To determine the site of action of serotonin and of baclofen in depressing the amplitude of the evoked IPSC, we adopted a paired-pulse protocol. GABAA IPSCs were evoked by single shocks of equal strength and duration paired at 50 msec intervals, with the stimulus strength adjusted in each experiment so that the second IPSC was always greater in amplitude (by 46 ± 38%; n = 8) than the first. Both serotonin (3 µM; in the presence of 3 µM ritanserin) and baclofen (3 µM) reduced the absolute amplitude of the IPSPs, but they also increased the degree of this paired-pulse facilitation (Fig. 4). Thus, the ratio of the amplitudes of the second IPSC to the first was increased significantly by serotonin (by 29.2 ± 14.7%; p < 0.05 with paired t test; n = 4) and by baclofen (60.5 ± 17.5%; p < 0.01; n = 4). Such a change in the paired-pulse ratio of synaptic current amplitudes is attributable to an action of both serotonin and baclofen on presynaptic 5-HT1B and GABAB receptors, respectively, on the GABA-releasing nerve terminals (Davies et al., 1990; Travagli and Williams, 1996), causing reduction of GABA release. A postsynaptic site of action would be expected to reduce both the paired IPSCs to a similar extent, leaving the paired-pulse ratio unchanged.

Spontaneous GABAA IPSPs were facilitated by serotonin but depressed by baclofen

In the presence of glutamate receptor antagonists CNQX (10 µM) and D-AP5 (50 µM), 30% of cells (12/40) exhibited discernible spontaneous fast outward currents (sIPSCs; recorded at -50 mV). These were blocked by TTX (1 µM; n = 2; Fig. 6A), suggesting their dependence on spontaneous activity of neurons within the preparation, and also by picrotoxin (50 µM; 1 cell; Fig. 5B) and were therefore considered to be GABAA receptor-mediated synaptic currents. Serotonin (3-10 µM) caused a clear and reversible increase in the frequency of these sIPSCs in all five cells tested (Fig. 5C), an action that additionally was observed in the presence of pindolol (3 µM; n = 2), but not ritanserin (3 µM; n = 2). In contrast, baclofen (3 µM) reduced the frequency of spontaneous IPSCs in both cells tested (Fig. 5D).
Fig. 5. Spontaneous IPSCs mediated by GABA are reduced in frequency by baclofen but enhanced by serotonin. A, Spontaneous transient outward currents were abolished by TTX (1 µM) and also (B) by picrotoxin (50 µM). C, Spontaneous IPSCs were increased in frequency by serotonin (10 µM), which was reversible on washout. D, Spontaneous IPSCs were abolished reversibly by baclofen (3 µM). Records are from four different cells voltage-clamped at -50 mV, with CNQX (10 µM) and D-AP5 (50 µM) present throughout in all cases.
[View Larger Version of this Image (38K GIF file)]

DISCUSSION

Depression of the evoked IPSC by serotonin: a presynaptic action mediated by 5-HT1B receptors

The depression of the evoked IPSC by serotonin was resistant to ritanserin but blocked by pindolol (3 µM; Fig. 3). Pindolol is a selective 5-HT1B receptor antagonist (Hoyer, 1989) and, unlike ritanserin, does not block the serotonin inward current (present study) or the excitation of SNr neurons by serotonin (Rick et al., 1995), suggesting that this pindolol-sensitive site of the IPSC depression by serotonin is presynaptic. Although 5-HT1B binding in rat SN has been demonstrated (Bruinvels et al., 1993b), the location of 5-HT1B receptors on exclusively presynaptic sites is suggested by (1) the loss of radioligand binding to 5-HT1D receptor binding in guinea pig SN (homologous to 5-HT1B receptors in rat) after lesion of the striatonigral pathway (Waeber et al., 1990) and (2) the lack of messenger RNA encoding the 5-HT1B receptor in SN (but considerable amounts in striatum; Bruinvels et al., 1993a). The enhancement of the paired-pulse ratio accompanying the IPSC inhibition seen with serotonin (Fig. 4) also points to a presynaptic location for the 5-HT1B receptors. This resembles the report of presynaptic inhibition (via 5-HT1D receptors) by serotonin of evoked glutamate release onto guinea pig substantia gelatinosa neurons (Travagli and Williams, 1996). Presynaptic 5-HT1B/1D heteroreceptors acting to reduce transmitter release also have been reported in locus coeruleus (Bobker and Williams, 1989a).

