Cocaine Or Selective Block of Dopamine Transporters Influences Multisecond Oscillations in Firing Rate in the Globus Pallidus David N

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Cocaine or Selective Block of Dopamine Transporters Influences Multisecond Oscillations in Firing Rate in the Globus Pallidus David N. Ruskin, Ph.D., Debra A. Bergstrom, Ph.D., David Baek, B.S., Lauren E. Freeman, B.S., and Judith R. Walters, Ph.D.

Previous studies have shown that direct-acting dopamine pretreatment, as well as by N-methyl-D-aspartate receptor agonists modulate the multisecond oscillations which are antagonist (MK-801) pretreatment. Desipramine and present in globus pallidus spike trains in vivo in awake fluoxetine (blockers of norepinephrine and serotonin rats. To investigate possible modulation by endogenous uptake, respectively) had no significant effects on dopamine and by other monoamines, and by drugs with multisecond oscillations. The results suggest that abuse potential, cocaine or selective monoamine uptake dopamine has a primary role among monoamines in blockers were injected systemically during extracellular modulating multisecond oscillations in globus pallidus recording of single globus pallidus neurons and the results activity, and that tonic dopaminergic and glutamatergic analyzed with spectral and wavelet methods. Both cocaine transmission is necessary for normal slow oscillatory and the selective dopamine uptake blocker GBR-12909 function. significantly shortened the period of multisecond [Neuropsychopharmacology 25:28–40, 2001] oscillations, as well as increasing overall firing rate. © 2001 American College of Neuropsychopharmacology. Cocaine effects were blocked by dopamine antagonist Published by Elsevier Science Inc.

KEY WORDS: Cocaine; Dopamine; GBR-12909; Globus from 1 Hz (the slow end of the delta rhythm) up to pallidus; NMDA receptor; Oscillation; Wavelet roughly 60 Hz (the fast end of the gamma rhythm). However, recent studies have demonstrated that much Periodicities in brain electrical activity occur in many slower periodic oscillations are commonly present in nuclei and in many frequency ranges, and have been the spike trains of tonically firing neurons in the basal described in the electroencephalogram, in field poten- ganglia. The firing rates of a majority of neurons in the tials, and in the spiking activity of single neurons. globus pallidus (GP), the subthalamic nucleus, the sub- Much of the attention that brain periodicities have re- stantia nigra pars reticulata and the entopeduncular nu- ceived has been directed to the range of frequencies cleus oscillate in vivo with slow periods, most often in the range of 10–60 s (0.1–0.017 Hz) (Ruskin et al. 1999a; From the Experimental Therapeutics Branch, National Institute of Ruskin et al. 1999c; Wichmann et al. 1999; Allers et al. Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD. 2000). These multisecond periodicities in tonic activity Address correspondence to: David N. Ruskin, 10 Center Dr., are present in awake rats, but are markedly attenuated Room 5C103, Bethesda, MD, 20892-1406, Tel.: 301-496-2067, Fax: by general anesthesia (Ruskin et al. 1999a). 301-496-6609, E-mail: [email protected] Received Jun 22, 2000; revised September 22, 2000; accepted One of the most striking characteristics of these slow November 17, 2000. oscillations is their strong modulation by dopamine

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NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 1 Dopamine Effects on Pallidal Oscillations 29

