Research ArticleNEUROPHARMACOLOGY

Alterations in Responses of Ventral Pallidal Neurons to Excitatory Amino Acids after Long-Term Dopamine Depletion

Michael S. Turner, Laurence Mignon and T. Celeste Napier
Journal of Pharmacology and Experimental Therapeutics April 2002, 301 (1) 371-381; DOI: https://doi.org/10.1124/jpet.301.1.371

Abstract

The present study explored the possibility that excitatory amino acid (EAA) sensitivity within the ventral pallidum (VP) is altered by long-term removal of dopamine (DA). Electrophysiological experiments were conducted in chloral hydrate-anesthetized rats 21 to 28 days after they received unilateral substantia nigra injections of the dopaminergic toxin 6-hydroxydopamine (6-OHDA). VP neurons increased firing at low microiontophoretic ejection currents of the EAA agonistsN-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA); however, high currents decreased action potential amplitude and rapidly caused cessation of neuronal firing. These responses likely reflected the induction of depolarization block for they were reversed by coiontophoresis of the hyperpolarizing transmitter γ-aminobutyric acid (GABA) at ejection current levels that normally suppressed firing. The ability of NMDA and AMPA to induce such inactivation was greater in the VP of 6-OHDA-lesioned hemispheres, but unchanged in reserpinized rats, verifying that the alterations in responding to NMDA were the result of chronic, rather than acute, DA removal. The adaptations do not appear to be the consequence of a diminished GABAergic tone for the ability of bicuculline to increase firing (due to blocking a tonic GABAergic input) was not changed. However, low ejection currents of GABA that were insufficient to alter firing rate greatly attenuated the ability of NMDA to induce an apparent depolarization inactivation when coiontophoresed with NMDA onto VP neurons of the lesioned, but not the unlesioned, hemisphere. These studies show that chronic DA removal altered the EAA-induced amplitude-decreasing (i.e., the apparent depolarization inactivation) effects in VP neurons in the absence of a decrease in GABAergic tone.

EAAs provide the major excitatory drive within the basal ganglia and limbic systems of the brain. Popular circuitry models for basal ganglia adaptations that accompany chronic near-total lesions of the ascending dopaminergic system incorporate the wealth of evidence for an up-regulation of EAA transmission (for review, see Ossowska, 1994). Moreover, suppression of EAA transmission by EAA antagonists attenuates motor dysfunction and augments the beneficial effects of levodopa in animal models of PD (Ossowska, 1994). The neuroanatomical substrates engaged by the up-regulation of EAA transmission in the DA-deafferented brain include those influenced by the enhancement in activity of STN EAA-containing projections, e.g., the GPi (Brotchie et al., 1991;Filion and Tremblay, 1991) and the substantia nigra zona reticulata (Rohlfs et al., 1997).

The VP receives direct innervation of EAA-containing afferents from limbic regions (e.g., amygdala; Russchen and Price, 1984;Maslowski-Cobuzzi and Napier, 1994) and the basal ganglia (e.g., STN;Groenewegen and Berendse, 1990; Turner et al., 2001). These inputs act on two major subtypes of ionotropic EAA receptors in the VP, NMDA, and non-NMDA (Monaghan and Cotman, 1985; Standaert et al., 1994). Agonists to each subtype (i.e., NMDA and AMPA, respectively) induce robust alterations in VP neuronal activity, with low synaptic concentrations enhancing firing and higher concentrations producing an excessive stimulation of the receptor to the point of inducing a state of inactivation (Turner et al., 2001). As shown in several other brain regions, when extreme, acute overexcitation can lead to long-term dysregulation of neuronal function and even excitotoxic cell death (for review, see Choi, 1992). Thus, if the STN projection to the VP is up-regulated after chronic DA depletion, this may increase the propensity for VP neurons to enter a persistent dysfunctional state. The present study tested this hypothesis by monitoring enhancements in spiking rate, as well as the apparent depolarization-induced attenuation of spiking, seen with microiontophoretically applied NMDA and AMPA in VP neurons after long-term destruction of the ascending dopaminergic neurons.

In the dorsal striatal-pallidal system, the adaptations in striatal GABAergic transmission that occur after chronic DA depletion greatly influence pallidal structures (Smith et al., 1998). The VP receives a large GABAergic projection from the nucleus accumbens (Walaas and Fonnum, 1979; Groenewegen and Russchen, 1984), and it is likely that GABA- and EAA-containing projections converge onto the same VP neurons (Zaborszky et al., 1991; Johnson and Napier, 1997a). Thus, the possibility that DA depletion may alter the interactive effects of these two amino acid transmitter groups on VP neuron spiking also was explored.

Materials and Methods

Adult, male Sprague-Dawley rats (Harlan Bioproducts for Science, Indianapolis, IN) were allowed at least 1 week to acclimate to the local vivarium conditions before experimentation was initiated. They were housed in pairs, with a 12-h light/dark cycle and ad libitum access to food and water. All procedures were approved by the Loyola University Chicago Institutional Animal Care and Use Committee and were in accord with the Guide for the Care and Use of Laboratory Animals published by the National Research Council.

DA Depletion Treatments.

One group of rats was unilaterally treated with the dopaminergic toxin 6-OHDA to deplete DA in one hemisphere. To do so, rats (250–300 g) were pretreated with desipramine HCl (30 mg/kg as the salt, administered i.p. in saline, 60 min before 6-OHDA injection; Sigma-Aldrich, St. Louis, MO) and pargyline (50 mg/kg i.p. in saline, 30 min before 6-OHDA injection; Sigma-Aldrich), and then anesthetized with pentobarbital (50 mg/kg i.p.; Cardinal Health, Chicago, IL). A stereotaxically located hole was drilled over the substantia nigra (5.3 mm anterior to lambda, 2.1 mm lateral to midline, 7.2 mm ventral to dura). By using 33-gauge injectors connected to an infusion pump, 6-OHDA HBr (8 μg/4 μl as base; Sigma-Aldrich) or its 0.3% ascorbic acid vehicle was injected into the nigra of each hemisphere at a rate of 0.5 μl/min. The skull hole was filled with bone wax, the overlying skin was sutured, and the animals were allowed to recover from the anesthesia on a warm heating pad in a dimly lit environment. The rats were fed a high-calorie diet [sometimes also requiring tube feeding of warmed Similac (Ross Pediatrics, Columbus, OH) or i.p. injections of warmed saline] for a few days after surgery; thereafter, they were given standard laboratory rat chow and water ad libitum. To provide a functional indicator of the lesion extent, 14 days after the 6-OHDA treatments, the rats were given an injection of apomorphine (1 mg/kg i.p.; Sigma-Aldrich) and their circling behavior was quantified. Rats that circled at a rate of nine turns or more per minute were used for the electrophysiological experiments 7 to 14 days later (21 to 28 days postlesion).