5-HT1B/1D receptor activation also depresses the slow GABAB receptor-mediated IPSP in dopamine neurons of the ventral tegmental area (VTA; Johnson et al., 1992; Cameron and Williams, 1994). However, the fast GABAA IPSP was unaffected by serotonin (Johnson et al., 1992), leading these authors to conclude that this serotonin-sensitive synaptic input to dopamine neurons in the VTA, which was most likely of striatal origin (Waeber et al., 1990), was mediated solely by GABAB receptors. If, by the same argument, the 5-HT1B receptor-sensitive component of GABA-mediated synaptic input to SNr also is derived from the striatum, then it seems that, in contrast to the dopamine neurons in VTA, striatal input to SNr uses postsynaptic GABAA receptors. Indeed, using the same stimulus protocol as reported by Johnson et al. (1992), we have been unable to elicit a GABAB IPSC in SNr neurones, although a GABAB IPSC was readily demonstrable in SNc dopamine neurons (I. M. Stanford and M. G. Lacey, unpublished observations). Thus the serotonin-sensitive striatonigral input may use exclusively GABAA receptors on SNr neurons and GABAB receptors on dopamine neurons.

Pre- and postsynaptic actions of baclofen

The GABAB receptor agonist baclofen also considerably depressed the amplitude of the IPSC, accompanied by an increase in the paired-pulse ratio (Fig. 5), again strongly supporting a presynaptic site of action. Although inhibition of GABA release in SN by terminal "autoreceptors" of the GABAB type has been demonstrated [Giralt et al. (1990) but also see Waldmeier et al. (1989)]; it cannot be assumed necessarily that this was from exclusively striatonigral terminals. Pallidonigral fibers (Smith and Bolam, 1991), as well as intrinsic afferents (see below), also may have made a contribution to the IPSC. The postsynaptic action of baclofen was weak and, at a concentration of 3 µM (sufficient to depress the IPSC by 78%), it was without effect on membrane current. Although able to reduce cell firing rate (Rick and Lacey, 1994), this low postsynaptic sensitivity to baclofen contrasts with the robust responses to GABAB receptor activation in dopamine neurons (Lacey, 1993).

The serotonin inward current

The ritanserin-sensitive serotonin inward current, which we have demonstrated previously to be mediated by postsynaptic 5-HT2C receptors (Rick and Lacey, 1994), was insensitive to pindolol. The firing rate increase induced by serotonin was also insensitive to pindolol and the 5-HT4 antagonist GR113808, ruling out 5-HT1B and 5-HT4 receptors in this effect (Rick and Lacey, 1994). The serotonin inward current was accompanied by a voltage-independent conductance increase over the voltage range examined (-100 to 0 mV). Although excitations mediated by 5-HT2 receptors in the nucleus accumbens (North and Uchimura, 1989), facial motoneurons (Larkman and Kelly, 1992), and cingulate cortex (Tanaka and North, 1993) have been shown to be attributable primarily to a decrease in resting potassium conductance, the increased conductance and apparent insensitivity of the reversal potential (-25 ± 5 mV) of the serotonin inward current to intracellular Cs+ suggests this is not the case here. Moreover, the voltage independence of the serotonin current and the lack of a pronounced Ih in SNr neurons (Fig. 1B) renders it unlikely that augmentation of this current by serotonin plays a major role, as described elsewhere (McCormick and Pape, 1990; Takahashi and Berger, 1990; Bobker and Williams, 1989b). A more likely mechanism underlying this current is an increased nonselective cation conductance. 5-HT2C receptors couple to phosphatidylinositol turnover (Conn et al., 1986) and intracellular calcium elevation (Watson et al., 1995) in choroid plexus epithelial cells; such a transduction mechanism well may be involved in the direct serotonin excitation of SNr neurons.