(DA) receptor activation (Ruskin et al. 1999a; Ruskin et previously described (Ruskin et al. 1999a). Briefly, all al. 1999c; Allers et al. 2000). Systemically injected DA surgical procedures (tracheotomy, scalp incision, skull agonists shift oscillatory periods from mean periods of drilling) were performed with rats under halothane an- 25–30 s to 5–15 s, depending on drug and dose. Spectral esthesia. Halothane anesthesia was induced in an in- analysis reveals that DA receptor activation also in- duction chamber, and was maintained during surgery creases the spectral power (i.e. the regularity) of multi- by administration of additional halothane as needed. second periodicities. Therefore, in addition to the well- To prevent discomfort, all surgical sites and pressure characterized ability of systemically-administered DA points were injected with the long-acting local anes- agonists to change the mean firing rate of basal ganglia thetic mepivacaine, and ear bar tips and tracheal can- neurons, they also change basal ganglia firing patterns nulas were coated with 2% lidocaine anesthetic gel. at multisecond time scales. The use of selective DA re- Corneal drying was prevented with LacriLube. A tra- ceptor agonists and antagonists has shown that this cheotomy was performed, and the trachea was cannu- modulation of slow firing pattern involves both the D1 lated. Rats were placed in a stereotaxic frame, and a and D2 subfamilies of DA receptors (Ruskin et al. 1999a; hole was drilled in the skull over the GP. After surgical Ruskin et al. 1999c). procedures were finished, halothane anesthesia was These initial studies of DAergic influences on multi- discontinued, the animal was paralyzed with gallamine second periodicities utilized direct-acting DAergic triethiodide (16 mg/kg i.v.) injected through the tail drugs. More recently, we have found that D-amphet- vein, and artificial respiration immediately begun with amine and methylphenidate, drugs that act on a rodent ventilator (model 683, Harvard Apparatus). monoamine transmission indirectly, also modulate Artificial respiration rates were adjusted to maintain slow oscillations (Ruskin et al. 2001). These drugs are exhaled CO2 between 3.6 and 4.5%. Supplements of gal- noted for their effects on attention and locomotor activ- lamine were given every 10–15 min. Body temperature ity, including beneficial effects on these parameters in was maintained at 36-38ЊC with a heating pad. patients with attention deficit/hyperactivity disorder. Glass microelectrodes (2.5-6 M⍀ at 135 Hz) filled D-amphetamine and methylphenidate also have serious with 2 M NaCl containing 1% Pontamine Sky Blue were abuse potential. To further explore the potential for lowered stereotaxically through skull holes to the fol- abused/addictive substances to affect multisecond os- lowing coordinates: 0.8-1.2 mm posterior to Bregma, cillatory activity, the present study examined the effects 2.6-3.0 mm lateral to the midline, 5.0-7.0 mm ventral to of cocaine on spiking activity in the GP. Since these dura. Fine vertical control of microelectrode placement three drugs raise levels of more than one brain was accomplished with micromanipulators (MO-8, monoamine, this study also tested the effects of the se- Narashige). Single unit activity was amplified (model lective uptake blockers GBR-12909, desipramine and 725, WPI) and monitored with an audio monitor and fluoxetine (selective for the DA, norepinephrine (NE) digital oscilloscope. Signals were band-pass filtered be- and serotonin (5-HT) uptake systems, respectively) to tween 250 and 5000 Hz, and spikes were identified with determine the relative importance of each monoamine. a voltage/window discriminator and recorded by In addition, because many of the effects of direct-acting Spike2 software (version 3.14, Cambridge Electronic dopamine agonists on mean firing rate in the basal gan- Design). All recorded GP units had biphasic ϩ/Ϫ glia depend on N-methyl-D-aspartate (NMDA) receptor waveforms (type II; Kelland et al. 1995), and had base- activity (Kelland and Walters 1992; Allers et al. 1996; line firing rates between 13 and 92 Hz (mean ϭ 36 Hz). Huang et al. 1998), the NMDA receptor antagonist MK- Five to six minutes of baseline activity was recorded be- 801 was utilized to test for a similar dependence of the fore the i.v. injection of experimental drugs through the effects of monoamine uptake blockade on multisecond tail vein. Drugs were injected as a single bolus, except periodicities. for GBR-12909, which in some instances was injected in four divided doses at 1-min intervals. Units were further recorded for 10–20 min. In some cases, a second METHODS drug was then injected and units were held for another 10 min. One unit was recorded per rat. After data col- Extracellular single unit activity was recorded in the GP lection, Pontamine Sky Blue was iontophoresed to mark of male Sprague-Dawley rats (250-400 g) in accordance the recording site for later histological confirmation. with the National Institutes of Health (USA) Guide for Experimental drugs used include (-)-cocaine HCl, de- the Care and Use of Laboratory Animals. In previous sipramine HCl (Norpramin), S(-)-eticlopride HCl, fluox- studies of GP unit activity, we have found that the inci- etine HCl (Prozac), GBR-12909 2.HCl (Vanoxerine), ha- dence of multisecond oscillations was greatly attenu- loperidol, (ϩ)-MK-801 hydrogen maleate (Dizocilpine), ated when animals were under general anesthesia and R(ϩ)-SCH-23390 HCl. All experimental drugs were (Ruskin et al. 1999a). Therefore, in the present study GP from Research Biochemicals Inc., except for haloperidol neurons were recorded in awake, immobilized rats as (McNeil Pharmaceuticals). Drugs were dissolved in