To allow comparisons between the effects of chronic and acute removal of DA, another group of rats was acutely depleted of monoamines with reserpine [5 mg/kg i.p. (Sigma-Aldrich); dissolved using glacial acetic acid then diluted with 0.3% tartaric acid in 1.5% ethanol solution and adjusted to pH 4.0 by using 0.01 M NaOH]. Electrophysiological studies were conducted 6 to 8 h later.

The lesion extent was verified for both 6-OHDA- and reserpine-treated rats. To do so, at the conclusion of the electrophysiological experiments, the striatum and olfactory tubercles were dissected. The tissue was assayed for monoamine content by HPLC-EC, as used previously (Napier and Potter, 1989). The HPLC-EC data, presented as nanograms per milligram of wet tissue ± S.E.M., were compared using ANOVA with post hoc Newman-Keuls (if significant) with P < 0.05 set for significance.

Electrophysiology and Microiontophoresis.

Rats (280–320 g) were anesthetized with chloral hydrate (400 mg/kg i.p. as the salt, in 0.9% NaCl; Sigma-Aldrich) and mounted in a stereotaxic apparatus. A tail vein was cannulated to allow anesthetic supplements as needed, and the animal's body temperature was maintained at 36°C throughout the experiment. A glass microelectrode/microiontophoretic pipette assembly (for construction, see Turner et al., 2001) was lowered into the VP (7.0–8.5 mm from dura) through a burr hole in the skull (0.4–0.7 mm posterior to bregma, 2.1–2.4 mm lateral to the midline).

The recording microelectrodes were filled with a 2% pontamine sky blue/0.5 M sodium acetate solution (tip diameter, 2–3 μm; 4–6 MΩ at 100 Hz in vitro; Winston Electronics Company, Millbray, CA). Action potentials from individual VP neurons were amplified, isolated, and quantified with standard extracellular recording techniques as used previously (Turner et al., 2001). To normalize the data collection, the window discriminator (Fintronics, Orange, CT) was set such that the minimal voltage level that an action potential must achieve to be counted (i.e., converted to a d.c. signal for the PC) was 50% of the initial spike amplitude (Figs. 1, B and C, and 4A). The action potentials were categorized as biphasic or triphasic and by the initial direction of the voltage deflection (positive or negative). Amplitude (μV) and duration (ms) also were determined. Neuronal firing was characterized by rate, ISI analysis of firing pattern (mean/mode ISI ratio), and the number of spontaneously firing neurons encountered per pass of the electrode through the VP (cells per tract). ANOVA was used to compare these profiles among the various treatment groups, with P < 0.05 set for significance.

Figure 1
Figure 1

Rate histograms illustrating the response of a VP neuron to NMDA. The 10-s applications of NMDA are indicated by the horizontal bars over the histogram. A, four panels of continuous recordings of a single VP neuron illustrating the approach used to generate ejection current-response curves for both the rate enhancement and apparent depolarization inactivation. The responses, indicated by the B (at 35 nA in panel 1) and C (at 110 nA in panel 4), are enlarged in the bottom histograms. B, typical rate enhancement seen at lower ejection currents. Shown in the inset is an example of an action potential that occurred during drug retention at the time indicated by the arrow. Also indicated is the discriminating voltage level (horizontal line crossing action potential), standardized to 50% of peak amplitude, used to detect the spike. C, typical responses seen at higher ejection currents. The detected spiking initially increased and after a few seconds of application it decreased as action potential amplitude was reduced until it could no longer be discriminated from background (apparent depolarization inactivation, e.g., right action potential inset). Note both the rate enhancement and apparent depolarization inactivation induced by NMDA outlast the period of drug ejection. Moreover, these effects are reversible, repeatable, and the response magnitude correlates with the ejection current magnitude.

Attached to the recording microelectrode, a five-barrel pipette (for construction description, see Turner et al., 2001) was used for microiontophoretic application of the following drugs: AMPA (10 mM in 150 mM NaCl, pH 8.0; Sigma-Aldrich), NMDA (50 mM in 200 mM NaCl, pH 8.0; Sigma-Aldrich), GABA (100 mM in 200 mM NaCl, pH 7.0; Sigma-Aldrich) and bicuculline (5 mM in H2O, pH 5.6; Sigma-Aldrich). In some cases, the side barrels were filled with the EAA antagonists CNQX and AP-5 instead of GABA and bicuculline. Results obtained with the EAA antagonists are reported inTurner et al. (2001). The center barrel was filled with the 2% pontamine sky blue/0.5 M sodium acetate solution and it was used to balance the net charge at the electrode tip. Electrode impedance was 25 to 60 MΩ for the drug-containing barrels and 20 to 45 MΩ for the balance barrel. AMPA and NMDA were ejected with various anionic currents and retained in the pipette by 10 nA of cationic current. Bicuculline was ejected with cationic currents 5 to 120 nA and retained with a 10-nA anionic current. To eject GABA, the current was incremented by 2-nA steps in the positive direction from the holding/retention current until the neuron stopped firing. GABA was retained in the pipette with a 10- to 20-nA anionic current. Retention currents were always applied in between drug application periods, including when baseline spiking was assessed.