Spontaneous IPSCs represent recurrent axon collateral input

Spontaneous GABA-mediated IPSCs were detected in 12 of 40 cells. Because they were blocked by TTX in both cells tested, they probably depended on action potential firing and thereby on intact, spontaneously active GABA-containing cells within the preparation. Indeed, a tonic activation of GABAA receptors on SNr neurons in rat brain slices has been demonstrated previously (Rick and Lacey, 1994), and spontaneous action potential firing is abolished by TTX in serotonin-sensitive SNr neurons (Rick et al., 1995). The most likely source of the sIPSCs is the axon collateral network of the SNr projection neurons themselves, for which there is both anatomical (Karabelas and Purpura, 1980; Deniau et al., 1982) and physiological evidence (Deniau et al., 1982). However, although evidence for there being GABA-containing interneurons in SNr is scant (Wilson et al., 1977; Francois et al., 1979), they cannot be ruled out of consideration completely as a source of this input. The increased rate of sIPSCs seen with serotonin (Fig. 5C), which was blocked by ritanserin, but not pindolol, is consistent with the somatodendritic excitation of these neurons by serotonin, resulting in increased GABA release from their collaterals. A parallel may be drawn between these observations and those on the actions of norepinephrine in the hippocampus, in which alpha 1-adrenoceptor activation both depolarized interneurons directly and increased the frequency and amplitude of spontaneous IPSCs recorded in pyramidal cells, an effect that was not seen in TTX (Bergles et al., 1996). Additionally, 5-HT2 and alpha 1 receptor activation both depolarize interneurons, causing spontaneous glycine and GABA-mediated synaptic potentials, respectively, in other neurons of the trigeminal nucleus (Grudt et al., 1995).

However, the relative sensitivity of the sIPSCs to depression by baclofen, as compared with the somatic membrane current itself, implicates GABAB receptors on the terminals of axon collaterals themselves in this effect (Fig. 5D). Again, this may parallel the situation in the hippocampus, in which depression by baclofen of sIPSCs in hippocampal neurons arising from interneurons has been attributed to a reduction of calcium influx into presynaptic terminals (Doze et al., 1995).

Implications for the regulation of SNr output by serotonin

Studies of the actions of serotonin on SNr neurons in vivo indicate that 5-HT has a net inhibitory action (see the introductory remarks). Moreover, to comply with the original hypothesis of Gale (1985) that "inhibition of nigral efferents reduces susceptibility to generalized seizures," an inhibitory action of serotonin would be required to account for the anticonvulsant effect of intranigral fluoxetine (Pasini et al., 1992). Our results show that serotonin not only will excite SNr neurons directly (Rick et al., 1995; present study) but also will disinhibit them by reducing GABA release from (probably) striatonigral terminals. However, the ability of serotonin to promote increased lateral inhibition via GABA release from axon collaterals (Chevalier and Deniau, 1990) would serve to offset these excitatory influences. For this to translate into a net inhibitory action on SNr output and to disinhibit both the superior colliculus and the thalamocortical pathway, the extent and influence of the collateral network in the SNr would have to be considerably greater in vivo than in our brain slice preparation. It should be noted that, although no clear evidence was obtained for modulation of evoked GABA release by any serotonin receptor other than 5-HT1B, it remains possible that, under different conditions, a significant role of 5-HT4 receptors, considered to be located on striatonigral neuron terminals (Patel et al., 1995), could emerge.

Ritanserin has been shown to increase excitability of SNc and VTA dopamine neurons in vivo (Ugedo et al., 1989). However, it has been demonstrated that, in addition to innervating other SNr neurons, axon collaterals of SNr neurons also innervate dopamine neurons in SNc (Tepper et al., 1995). Thus, rather than representing a direct action, this excitation may be a consequence of ritanserin reducing serotonin-stimulated GABA release from SNr collaterals and thereby disinhibiting dopamine neurons. Indeed, the rather inconsistent results of functional pharmacological studies of serotonin actions on dopamine neurons both in vivo (Kelland et al., 1990) and in vitro (Pessia et al., 1994) may, at least in part, reflect an indirect contribution arising from serotonin actions on SNr neurons.

FOOTNOTES

Received Aug. 1, 1996; revised Sept. 11, 1996; accepted Sept. 30, 1996.

  

We are grateful to the Wellcome Trust for their support (Grant 033978/Z/91/Z).

Correspondence should be addressed to Dr. Michael G. Lacey at the above address.