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0.9% NaCl, except for fluoxetine and GBR-12909 which pared to the single time resolution of windowed Fou- were dissolved in distilled water, and SCH-23390 which rier transform analysis. Scalograms were produced was dissolved as a 10X stock solution in 0.001 N HCl be- with the Time-Frequency Toolbox (http://www-syntim. fore dilution to final volume with saline. inria.fr/fractales/Software/TFTB) with Matlab 5.3.1 Spectral analysis of GP spike trains was performed (The MathWorks), and were computed with the Morlet by two methods. For assessing the significance of peri- wavelet (15 s half-width at coarsest scale), with 256 fre- odic activity, 180 s data segments from pre- and post- quencies being sampled within the analyzed range. drug epochs were analyzed with the Lomb peri- Spiking activity was binned at 0.75 s, to reach a Nyquist odogram (Kaneoke and Vitek 1996), performed on limit of 1.5 s (0.67 Hz). Spectral power was plotted on a binned spike trains. This method provides a measure of log10 scale, with greater power represented by redder statistical significance for spectral features: spectra color. The color axis was scaled so that the power levels were tested against the null hypothesis that binned within the scalogram data for a single neuron spanned spiking activity had a random Gaussian distribution, the full color range (blue to red). resulting in an exponential distribution of spectral power. This null hypothesis was rejected at the p ϭ .01 level. For spectral analysis, spiking activity was binned RESULTS with 200 ms bins (example spike trains in figures are Multisecond Periodicities in Baseline Activity shown binned at 500 ms), and periodicities were analyzed in the range of 1.5–60 s (0.67–0.017 Hz). Periodici- As reported previously (Ruskin et al. 1999a; Ruskin et al. ties slightly faster than 1.5 s in this preparation often re- 1999c), the baseline firing rate of most GP neurons relate to ventilation (Ruskin et al. 1999a). For example, of corded in awake rats oscillated at time scales of seconds the presently recorded GP neurons, 11.4% had signifi- to minutes (Figures 1 and 2). These periodic variations cant oscillations in this range, all having periods be- could be large in amplitude: in the baseline segment tween 0.77 and 0.84 s. This coincides with the range of shown in Figure 2, Panel A, the firing rate varies up to ventilator speeds, and when ventilator action was re- 180% and down to 60% of the overall mean. Using the corded simultaneously during the recording of a neu- Lomb algorithm to assess the periodicity of these oscilla- ron with this type of activity (n ϭ 5), the neuronal oscil- tions (examples in Figure 2), 80% of neurons displayed latory period and the ventilator period were equal to oscillations in baseline firing rate (with periods between within 1%. These ventilator-related oscillations were 1.5 and 60 s) that were sufficiently powerful (i.e., regu- not further analyzed. 180 s data segments were chosen lar) to be considered statistically significant. Oscillatory from baseline, and from the 5–10 min and (when avail- periods of the most powerful spectral peak from each able) 15–20 min time ranges after drug injection. To as- baseline power spectrum are plotted in Figure 3. These sess drug effects on oscillatory period, the period of the baseline oscillatory periods varied widely from neuron “main” spectral peak, i.e. the tallest (most powerful) to neuron (within the 1.5–60 s range), but mean values spectral peak within the studied range, was taken from for all treatment groups were approximately 30 s (28.2 Ϯ the power spectrum of each analyzed segment, and 2.1 s for all neurons combined). these numbers were analyzed with ANOVA followed by post hoc Dunnett’s comparisons to baseline. Data seg- Effects of Selective Monoamine Uptake Blockers ments that had no significant periodicity in the 1.5–60 s range were not entered into this analysis. To assess Most recorded units had significant slow oscillations drug effects on oscillatory regularity (i.e. spectral both before and after the injection of selective monoam- power) apart from effects on oscillatory period, the total ine uptake blockers (Table 1). However, among GBR- area under the spectral curve within the 1.5–60 s range 12909, desipramine and fluoxetine, only the selective was measured, including those cases where there were DA uptake blocker GBR-12909 robustly effected these no significant spectral peaks, and these data were ana- oscillations. Particularly striking oscillations appeared lyzed with repeated-measures ANOVA followed by after the i.v. injection of this drug (3.2 mg/kg), and, post hoc Dunnett’s comparisons to baseline. The ␣ level once they had appeared, could be remarkably stable for ANOVA and post hoc tests was p ϭ .05. (Figure 1). Spectral analyses indicated that these oscilla- In a second method of spectral analysis, focusing on tions occurred at a faster rate compared to baseline the evolution of periodic activity over time, entire re- (Figures 1 and 3, Panel A). The mean oscillatory period s, and 10ف cordings or recording segments were represented as within the 5–10 min post-drug epoch was time-frequency plots of spectral power. These scalo- this reduction in period was still significant out to 20 grams were based on the continuous wavelet transform min after drug injection, at which time a DA antagonist and are analogous to Fourier transform-based spectro- was typically administered (Figures 1 and 3, Panel A). grams. A wavelet-based approach was used to optimize In addition, GBR-12909 increased the power (regular- time resolution across all examined frequencies, com- ity) of the multisecond oscillations. This was visible in