To determine relative efficacy (i.e., maximal change in firing rate,Emax), and potency (i.e., the ejection current required to achieve 50% of this firing rate, ECur50), responses of VP neurons to microiontophoretically applied ligands were characterized over a wide range of ejection currents (typically 5–120 nA, in epochs of 10-s ejection: 30-s retention). Occasionally, it was necessary to extend the retention period to ensure that the neuronal firing rate and action potential shape returned to baseline in between ejection periods. This pulsatile paradigm produced repeatable, noncumulative, and reversible changes in VP neuronal firing as well as consistent interejection (baseline) spiking, even after repeated applications for several hours. Applying 5 to 120 nA to pipette solutions of 100 to 200 mM NaCl at a pH ranging 5.6 to 8.0 did not change neuronal firing rate (data not shown), indicating the effects seen during current application to drug-containing pipettes did not result from nonselective changes in local electrolyte concentrations or current application. To test the ability of GABA (via its hyperpolarizing effects) to reverse the apparent depolarization block induced by NMDA, constant ejection currents of NMDA were applied for 1 to 4 min. The NMDA ejection current was fine-tuned so that the action potential shape and amplitude remained stable for the duration of NMDA applications. Then GABA was coiontophoresed in 10- to 30-s ejection periods. For all treatment assessments, firing rate was quantified as spikes per 1-s bin.

At the end of the experiment, the rat was overdosed with chloral hydrate. The recording site was marked by depositing pontamine sky blue at the tip of the microelectrode. The brain was removed and the olfactory tubercles and dorsal striatum were dissected and quick-frozen on dry ice for HPLC-EC analysis. The remaining forebrain, which contained the VP, was cut into 50-μm coronal sections and stained with cresyl violet. The stereotaxically determined location of recording sites was verified histologically by two independent observers.

Analysis of Electrophysiological Data.

It has been demonstrated in several brain regions that after excessive neuronal activation, the firing rate progressively increases until action potentials show a decrement in amplitude and this often is followed by a cessation in spiking (Bunney and Grace, 1978; Grace and Bunney, 1986;Henry et al., 1992; Hollerman et al., 1992; White et al., 1995; Hu and White, 1996). When firing rate is quantified by discriminating individual spikes based on a minimum voltage requirement, this yields an inverted “U” or bimodal ejection current-response or dose-response curve. The cessation in spiking can be reversed when the membrane is hyperpolarized either electrically (Grace and Bunney, 1986) or by hyperpolarizing agents (Bunney and Grace, 1978; Grace and Bunney, 1986; Henry et al., 1992; Hollerman et al., 1992; White et al., 1995). By using similar electrophysiological approaches, these phenomena were assessed in the present study for EAA-induced effects in the VP.

Consistent with aforementioned reports, the increased spiking that occurred in the present study with lower EAA ejection currents is hereafter referred to as rate enhancements (Fig. 1, A and B). The decrease in action potential amplitude and eventual cessation of spiking that occurred with higher ejection currents is termed apparent depolarization inactivation (Fig. 1, A–C). EAA-induced rate enhancements were considered to be significant if firing in any one of the 10 one-s bins was greater than 20% above the mean spontaneous rate that immediately preceded EAA iontophoresis, and if this occurred for three consecutive applications. As ejection current was increased, the peak rate-enhancing response generally was not maintained due to encroaching apparent depolarization inactivation (Fig. 1). Thus, for analyses of the treatment-effect relationship of the EAA-induced rate enhancement, the ejection current range evaluated for each neuron began at 5 nA and ended at the ejection current level where firing in three subsequent bins was decreased from the peak excitatory response level by at least 20%. To quantify rate enhancement for each 5-nA interval, the peak spikes per 1-s bin was used. Two criteria also were used to define apparent depolarization inactivation: 1) During EAA application, the action potential decreased by more than 50% of the baseline amplitude (i.e., during drug retention). 2) Spike amplitude was restored to baseline levels during EAA retention. This continuous, on-line assessment of spike amplitude as well as using a drug ejection/drug retention amplitude ratio assured that our measures of the drug-induced amplitude changes were not caused by nonspecific variations in the status of the recording (e.g., the microelectrode moving away from the neuron). The ejection current range used for evaluating the treatment-effect relationship of apparent depolarization inactivation started from the current level were apparent depolarization inactivation began (i.e., peak firing per bin changed by 20%), and ended at the maximal ejection current tested (i.e., 120 nA). As shown in Fig. 1C, maximal apparent depolarization inactivation generally occurred 8 to 11 s after initiating ejection of relatively high currents of an EAA agonist (the effects of the agonist often remained for a few seconds after ending the 10-s ejection period). Due to the rapidly changing nature of the response, averaging across several bins dampened down the measured effect rather than producing the desired effect of minimizing variability. Thus, the minimum number of spikes per 1-s bin in the time frame where the amplitude-decreasing effect was the greatest (8–11 s from the initiation of the 10-s EAA ejection period) was used for data analysis.

Linear regression analysis of both the ascending (i.e., rate-enhancing) and descending (inactivation) limbs of the population ejection current-firing rate response relationship was used to ascertain whether the magnitude of the ejection current of microiontophoretically applied ligands was related to the response magnitude of VP neurons. Treatment-effect associations were considered significant if the slope was significantly different from zero (P < 0.05). To optimize the accuracy of single point descriptors of this relationship (e.g., Emax and ECur50), the ascending and descending limbs of the treatment-effect data obtained for each neuron were first fitted to a third order polynomial. This typically yielded anr2 > 0.9, and only curves with anr2 ≥ 0.7 were used for further analysis. For neurons exhibiting highly fluctuating spiking (n = 36 of the 204 neurons analyzed) and correspondingly low r2, an average of the response at a given current with the response to 5 nA higher and 5 nA lower was used. From the polynomials, theEmax and ECur50for both the ascending and descending limbs of the treatment-effect curves were calculated (GraphPad Prism; GraphPad Software, San Diego, CA). If the calculated Emax or ECur50 was ± 3 S.E.M. from the mean, it was considered to be an outlier (and thus an erroneous estimate of the event) and the neuron was excluded from analysis. Using this criterion, no more than two cells were omitted per treatment condition.