REFERENCES

  • Alexander GE, Crutcher MD (1990) Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci 13:266-271 . [Web of Science][Medline]
  • Baxter G, Kennett G, Blaney F, Blackburn T (1995) 5-HT2 receptor subtypes: a family re-united. Trends Pharmacol Sci 16:105-110 . [Medline]
  • Bergles DE, Doze VA, Madison DV, Smith SJ (1996) Excitatory actions of norepinephrine on multiple classes of hippocampal CA1 interneurons. J Neurosci 16:572-585 . [Abstract/Free Full Text]
  • Bobker DH, Williams JT (1989a) Serotonin agonists inhibit synaptic potentials in the rat locus ceruleus in vitro via 5-hydroxytryptamine1A and 5-hydroxytryptamine1B receptors. J Pharmacol Exp Ther 250:37-43 . [Abstract/Free Full Text]
  • Bobker DH, Williams JT (1989b) Serotonin augments the cationic current Ih in central neurons. Neuron 2:1535-1540 . [Web of Science][Medline]
  • Bruinvels AT, Landwehrmeyer B, Gustafson EL, Durkin MM, Mengod G, Branchek TA, Hoyer D, Palacios JM (1993a) Localisation of 5HT1B, 5HT1Dalpha , 5HT1E, and 5HT1F receptor messenger RNA in rodent and primate brain. Neuropharmacology 33:367-386. [Web of Science]
  • Bruinvels AT, Palacios JM, Hoyer D (1993b) Autoradiographic characterisation and localisation of 5-HT1D compared to 5-HT1B binding sites in rat brain. Naunyn Schmiedebergs Arch Pharmacol 347:569-582 . [Web of Science][Medline]
  • Cameron DL, Williams JT (1994) Cocaine inhibits GABA release in the VTA through endogenous 5-HT. J Neurosci 14:6763-6767 . [Abstract]
  • Chevalier G, Deniau JM (1990) Disinhibition as a basic process in the expression of striatal functions. Trends Neurosci 13:277-281 . [Web of Science][Medline]
  • Conn CJ, Sanders-Bush E, Hoffman BJ, Hartig PR (1986) A unique serotonin receptor in choroid plexus is linked to phosphatidylinositol turnover. Proc Natl Acad Sci USA 83:4086-4088. [Abstract/Free Full Text]
  • Corvaja N, Doucet G, Bolam JP (1993) Ultrastructure and synaptic targets of the raphe-nigral projection in the rat. Neuroscience 55:417-427 . [Web of Science][Medline]
  • Davies CH, Davies SN, Collingridge GL (1990) Paired-pulse depression of monosynaptic GABA-mediated inhibitory postsynaptic responses in rat hippocampus. J Physiol (Lond) 424:513-532 . [Abstract/Free Full Text]
  • Deniau JM, Hammond C, Riszk A, Feger J (1978) Electrophysiological properties of identified output neurons of the rat substantia nigra (pars compacta and pars reticulata): evidence for the existence of branched neurones. Exp Brain Res 32:409-422 . [Web of Science][Medline]
  • Deniau JM, Kitai ST, Donoghue JP, Grofova I (1982) Neuronal interactions in the substantia nigra pars reticulata through axon collaterals of the projection neurons. Exp Brain Res 47:105-113 . [Web of Science][Medline]
  • Depaulis A, Vergnes M, Marescaux C (1994) Endogenous control of epilepsy: the nigral inhibitory system. Prog Neurobiol 42:33-52 . [Web of Science][Medline]
  • Doze VA, Cohen GA, Madison DV (1995) Calcium channel involvement in GABAB receptor-mediated inhibition of GABA release in area CA1 of the rat hippocampus. J Neurophysiol 74:43-53 . [Abstract/Free Full Text]
  • Dray A, Gonye TJ, Oakley NR, Tanner T (1976) Evidence for the existence of a raphe projection to the substantia nigra in rat. Brain Res 113:45-57 . [Web of Science][Medline]
  • Fibiger HC, Miller JJ (1977) An anatomical and electrophysiological investigation of the serotonergic projection from the dorsal raphe to the substantia nigra in the rat. Neuroscience 2:975-987. [Web of Science]
  • Francois C, Percheron G, Yelnik J, Heyner S (1979) Demonstration of the existence of small local circuit neurons in the Golgi-stained primate substantia nigra. Brain Res 172:160-164 . [Web of Science][Medline]
  • Gale K (1985) Mechanisms of seizure control mediated by gamma-aminobutyric acid: role of the substantia nigra. Fed Proc 44:2414-2424 . [Web of Science][Medline]
  • Gale K (1986) Role of the substantia nigra in GABA-mediated anticonvulsant actions. Adv Neurol 44:343-364 . [Medline]