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Figure 1. Effects of DA uptake blockade on multisecond oscillations in firing rate in GP neurons. Two complete firing rate records are shown, with accompanying wavelet-based time vs. frequency plots (scalograms) for illustration of oscillatory frequency between 0.67 and 0.017 Hz (1.5–60 s). The frequency (y) axis of the scalograms is log10(Hz). Redder colors represent higher power (scale bar). Both neurons had somewhat irregular slow activity in baseline, which appears in the scalograms as low-power bands between 0.025 and 0.017 Hz (40–60 s). In both units, 3.2 mg/kg GBR-12909 (given as bolus dose in Panel A, divided doses in Panel B), caused the emergence of faster, and more regular, oscillations in firing rate which are readily apparent in the firing rate records. The scalograms illustrate the emergence of these oscillations as the appearance of powerful bands centered around 0.15 Hz (7.5 s) in Panel A, and 0.1 Hz (10 s) in Panel B. These faster oscillations appeared promptly after GBR-12909 injection in A, but were somewhat delayed in Panel B. GBR-12909 also increased average firing rate in both neurons. In both units, oscillatory activity remains fairly stable until the injection of 0.2 mg/kg haloperidol, a D2 antagonist, which reversed the effects of GBR-12909 on multisecond pattern and average firing rate. scalograms as the emergence of higher power bands oscillatory period did not significantly correlate with (Figure 1), and was quantified by the measurement of baseline firing rate or with post-desipramine firing rate spectral area in Lomb algorithm-generated power spec- (as absolute rate or as percent of baseline). However, tra. GBR-12909 increased mean spectral power by al- these data do not rule out the possibility of a “de- most 70% (Figure 4). sipramine-responsive” subpopulation of neurons or rats. In contrast to GBR-12909, neither the NE uptake In addition to effects on multisecond oscillations, blocker desipramine nor the 5-HT uptake blocker fluox- GBR-12909 was the only selective monoamine uptake etine had significant effects on oscillatory period (Figure blocker to have robust effects on overall firing rate. This 3, Panels B and C). Also, neither drug significantly af- drug increased overall firing rates in all tested neurons, fected spectral power (data not shown). After des- whereas desipramine and fluoxetine had only minor ef- ipramine injection, there did appear to be a modest pre- fects (Figure 5). s. To GBR-12909 (3.2 mg/kg) given i.v. to freely-moving 20ف ponderance of oscillation periods below address the possibility that this pattern might indicate rats induced a pattern of strong downward sniffing the existence of a “desipramine-responsive” subpopula- and/or chewing, sometimes combined with slow or in- tion, more detailed analyses were performed. Neurons termittent locomotion. This pattern was present in both were characterized as having high or low baseline firing the 5-10 and 15-20 min post-drug time ranges. rate (defined by a median split), or as responding to desipramine with increases or decreases in firing rate (com- Effects of Cocaine pared to baseline). Separate ANOVAs on desipramine effects on oscillatory period for each of these groups Striking multisecond oscillations appeared after injec- were all non-significant. In addition, post-desipramine tion of the non-specific monoamine uptake blocker co-