To contrast the mean Emax and ECur50 obtained from the various iontophoretically applied ligands in lesioned and unlesioned conditions, two sets of comparisons were performed. The first set had three conditions: control (pooled untreated rats + contralateral to lesioned hemisphere), 6-OHDA-treated, and reserpine-treated rats. The second set had four conditions: NMDA alone in pooled control, NMDA alone in 6-OHDA-treated hemispheres, NMDA + GABA in hemispheres contralateral to the 6-OHDA treatment, and NMDA + GABA in 6-OHDA-treated hemispheres. If ANOVA proved significant then Student-Newman-Keuls was used for pairwise comparisons. For analysis of both sets of NMDA-evoked responses, the same lesion and control groups were used. Because of these multiple comparisons, a more conservative α of 0.025 was used for determining statistical significance for ANOVA. For AMPA, only control and 6-OHDA-treated conditions were examined and the results compared using Student's t test with P < 0.05. These data are reported as mean spikes per second ± S.E.M. Categorical comparisons were made using Pearson's chi square (χ2) test of association, with P < 0.05. Degrees of freedom are indicated in subscript following the variables for F, t, and χ2.

Results

Electrophysiological Profile of VP Recordings.

Neurons (303) were histologically verified within the rostral-caudal and medial-lateral extent of the subcommissural VP and rostral sublentular substantia innominata (refer to Turner et al., 2001for details of VP borders and stereotaxic maps of recording sites). These sites were equally sampled from three groups of rats: untreated rats (n = 68), rats that received unilateral 6-OHDA microinjections into the substantia nigra to destroy DA-containing neurons (n = 20), and rats acutely depleted of monoamines by reserpine (n = 9).

Pallidal neuronal subpopulations have been identified by their electrophysiological characteristics that demonstrate distinct pharmacological profiles to DA (Napier et al., 1991) and to opioids (Mitrovic and Napier, 1995). This possibility was also explored in the present study. Consistent with prior reports (Napier et al., 1991;Mitrovic and Napier, 1995; Johnson and Napier, 1997b; Turner et al., 2001), the most frequently encountered action potential profile was a biphasic, initially negative waveform. This profile comprised 80% of neurons (137/172) recorded from intact rats, 95% of neurons (40/42) from hemispheres contralateral to 6-OHDA-injections), 72% (44/61) of neurons recorded from the 6-OHDA-lesioned hemisphere, and 100% of neurons (40/40) from reserpine-treated rats (Table1). Triphasic, initially positive waveforms also were encountered, but less frequently (refer to cells/track for intact controls in Table 1;t198 = 7.7, P < 0.001). The triphasic action potentials displayed a larger action potential amplitude (t157 = 4.6,P < 0.001) and a longer duration (t157 = 9.6, P < 0.001) than did the biphasic action potentials (Table 1, intact controls). Qualitative histological assessments clearly revealed that the probability to encounter either neuronal profile was not correlated with the anatomical locale of the recording site within the VP. Because these two types of neuronal profiles did not distinguish themselves with regard to lesion state or to EAA-induced effects (see below), results obtained from recordings with these two profiles were pooled.

View this table:
Table 1

Action potential and spiking characteristics from initially negative biphasic and initially positive triphasic action potentials recorded in the VP: comparisons among the various control and treatment conditions

EAA-Induced Responding in VP of Controls.

NMDA induced rate enhancements (Fig. 1) in 12 of the 20 neurons tested in the hemisphere contralateral to the 6-OHDA infusions and in eight of eight tested in the intact rats (χ2 = 2.7; N.S.). AMPA increased firing in 100% of the neurons tested in both control conditions (two were tested in the contralateral hemispheres and nine were tested in intact rats). The Emax and ECur50 were not different for NMDA between the two control conditions (t14 = 0.2–0.6, P = 0.57–0.84) (n = 2 for AMPA-tested cells in contralateral controls and this is too few for an accurate comparison of means). Thus, the data were pooled for these two conditions and presented hereafter as “control”.

As previously shown in intact controls (Turner et al., 2001), at low ejection currents for EAA, sensitive VP neurons only responded with an increase in firing. Increases in the ejection current magnitude incremented the rate enhancements between 5 and 60 nA for AMPA (linear regression: slope 0.67 ± 0.04 spikes/s/nA,r2 = 0.96;F1,10 = 306, P < 0.001; Fig. 2A) and 5 to 70 nA for NMDA (slope 0.51 ± 0.02, r2 = 0.97;F1,13 = 496, P < 0.001; Fig. 3A). Our prior work demonstrated that, in these current ranges, the AMPA-induced effects are attenuated by the AMPA receptor-selective antagonist CNQX (and not by the NMDA receptor-selective antagonist AP-5), whereas NMDA is blocked by AP-5 and not by CNQX (Turner et al., 2001). This verifies that with the ejection current ranges tested, AMPA and NMDA are acting selectively at the non-NMDA and NMDA receptors, respectively.

Figure 2
Figure 2

Response of ventral pallidal neurons to AMPA in control and 6-OHDA-treated conditions. Rate-enhancing (A and B) and apparent depolarization inactivation (C and D) effects are shown. Neurons were included in this analysis only if 50 nA (or less) of AMPA reproducibly increased firing by more than 20%, and if the goodness-of-fit (r2) for a third order polynomial of their ejection current-response relationship was >0.7. A and C, population average ejection current-response curves. B and D,Emax and ECur50 and as determined from the individual ejection current-neuronal response curves and then averaged (see Materials and Methods). ★, Emax for the rate enhancement induced by AMPA was significantly different between the control and the 6-OHDA-treated hemisphere (t21 = 3.6,P < 0.05).

Figure 3
Figure 3

Responses of ventral pallidal neurons to NMDA was enhanced after 6-OHDA-induced lesions; however, acute depletion of monoamines did not alter the response. Rate enhancement (A and B) and apparent depolarization inactivation (C and D) are shown. The criteria for inclusion in these analyses and the data presentations are the same as those defined in legend for Fig. 2. B, ANOVA for NMDA-induced rate enhancement Emax:F2,53 = 4.3, P < 0.025. a, Emax for the NMDA-induced rate enhancement differed between control and the 6-OHDA-treated hemisphere (Newman-Keuls; q = 3.8,P < 0.05). b,Emax differed between the reserpine-treated rats and the 6-OHDA-treated hemisphere (q = 3.4,P < 0.05). D, ANOVA for NMDA-induced apparent depolarization inactivation Emax:F2,65 = 4.0, P < 0.025. c, Emax from 6-OHDA and reserpine conditions differed (q = 4.0,P < 0.05). ANOVA for ECur50 of NMDA-induced apparent depolarization inactivation:F2,67 = 5.1, P < 0.025. d, ECur50 differed between control and the 6-OHDA-treated hemisphere (q = 4.3,P < 0.05). e, significant difference between the 6-OHDA-treated and the reserpine condition (q = 3.5, P < 0.05). All other comparisons were nonsignificant.