  • Garant DS, Gale K (1987) Substantia nigra-mediated anticonvulsant actions: role of nigral output pathways. Exp Neurol 97:143-159 . [Web of Science][Medline]
  • Giralt MT, Bonanno G, Raiteri M (1990) GABA terminal autoreceptors in the pars compacta and in the pars reticulata of the rat substantia nigra are GABAB. Eur J Pharmacol 175:137-144 . [Web of Science][Medline]
  • Grossman CJ, Kilpatrick GJ, Bunce KT (1993) Development of a radioligand binding assay for 5-HT4 receptors in guinea-pig and rat brain. Br J Pharmacol 109:618-624 . [Web of Science][Medline]
  • Grudt TJ, Williams JT, Travagli RA (1995) Inhibition by 5-hydroxytryptamine and noradrenaline in substantia gelatinosa of guinea-pig spinal trigeminal nucleus. J Physiol (Lond) 485:113-120 . [Abstract/Free Full Text]
  • Hajós M, Greenfield SA (1994) Synaptic connections between pars compacta and pars reticulata neurones: electrophysiological evidence for functional modules within the substantia nigra. Brain Res 660:216-224 . [Web of Science][Medline]
  • Hoyer D (1989) 5-Hydroxytryptamine receptors and effector coupling mechanisms in peripheral tissues. In: The peripheral actions of 5-hydroxytryptamine (Fozard, JR, eds) , p. 72. New York: Oxford UP.
  • Johnson SW, Mercuri NB, North RA (1992) 5-Hydroxytryptamine1B receptors block the GABAB synaptic potential in rat dopamine neurons. J Neurosci 12:2000-2006 . [Abstract]
  • Kalivas PW (1993) Neurotransmitter regulation of dopamine neurons in the ventral tegmental area. Brain Res Rev 18:75-113 . [Medline]
  • Karabelas AB, Purpura DP (1980) Evidence for autapses in the substantia nigra. Brain Res 200:467-473 . [Web of Science][Medline]
  • Kelland MD, Freeman AS, Chiodo LA (1990) Serotonergic afferent regulation of the basic physiology and pharmacological responsiveness of nigrostriatal dopamine neurons. J Pharmacol Exp Ther 253:803-811 . [Abstract/Free Full Text]
  • Kilpatrick IC, Collingridge GL, Starr MS (1982) Evidence for the participation of nigrotectal gamma-aminobutyrate-containing neurones in striatal and nigral-derived circling in the rat. Neuroscience 7:207-222 . [Web of Science][Medline]
  • Lacey MG (1993) Neurotransmitter receptors and ionic conductances regulating the activity of neurones in substantia nigra pars compacta and ventral tegmental area. Prog Brain Res 99:251-276 . [Web of Science][Medline]
  • Larkman PM, Kelly JS (1992) Ionic mechanisms mediating 5-hydroxytryptamine- and noradrenaline-evoked depolarization of adult rat facial motoneurones. J Physiol (Lond) 456:473-490 . [Abstract/Free Full Text]
  • Liminga U, Johnson AE, Andren PE, Gunne LM (1993) Modulation of oral movements by intranigral 5-hydroxytryptamine receptor agonists in the rat. Pharmacol Biochem Behav 46:427-433 . [Web of Science][Medline]
  • McCormick DA, Pape HC (1990) Noradrenergic and serotonergic modulation of a hyperpolarization-activated cation current in thalamic relay neurones. J Physiol (Lond) 431:319-342 . [Abstract/Free Full Text]
  • Nakanishi H, Kita H, Kitai ST (1987) Intracellular study of rat substantia nigra pars reticulata neurons in an in vitro slice preparation: electrical membrane properties and response characteristics to subthalamic stimulation. Brain Res 437:45-55 . [Web of Science][Medline]
  • North RA, Uchimura N (1989) 5-Hydroxytryptamine acts at 5-HT2 receptors to decrease potassium conductance in rat nucleus accumbens neurones. J Physiol (Lond) 417:1-12 . [Abstract/Free Full Text]
  • Oberlander C, Hunt PF, Dumont C, Boissier JR (1981) Dopamine independent rotational response to unilateral injection of serotonin. Life Sci 28:2595-2601 . [Web of Science][Medline]
  • Parent A, Hazrati L-N (1995) Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop. Brain Res Rev 20:91-127 . [Medline]
  • Pasini A, Tortorella A, Gale K (1992) Anticonvulsant effect of intranigral fluoxetine. Brain Res 593:287-290 . [Web of Science][Medline]