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Figure 2. Effect of cocaine on oscillatory frequency in GP neurons. 180 s segments of binned spiking activity (scaled to their highest point) are shown from baseline and post-cocaine (3.2 mg/kg) epochs, with accompanying spectral analyses. Directly below the data segments (and plotted on the same time scale) are corresponding sections of the wavelet-based scalograms for each unit, showing oscillatory frequency and power over time. Conventions for scalograms are as in Figure 1; the color scale is identical for scalograms taken from a given unit. Below scalograms are power spectra derived from Lomb algorithm analyses on the same 180 s segments. These power spectra are shown with lines signifying the p ϭ .01 significance level; spectral peaks above this line are considered statistically significant (see Methods). The period of the main (most powerful) significant spectral peak in each spectrum is indicated. Panel A: This unit had slow, somewhat irregular (but high amplitude) firing rate variations in baseline, visible in the scalogram and identified as having a main period of 25 s in the power spectrum. At 4–7 min after the injection of cocaine, oscillation period decreased to 12 s, and power (regularity) increased. A very stable and powerful band is apparent in the scalogram. Later (16–19 min after injection), the effects of cocaine spontaneously reversed: slow oscillatory activity decreased in power, and increased in period. Panel B: This unit did not have significant oscillatory activity in baseline. At 6–9 min after cocaine injection, very regular oscillations were noted, identified in the power spectrum as having a main period of 4.9 s. The accompanying scalogram indicates that the oscillation period varied somewhat over time. The effects of cocaine eventually wore off: 16–19 min post-drug, oscillatory power decreased (visible in both the scalogram and the power spectrum), and oscillatory activity became disorganized. Several peaks (and bands) are visible across a wide range of periods in the power spectrum (and the scalogram). Cocaine also increased average firing rates in both neurons.

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Figure 3. The effect of monoamine uptake blockers on oscillatory period, and the effect of pretreatment with DA receptor or NMDA receptor antagonists. Bars represent the mean Ϯ SEM of the periods of the most powerful Lomb spectral peaks (examples in Figure 2) of neurons within a particular condition. The total number of cells for each group is given at the base of each bar; the number of cells in the group that are without significant periodicity (i.e. no spectral peaks above the p ϭ .01 significance level) is indicated above each bar (“no osc”). ANOVA results (F and p values) for each treatment group are given above each graph. Panels A, B, C: Period was significantly reduced by GBR-12909 (3.2 mg/kg), but not by desipramine (2.0 and 5.0 mg/kg) or by fluoxetine (3.2 mg/kg). Separate ANOVAs on desipramine at these two doses indicated no significant effect of either; therefore, the groups are combined here. Panel D: Period was also significantly reduced by cocaine (3.2 mg/kg), although this effect was no longer apparent in the 15–20 min time range. Panels E, F: The effect of cocaine was blocked by pretreatment with either combined D1 and D2 antagonists (SCH-23390, 0.5 mg/kg, and eticlopride, 0.2 mg/kg; “DA antagonists”) or by MK-801 (0.15 mg/kg). Cocaine data in Panels E and F are from the 5–10 min range. Neither the DA antagonist treatment or MK-801 had significant effects on period alone. ns: non-significant. * p Ͻ .05, ** p Ͻ .02. caine (Figure 2), and like GBR-12909, cocaine reduced compared to baseline), there was no consistent power .(s response (Figure 4 10ف the periods of these oscillations to a mean of within the 5–10 min epoch (Figure 2 and 3, Panel D). Although the large majority of type II (ϩ/- wave- However, cocaine effects on oscillatory period were form) GP neurons respond to indirect-acting or direct- short-lived, not lasting through the 15–20 min post- acting DA agonists with net increases in firing rate, drug epoch, as illustrated by visual inspection of firing rare type II neurons are found that respond with de- activity and scalograms (Figure 2), and confirmed by creased net firing rate (e.g. Figure 4 in Ruskin et al. Lomb analysis (Figure 3, Panel D). Cocaine-induced in- 1998). Of the eleven GP neurons recorded during co- creases in overall firing rate were also typically short- caine treatment, one fell into this latter category. Nota- lived, reaching a plateau at 4–9 min and dropping bly, although cocaine caused a 66% decrease in overall thereafter. These results are consistent with the rela- firing rate in this one case, the unit still displayed the tively short biological half-life of this drug in rats after cocaine-induced reduction in oscillatory period similar i.v. administration (Barbieri et al. 1992). Unlike GBR- to the typical “firing rate-increasing” population (Fig- 12909, cocaine did not have significant effects on spec- ure 6). Similar period reductions have been noted in tral power. Although some units responded to cocaine rare type II units demonstrating firing rate decreases with an increase in power (e.g. Figure 2, Panel B: there after D-amphetamine or direct-acting D1/D2 agonists is an 83% increase in spectral area (middle column) (unpublished results).