Effects of Chronic DA Depletion on Responses of VP Neurons to EAA.

HPLC-EC evaluations of DA and its metabolites were used to verify the extent of the 6-OHDA-induced lesions in the striatum, a termination site for dopaminergic projections from the substantia nigra, and the olfactory tubercles, a termination of ventral tegmental dopaminergic neurons. In intact controls, DA content in the striatum was 99.9 ± 6.1 (all monoamine content data are in nanograms per milligram of wet tissue), 3,4-dihydroxyphenylacetic acid was 6.7 ± 0.4, and homovanillic acid was 2.5 ± 0.1. After 6-OHDA treatments, DA and its metabolites were reduced by 99%. Norepinephrine (intact control levels, 5.2 ± 0.3) was reduced by 98%. Serotonin (2.5 ± 0.2 in intact controls) remained unchanged in lesioned striata, and consistent with a compensatory increase in serotonin turnover, its metabolite 5-hydroxyindoleacetic acid (1.9 ± 0.1) was increased by 74%. DA levels in the olfactory tubercle of intact controls were 46.8 ± 2.4, and despite receiving part of its DA innervation from the ventral tegmental area, it demonstrated a profound reduction (by 97%) of DA after the nigrally targeted 6-OHDA treatments. Therefore, on the day when electrophysiological experiments were conducted (i.e., 21–28 days post 6-OHDA treatment), near-total depletions of DA and its major metabolites remained for both major ascending dopaminergic projections.

The 6-OHDA treatment did not alter several of the measured electrophysiological parameters. Baseline firing rate, cells per tract, and action potential characteristics were unchanged (Table 1). The proportion of neurons that responded to EAA iontophoresis was similar to controls; AMPA enhanced firing in 94% (16/17) of neurons in the lesioned hemisphere and in 100% (11/11) tested in pooled controls, and NMDA increased firing in 88% (28/32) and 71% (20/28) of VP neurons tested in lesioned hemispheres and controls, respectively (χ2 = 0.05–2.01; N.S. for AMPA and NMDA). The potency (ECur50) of AMPA (Fig. 2, A and B) and NMDA (Fig.3, A and B) to induce rate increases was unchanged after 6-OHDA treatments. In contrast, the Emax for AMPA- and NMDA-induced rate enhancements was decreased by 6-OHDA-induced lesions (Figs. 2, A and B, and 3, A and B). But rather than reflecting a decrease in the efficacy of the agonist to enhance firing per se, this observation may reflect the ability of the EAA agonists to induce apparent depolarization inactivation at lower firing rates in the lesioned state.

Inactivation of spiking ensued within a few seconds of EAA application, even when using moderate ejection currents that initially increased firing rate. This biphasic response to a single ejection current level is shown in Fig. 1, A and C. The phenomenon also is illustrated by the fact that the right-most extreme of the EAA ejection current-response curves (Figs. 2A and 3A), which show the peak rate enhancement usually obtained in the first few seconds of EAA application (illustrated in Fig. 1, A and B), has a greater spikes per second than the left-most extreme of the apparent depolarization inactivation curves (Figs. 2C and 3C, showing data collected 8–11 s after the onset of EAA ejection, as seen in Fig. 1C). The Emax and Ecur50 for AMPA-induced apparent depolarization inactivation were not altered by long-term DA deafferentation (Fig.2D). This is in stark contrast to the apparent depolarization inactivation seen during NMDA application where ECur50 was reduced in the lesioned condition (Fig. 3D). The results suggest that after chronic lesions of DA-containing neurons there is an enhancement in the potency for NMDA (but not AMPA) to induce apparent depolarization inactivation effects in VP neurons. Thus, NMDA was used for further characterization of VP neuronal responses after DA deafferentation.

Effects of Acute DA Depletion on Responses of VP Neurons to NMDA.

The change in the response of VP neurons to the application of NMDA could be due to the loss of the direct dopaminergic input, or to adaptations in the circuitry that includes the VP as the system attempts to compensate for the loss. To examine whether similar changes occur with acute DA removal, the sensitivity of VP neurons to NMDA was examined within hours after rats were treated with reserpine. As indicated by HPLC-EC assays of tissue harvested at the conclusion of the electrophysiological evaluations, the reserpine treatment essentially depleted DA (98% reduction) in the striatum, but did not alter levels of the DA metabolites 3,4-dihydroxyphenylacetic acid or homovanillic acid. Reserpine depleted striatal norepinephrine (by 100%) and serotonin (by 92%), but 5-hydroxyindoleacetic acid remained similar to controls. Olfactory tubercle monoamine content displayed a similar pattern after reserpine treatment. The data show that the reserpine treatment protocol provided an acute removal of brain monoamine content that was similar in extent to that obtained with the 6-OHDA treatment. However, in contrast to the 6-OHDA-induced lesions, the reserpine treatment did not result in compensatory alterations in DA or serotonin turnover (suggested by the stable levels of DA and serotonin metabolites).

The firing rate and action potential duration of VP neurons from reserpine-treated rats were greater than in controls; effects that were not seen in 6-OHDA-treated rats (Table 1). Eighty-nine percent of the 37 VP neurons recorded from reserpinized rats showed rate increases to NMDA. This response distribution was comparable to that seen 21 to 28 days after 6-OHDA treatments (χ2 = 0.03, N.S.) and to controls (χ2 = 1.6, N.S.). TheEmax for the rate-enhancing effects of NMDA in reserpinized rats differed from that seen in the 6-OHDA state but not that from controls (Fig. 3, A and B). Following the same trend, the Emax and ECur50 for the apparent depolarization inactivation observed in reserpinized rats were different from the chronic lesion state but not from controls (Fig. 3, C and D). These findings indicate that acute removal of monoaminergic inputs enhances baseline firing rate but does not alter responses to NMDA, whereas chronic removal 1) makes VP neurons shift more readily into apparent depolarization inactivation upon exposure to NMDA so that the peak rate-enhancing effects can not be obtained, and 2) renders NMDA more potent in inducing this inactivation.