  • Patel S, Roberts J, Moorman J, Reavill C (1995) Localization of serotonin-4 receptors in the striatonigral pathway in rat brain. Neuroscience 69:1159-1167 . [Web of Science][Medline]
  • Pazos A, Palacios JM (1985) Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors. Brain Res 346:205-230 . [Web of Science][Medline]
  • Pessia M, Jiang Z-G, North RA, Johnson SW (1994) Actions of 5-hydroxytryptamine on ventral tegmental area neurons of the rat in vitro. Brain Res 654:324-330 . [Web of Science][Medline]
  • Rick CE, Lacey MG (1994) Rat substantia nigra pars reticulata neurones are tonically inhibited via GABAA, but not GABAB, receptors in vitro. Brain Res 659:133-137 . [Web of Science][Medline]
  • Rick CE, Stanford IM, Lacey MG (1995) Excitation of rat substantia nigra pars reticulata neurones by 5-hydroxytryptamine in vitro: evidence for a direct action mediated by 5HT2C receptors. Neuroscience 69:903-913 . [Web of Science][Medline]
  • Scheel-Kruger J, Arnt J, Magelund S (1977) Behavioural stimulation induced by muscimol and other GABA agonists injected into the substantia nigra. Neurosci Lett 4:351-356. [Medline]
  • Smith Y, Bolam JP (1991) Convergence of synaptic inputs from the striatum and the globus pallidus onto identified nigrocollicular cells in the rat: a double anterograde labelling study. Neuroscience 44:45-73 . [Web of Science][Medline]
  • Stanford IM, Lacey MG (1995a) Actions of serotonin on substantia nigra pars reticulata neurons in vitro. Soc Neurosci Abstr 21:A1660.
  • Stanford IM, Lacey MG (1995b) Regulation of a potassium conductance in rat midbrain dopamine neurons by intracellular adenosine triphosphate (ATP) and the sulfonylureas tolbutamide and glibenclamide. J Neurosci 15:4651-4657 . [Abstract]
  • Stanford IM, Lacey MG (1996) Electrophysiological investigation of adenosine trisphosphate-sensitive potassium channels in the rat substantia nigra pars reticulata. Neuroscience 74:499-509 . [Web of Science][Medline]
  • Stuart GJ, Dodt HU, Sakmann B (1993) Patch-clamp recordings from the soma and dendrites of neurons in brain slices using infrared video microscopy. Pflügers Arch 423:511-518 . [Web of Science][Medline]
  • Takahashi T, Berger AJ (1990) Direct excitation of rat spinal motoneurones by serotonin. J Physiol (Lond) 423:63-76 . [Abstract/Free Full Text]
  • Tanaka E, North RA (1993) Actions of 5-hydroxytryptamine on neurons of the rat cingulate cortex. J Neurophysiol 69:1749-1757 . [Abstract/Free Full Text]
  • Tepper JM, Martin LP, Anderson DR (1995) GABAA receptor-mediated inhibition of rat substantia nigra dopaminergic neurons by pars reticulata projection neurons. J Neurosci 15:3092-3103 . [Abstract]
  • Travagli RA, Williams JT (1996) Endogenous monoamines inhibit glutamate transmission in the spinal trigeminal nucleus of the guinea-pig. J Physiol (Lond) 491:177-185. [Abstract/Free Full Text]
  • Ugedo L, Grenhoff J, Svensson TH (1989) Ritanserin, a 5-HT2 receptor antagonist, activates midbrain dopamine neurons by blocking serotonergic inhibition. Psychopharmacology (Berl) 98:45-50 . [Medline]
  • Waeber C, Zhang LA, Palacios JM (1990) 5-HT1D receptors in the guinea pig brain: pre- and postsynaptic localizations in the striatonigral pathway. Brain Res 528:197-206 . [Web of Science][Medline]
  • Waldmeier PC, Wicki P, Feldtrauer JJ, Baumann PA (1989) Release of endogenous GABA from the substantia nigra is not controlled by GABA autoreceptors. Naunyn Schmiedebergs Arch Pharmacol 340:372-378 . [Web of Science][Medline]
  • Watson JA, Elliott AC, Brown PD (1995) Serotonin elevates intracellular Ca2+ in rat choroid plexus epithelial cells by acting on 5-HT2C receptors. Cell Calcium 17:120-128 . [Web of Science][Medline]
  • Wilson CJ, Young SJ, Groves PM (1977) Statistical properties of neuronal spike trains in the substantia nigra: cell types and their interactions. Brain Res 136:243-260 . [Web of Science][Medline]
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