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Table 1. Expression of Multisecond Periodicities in GP Neurons

Before/After Before/After Before/After Before/After

Treatment ϩ/ϩϪ/ϩϩ/ϪϪ/Ϫ n

GBR-12909 (3.2) 78 11 11 0 9 Desipramine (2.0,5.0) 68 16 10 5 19 Fluoxetine (3.2) 67 22 11 0 9 Cocaine (3.2) 82 9 0 9 11

Most GP units have significant multisecond periodicities both before and after monoamine uptake blockade. Each GP unit is classified into one of four categories based on the expression of slow oscillations in firing rate ‘before’ and ‘after’ drug injection. The ‘after’ category refers to the 5-10 min post-injection time range. ‘ϩ’ and ‘Ϫ’ indicate the presence and absence, respectively, of statistically significant periodic activity in the 1.5-60 s range of periods. Numbers are percentages. For example, in the rats receiving fluoxetine, 67% of neurons had oscillations both in baseline and after drug injection, 22% did not have baseline oscillations but did have oscillations after drug, 11% had baseline oscillations but no oscillations after drug, and no neurons were without oscillations in baseline and drug epochs. Numbers in parentheses are i.v. doses in mg/kg.

Because cocaine caused reductions in oscillatory pe- although it was also not significantly different from that riod similar to those caused by the selective DA uptake after DA antagonist alone (p ϭ.11, Tukey test). blocker GBR-12909, we attempted to confirm the DAer- Pretreatment with the non-competitive NMDA re- gic mediation of cocaine effects with DA receptor an- ceptor antagonist MK-801 also prevented the effects of tagonists. A pretreatment with combined D1 and D2 an- cocaine on oscillatory period, without having any effect tagonists (for complete antagonism of both DA receptor by itself on period (Figure 3, Panel F). In addition, MK- subfamilies) completely prevented the effects of cocaine 801 by itself significantly decreased oscillatory power, on oscillatory period (Figure 3, Panel E). The combined and power remained reduced after subsequent injection DA antagonist treatment did not change oscillatory pe- of cocaine (Figure 4). riod by itself (Figure 3, Panel E), but did significantly In the 5–10 min post-drug time range, freely-moving reduce oscillatory power compared to baseline. After rats injected with 3.2 mg/kg cocaine i.v. demonstrated subsequent cocaine injection, oscillatory power was no strong sniffing (directed downward, upward, or at the longer significantly different from baseline (Figure 4), walls of the chamber), concomitant with almost contin-

Figure 4. The effect of GBR-12909 or cocaine on oscillatory power, and the effect of pretreatment with DA receptor or NMDA receptor antagonists. Drug effects on spectral power (taken from the Lomb algorithm) are expressed as percent of baseline power. Significant main effects were found for GBR-12909 (F ϭ 3.8, p Ͻ .05), combined injection of SCH-23390 and ϭ Ͻ ϭ Ͻ eticlopride (D1 and D2 antagonists) followed by cocaine (F 6.0, p .01) and MK-801 followed by cocaine (F 6.1, p .01). Only data for the 5–10 min time range are shown. * p Ͻ .05, ** p Ͻ .02. GBR-12909 also demonstrated a trend (p ϭ .10) to increased power in the 15–20 min time range (not shown). ‘n’ for groups same as Figure 3. NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 1 Dopamine Effects on Pallidal Oscillations 35

Figure 5. The effect of monoamine uptake blockers on mean firing rates in the GP. Firing rates are shown as minute- by-minute mean Ϯ SEM, and are expressed as percent of baseline firing rate. Cocaine (3.2 mg/kg, n ϭ11) and GBR-12909 (3.2 mg/kg, n ϭ 9) increase GP firing rates up to approximately 180% of baseline. Note the shorter-acting effect of cocaine, consistent with its shorter-acting effect on multisecond periodicities. Fluoxetine (3.2 mg/kg, n ϭ 9) and desipramine (5.0 mg/kg, n ϭ 10) caused minor decreases in firing rate. Desipramine had similar effects at 2.0 mg/kg (not shown). In cases where GBR-12909 was injected as a single bolus dose (n ϭ 3), the time of this injection is aligned with the first of the four arrows.