Effects of GABA on Ability of NMDA to Produce Rate Enhancement and Apparent Depolarization Inactivation.

To further evaluate the ability of NMDA to evoke the above-described responding patterns, we conducted two sets of experiments. The first experiment tested the hypothesis that if VP neurons were unable to generate action potentials because of a persistent depolarization induced by NMDA then the addition of a hyperpolarizing agent such as GABA would be able to reinstate spiking (Grace and Bunney, 1986; Henry et al., 1992;Hollerman et al., 1992; White et al., 1995). To make this determination, four VP neurons recorded from three intact rats were tested. All of these neurons demonstrated a robust decrease in spontaneous firing rate with GABA and an increase in firing with NMDA (Fig. 4A). Additionally, in all four neurons, suprathreshold ejection currents of GABA (i.e., those that decreased spontaneous firing) reversed the decreases in spike amplitude and number of detected spikes caused by excessive NMDA receptor stimulation (Fig. 4). Thus, consistent with prior literature (Grace and Bunney, 1986; Henry et al., 1992; Hollerman et al., 1992; White et al., 1995), the fact that GABA was able to enhance VP neuronal firing rate when coapplied with NMDA, rather than inhibiting it, provides strong evidence that the observed NMDA-induced rate decreases were due to depolarization inactivation.

Figure 4
Figure 4

GABA reverses the apparent depolarization inactivation induced by NMDA. Rate histograms from three different neurons are shown (A–C). Horizontal lines above the histograms illustrate the time of drug application by using the ejection currents indicated. The time scale in A and B is the same as that shown in C. A, action potentials obtained at different points in the experiment are shown under the histogram with the minimal spike voltage required for detection indicated by the horizontal line. Although GABA alone decreased firing rate, the action potential remained intact. NMDA (40 nA) initially increased firing rate, but with sustained application this current level was sufficient to induce a substantial decrease in the action potential height and a concomitant decrease in the detectable spikes per second. Coapplication of GABA, at an ejection current that when used alone suppressed firing (15 nA), was able to attenuate the effects of NMDA both on the action potential and the firing rate. Termination of the ejection current to both NMDA and GABA allowed the action potential to return to its baseline configuration. B and C, two additional ventral pallidal neurons demonstrating the same phenomenon, i.e., GABA coiontophoresis was able to reverse the apparent depolarization inactivation caused by NMDA.

To determine whether the enhanced potency of NMDA to induce this apparent depolarization inactivation after chronic DA removal was paralleled by an enhancement in the GABA reinstatement profile, a second experiment was performed in 14 unilaterally lesioned rats. In each of the neurons that were sensitive to both GABA and NMDA (n = 14), an ejection current of GABA below that necessary to induce a significant change in firing rate (<20%) was determined. This “subthreshold” ejection current was used for further testing to avoid the possible confound of GABA-induced rate decreases on the effects seen when it was coiontophoresed with NMDA. Indeed, in the contralateral control, the rate-enhancing (Fig.5, A and B) and apparent depolarization inactivation (Fig. 6, A and B) effects of NMDA in VP neurons were unchanged by coiontophoresis with subthreshold GABA. In contrast, GABA generally had a restorative effect on NMDA-induced rate enhancement and apparent depolarization inactivation in the lesioned hemisphere (Figs. 5 and 6, A and B), making the responses more like those seen in controls. Thus, the ECur50 of NMDA-induced apparent depolarization inactivation in the lesioned hemisphere when coiontophoresed with GABA was not different from NMDA alone in control (Fig. 6, B versus D;Emax). (Note: the ECur50of NMDA done in the lesioned hemisphere was lower than control; see Fig. 3D). There also was a trend to alter the NMDA efficacy of the apparent depolarization inactivation response with GABA coapplication in the lesioned state; however, this trend did not reach statistical significance at α = 0.025 (see Materials and Methods; Fig. 6D). These data indicate that the increase in apparent depolarization inactivation seen with NMDA in the lesioned hemisphere is attenuated by a hyperpolarizing influence on these neurons.

Figure 5
Figure 5

Effects of subthreshold applications of GABA on the rate-enhancing effects of NMDA in the control condition (A and B), and in the 6-OHDA-treated hemisphere (C and D). The criteria for inclusion in these analyses and the data presentations are defined in the legend for Fig. 2. Comparing NMBA-induced responses with and without GABA in controls and in 6-OHDA-treated hemispheres for bothEmax and ECur50 revealed that the ECur50 (★) for the NMDA rate-enhancing effect in the lesioned hemisphere was significantly increased after coiontophoresis with GABA (F3,44 = 3.5,P < 0.025; q = 4.2,P < 0.05). Remaining comparisons were not significant.

Figure 6
Figure 6

Subthreshold applications of GABA on the apparent depolarization inactivation seen with NMDA. A and B, NMDA-induced apparent depolarization inactivation in the control condition. C and D, NMDA-induced apparent depolarization inactivation in the 6-OHDA-treated condition. The criteria for inclusion in these analyses and the data presentation are defined in the legend for Fig. 2. Comparing NMBA-induced responses with and without GABA in controls and in 6-OHDA-treated hemispheres for both Emax and ECur50 revealed that the ECur50 for the NMDA-induced apparent depolarization inactivation in the lesioned hemisphere was significantly increased after coiontophoresis with GABA (F3,44 = 6.8, P < 0.025; q = 5.0, P < 0.05). Other comparisons among these four treatment conditions were not different.

Effect of Chronic Removal of DA on Function of Tonically Active Endogenous GABA Transmission.

To investigate whether chronic DA depletion changes the sensitivity of VP neurons to GABA or the tonic influence of endogenous GABA on VP neurons, two lines of investigation were pursued. The response of VP neurons to iontophoretic GABA was determined, and the effect of blocking endogenous GABA with the GABAA receptor antagonist bicuculline was measured.

GABA decreased the firing rate in all of the VP neurons tested in both the lesioned hemispheres (n = 10 cells) and in the contralateral control hemispheres (n = 6), often resulting in near-complete cessation of firing with the higher ejection currents. As shown in Fig. 7A, the magnitude of the GABA ejection current was directly related to the magnitude of the response (control: slope −0.47 ± 0.01 spikes/s/nA, F1,14 = 1219,P < 0.05; lesion: slope −0.43 ± 0.03.F1,12 = 175, P < 0.05) and the treatment-effect curves in the lesioned and unlesioned conditions were superimposable. Thus, chronic removal of dopaminergic neurons did not alter the ability of GABA to decrease VP cell firing.

Figure 7
Figure 7

6-OHDA treatments did not alter the ability of GABA to suppress, or bicuculline to enhance, ventral pallidal neuron firing. The criteria for inclusion in these analyses and the data presentation are defined in the legend for Fig. 2. For these evaluations, the control condition was the hemisphere contralateral to the 6-OHDA-injected hemisphere. A, GABA ejection current-firing rate relationships for the control and 6-OHDA-treated conditions were superimposable. B, blockade of the GABAA receptor with bicuculline produced an equivalent increase in firing rate in the control and lesioned states. This observation indicates that there is no change in tonic GABA release in the VP of the DA-depleted hemisphere.

Blockade of GABAA receptors with bicuculline resulted in an increase in neuronal firing rate, indicating that there is a tonic level of GABA released on these VP neurons that acts to decrease neuronal firing rate. However, the response to bicuculline by neurons in the VP of the lesioned hemisphere was not different from that obtained in controls (Fig. 7B). Thus, it appears that the level of tonic GABA release in the lesioned hemisphere remains functionally unaltered.

Discussion

This report revealed that a consequence of chronic lesions of the brain's ascending dopaminergic neuronal system is an enhancement in the effects of activating NMDA receptors within the VP. This included a substantial increase in the ability of the agonist to disrupt normal action potential generation in VP neurons. When considered in the context of the adaptive processes that may be relevant to PD, there are several salient features that warrant close examination.

None of the action potential characteristics often used to identify neuronal subpopulations (e.g., action potential waveform, duration, or amplitude) or indices of basal spiking activity (i.e., frequency of encountering spontaneously firing neurons, firing rate, or firing pattern) were altered in the VP of 6-OHDA-treated hemispheres. These findings distinguish this more limbically oriented VP from the adaptations that occur after chronic DA depletion in either one of the pallidal structures that serve as basal ganglia outputs, i.e., the GPi/entopeduncular nucleus or the GPe/globus pallidus, which, respectively, show rate increases (Filion and Tremblay, 1991) and decreases (Pan and Walters, 1988; Filion and Tremblay, 1991). One mechanism posed for these differential adaptations is a divergence in the effects of chronic DA removal on striatal GABAergic outputs. That is, the GABAergic projection to the GPi/entopeduncular nucleus is thought to be diminished, whereas an enhancement occurs in GABAergic influences on the GPe/globus pallidus (Gerfen et al., 1990). However, we did not observe any difference in the effects of tonically released GABA on VP neurons in the lesioned and unlesioned conditions (evidenced by similar responding to bicuculline). Because the nucleus accumbens provides the major GABAergic input to the VP (Walaas and Fonnum, 1979;Groenewegen and Russchen, 1984), these findings concur with reports showing a lack of changes in nucleus accumbens firing rate after lesions of midbrain dopaminergic neurons (Debonnel and De Montigny, 1988). Thus, it may be that adaptations in the limbic system differ from those observed in the basal ganglia.

Acute depletion of brain monoamines (by reserpine treatment) also did not alter the number of spontaneously firing cells, but in contrast to VP effects of chronic lesions, it did lead to an enhancement in spontaneous firing rate. One possible mechanism for this finding may involve interactions among local (VP) neurotransmitters. The VP is directly innervated by DA-containing terminals (Voorn et al., 1986), and local applications of DA induce robust changes in VP neuronal firing rate (Napier and Potter, 1989; Napier et al., 1991;Maslowski-Cobuzzi and Napier, 1994). DA also normally regulates the effects of several VP transmitters, including inhibiting glutamate-induced excitations (Johnson and Napier, 1997a). Subthreshold levels (so that spontaneous firing is not altered) of exogenously applied or endogenously released DA are capable of attenuating the effects of exogenously applied or endogenously released glutamate (Maslowski-Cobuzzi and Napier, 1994; Johnson and Napier, 1997a), including the EAA released upon activation of the amygdala (Maslowski-Cobuzzi and Napier, 1994), a source of EAA to the VP. The VP also receives EAA-containing inputs from the STN (Groenewegen and Berendse, 1990; Turner et al., 2001), a brain region that is known to demonstrate increases in activity and changes in firing pattern in the DA-deafferented state (Bergman et al., 1994). This enhanced drive to the VP would no longer be modulated by DA and such a scenario may render VP neurons more susceptible to various toxic effects of increased EAA input. Thus, it is plausible that acute removal of DA modulatory influences allowed for a larger excitatory drive to be exerted onto those neurons that are innervated by EAA-containing afferents. However, because the increase in firing rate is no longer seen 3 weeks after 6-OHDA treatments, it appears that the engaged adaptive processes, which do not involve GABA transmission, are sufficient to counter the effects of acute DA removal.

Even though indices of basal firing were unchanged in the VP after chronic DA-deafferentation, VP responding to EAA was greatly altered. The most profound effect occurred in the ability of EAAs, especially NMDA, to diminish spike amplitude to the point of rendering it indistinguishable from background activity. This response profile is consistent with the theory of a depolarization blockade, a phenomenon well characterized in other brain regions of intact rats (Bunney and Grace, 1978; Grace and Bunney, 1986; Henry et al., 1992; Hollerman et al., 1992; White et al., 1995; Hu and White, 1996). This theory maintains that with excessive exposure to rate-enhancing agents, neurons enter a depolarized, but inactive state. The depolarized nature of the membrane during this inactive state is verified by demonstrating that spiking can be restored with hyperpolarizing agents (Bunney and Grace, 1978; Grace and Bunney, 1986; Henry et al., 1992; Hollerman et al., 1992; White et al., 1995). Concurring with this dogma, we demonstrated that when VP spiking was no longer detected during excessive microiontophoretic application of NMDA, coapplication of GABA at levels that normally suppress firing, reinstated spiking.

The mechanisms underlying the apparent depolarization inactivation induced acutely by EAA are not yet known, but alterations in Na+ and/or Ca2+ conductance are likely candidates (Herrling et al., 1983; Lambert et al., 1989;Cepeda et al., 1991; Ciardo and Meldolesi, 1991). With intracellular recordings of striatal neurons, microiontophoretic applications of NMDA initiates spiking within a few hundred milliseconds of ejection current onset, and this is followed by a depolarization plateau upon which spikes with a decreased amplitude occur (Herrling et al., 1983; Cepeda et al., 1991). The initial burst of action potentials is likely mediated by Na+ and the longer lasting (several seconds) depolarized plateau is dependent on Ca2+currents (Herrling et al., 1983; Lambert et al., 1989; Cepeda et al., 1991; Ciardo and Meldolesi, 1991). In the present study, an apparent depolarization blockade was also observed with AMPA. Some AMPA receptor channels are permeable to Ca2+ and AMPA receptor activation promotes the opening of voltage-dependent Ca2+ channels (Choi, 1992); thus, such effects would be expected. An involvement of long-lasting Ca2+ plateaus with an acute depolarization inactivation is consistent with the response profile seen with EAA application on VP neurons. That is, with either continued EAA exposure or the use of higher ejection currents, more and more Ca2+ channels may be recruited to increasingly summate the plateau current. This would result in the observed response continuum of an initial decrease in spike amplitude to a complete blockade where spiking no longer occurred.

Persistent alterations in such membrane parameters and/or intracellular handling of the influx of cations may underlie the enhanced propensity of EAA to cause an apparent depolarization inactivation in VP neurons in the 6-OHDA condition. Grace and Bunney (1986) demonstrated in rats chronically treated with neuroleptics that dopaminergic neurons recorded in vivo exist in a depolarized state, and these neurons more readily enter into a depolarization block upon subsequent neuroleptic administration. Likewise, Tseng et al. (2001) have shown in vivo in rats chronically depleted of DA, that spontaneously active striatal medium spiny neurons spend less time in the “down” state (hyperpolarized) relative to unlesioned controls, both the “up” and down states are relatively depolarized, and neurons in the up state are much more likely to fire action potentials (although such effects were not seen in vitro by Calabresi et al., 1993). If VP neurons are depolarized at rest in the chronic DA-deafferented condition, this would make them more susceptible to effects of EAAs. But a persistent depolarization alone may not always be sufficient or necessary for the observed effects. For example, Mulder et al. (1996) saw profound changes in responses of nucleus accumbens neurons to iontophoretically applied glutamate in vivo despite finding no changes in intrinsic membrane properties (determined in vitro). It also is possible that alterations in the ability of VP neurons to process intracellular Ca2+ may be relevant to the enhanced effects seen with EAA in the lesioned state. Calcium-binding proteins, like calbindin, calretinin, and parvalbumin are important buffers that are critical to maintaining appropriate intracellular concentrations of Ca2+ (for review, see Heizmann and Braun, 1992). Although still controversial, there is evidence that forebrain levels of these proteins are decreased in PD (Iacopino and Christakos, 1990;Heizmann and Braun, 1992), and that calbindin may be neuroprotective in humans with PD and animal models of this disease (German et al., 1992). If the capacity of VP neurons to buffer Ca2+ is diminished in the 6-OHDA-lesioned state, the effects of the Ca2+ influx caused by excessive EAA receptor activation would be enhanced. Moreover, as observed in the present study for measures of basal spontaneous firing in the VP of the chronically lesioned hemisphere, the enhancement in EAA-induced effects could occur in the absence of changes in basal levels of neuronal activity.

It has been demonstrated in several other brain regions that a consequence of excessive EAA is excitotoxic damage and cell death (Choi, 1992); however, this remains to be fully investigated for the VP. The possibility that there is a physiological change, or neuronal damage or loss, in the VP is supported by reports showing alterations in cognitive tasks (Rammsayer and Classen, 1997) and affective states (Cummings, 1992) in PD patients, for these functions are influenced by the VP (learning, Chrobak et al., 1991; motivation, Mogenson and Yang, 1991; and reward, McAlonan et al., 1993; Panagis et al., 1995; Gong et al., 1997). Such effects may explain part of the limbic circuitry changes underlying the affective and cognitive symptoms of PD.

Acknowledgments

We thank Dr. William Wolf for the use of HPLC-EC equipment.

Footnotes

  • ↵1 Present address: Department of Neurology, Reed Neurological Research Center, UCLA School of Medicine, Los Angeles, CA 90095.

  • This work was supported by U.S. Public health Service Grant MH11607 (to M.S.T. and T.C.N.), and by the M.D./Ph.D. and Neuroscience graduate programs at Loyola University Chicago.

  • Abbreviations:
    EAA
    excitatory amino acid
    PD
    Parkinson's Disease
    DA
    dopamine
    STN
    subthalamic nucleus
    GPi
    internal segment of globus pallidus
    VP
    ventral pallidum
    NMDA
    N-methyl-d-aspartate
    AMPA
    α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid
    GABA
    γ-aminobutyric acid
    6-OHDA
    6-hydroxydopamine
    HPLC-EC
    high-performance liquid chromatography with electrochemical detection
    ANOVA
    analysis of variance
    ISI
    interspike interval
    CNQX
    6-cyano-2,3-dihydroxy-7-nitroquinoxaline
    AP-5
    2-amino-5-phosphopentanoic acid
    GPe
    external segment of globus pallidus
    • Received August 30, 2001.
    • Accepted January 8, 2002.

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Research ArticleNEUROPHARMACOLOGY

Alterations in Responses of Ventral Pallidal Neurons to Excitatory Amino Acids after Long-Term Dopamine Depletion

Michael S. Turner, Laurence Mignon and T. Celeste Napier
Journal of Pharmacology and Experimental Therapeutics April 1, 2002, 301 (1) 371-381; DOI: https://doi.org/10.1124/jpet.301.1.371
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