uous locomotion or rearing. Drug effects noticeably ylphenidate supports this conclusion (Baek et al. 1999; waned by the 15–20 min post-injection time range: rats Ruskin et al. 2001). These results are therefore relevant occasionally sniffed, locomoted, or groomed, but were to drug abuse and addictive processes in humans, since still most of the time. abused catecholaminergic stimulants (including cocaine) act via endogenous transmitter. The effects of GBR-12909 or cocaine treatment on GP DISCUSSION firing rate and pattern, prevented and reversed by DA receptor antagonists, are consistent with the marked in- Previous studies from our laboratory demonstrated creases in DA overflow caused by these drugs at or that DA strongly modulates multisecond periodicities around the presently tested doses (Church et al. 1987; that are present in the spike trains of many GP neurons Baumann et al. 1994; Fink-Jensen et al. 1994; Engberg et in awake rats. To extend these findings, the effects of al. 1997). However, our observations indicate that other other monoamines on GP firing rate oscillations were transmitter systems are involved in these electrophysio- investigated. The present data show that augmenting logical effects. For instance, pretreatment with the NEergic or 5-HTergic transmission alone has minor ef- NMDA receptor antagonist MK-801 blocked cocaine’s fects on multisecond periodicities, and confirm the reduction of oscillatory period, suggesting that ongoing dominance of the DA system. These data also confirm activity at NMDA receptors is necessary for this DA- that DA has a primary role among the monoamines for induced effect. This type of NMDA receptor depen- inducing increases in average firing rate in the GP dence has been noted for other electrophysiological ef- (Bergstrom and Walters 1981). Because the DA agonists fects of DA agonists in the basal ganglia (Kelland and used in this study are indirect-acting, i.e. they augment Walters 1992; Allers et al. 1996; Huang et al. 1998), as levels of endogenous transmitter rather than directly well as for other measures of basal ganglia activity (re- activate receptors, these data demonstrate that an in- viewed in Huang et al. 1998). In addition, a comparison crease in endogenous DA is as effective in modulating of the effects of GBR-12909 and cocaine reveals that al- the period and regularity (power) of slow oscillations in though both drugs reduced oscillatory period (from s), only GBR-12909 increased oscillation 10ف s to 30ف -the GP as is direct activation of DA receptors by exoge nous agonists. Work with D-amphetamine and meth- power. Direct-acting DA receptor agonists such as apo- 36 D.N. Ruskin et al. NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 1

Figure 6. The lack of relationship between stimulant effects on oscillatory period effects on net firing rate. Tick marks on the time axes indicate 10-s increments. One minute of binned spiking activity (from several minutes after i.v. cocaine injection) is shown, along with a short epoch of baseline activity for comparison of overall firing rate. Both units have typical, short-period oscillations after cocaine, even though the effects of cocaine on overall firing rate in the two neurons are opposite. The net firing rate of the unit on the left increased by 57% compared to baseline, while the unit on the right responded to cocaine with a 66% decrease in net firing rate. morphine also increase power (Ruskin et al. 1999a). Be- are minor compared with the effects of DA agonists. On cause cocaine blocks uptake of NE and 5-HT, in addi- the other hand, DA antagonists have striking effects tion to DA uptake, these results suggest that increased when administered during pharmacologically-stimu- NE or 5-HT levels might diminish DA-mediated in- lated DA release (Figure 1). Other transmitter systems creases in oscillatory power (while not affecting DA are also involved in supporting slow oscillatory power: modulation of oscillatory period). A number of studies general anesthetics (specifically, urethane and ket- have demonstrated a reduction in DA-stimulated be- amine/xylazine), which affect a number of transmitter haviors by 5-HTergic or NEergic systems (Ungerstedt systems, reduce spectral power in GP spike trains in the 1971; Mabry and Campbell 1973; Grabowska 1976; Fox 1.5–60 s range by 50 to 60% (unpublished results), lead- and Brotchie 1996, 2000; Henry et al. 1998; Rocha et al. ing to a severe decrease in the incidence of statistically 1998; Gainetdinov et al. 1999). More generally, the significant multisecond oscillations (Ruskin et al. 1999a; present results demonstrate that the period and power Ruskin et al. 2001). of multisecond oscillations in the basal ganglia can be The decrease in spectral power after DA antagonist independently affected, in agreement with a previous administration was partially reversed by subsequent study of DA agonist effects in another basal ganglia re- cocaine injection. Such data suggest that the non- gion, the entopeduncular nucleus (Ruskin et al. 1999b). dopaminergic effects of cocaine can increase multisec- In addition to being modulated by increased DAer- ond spectral power in the absence of DAergic tone. To- gic transmission, ongoing multisecond oscillations ap- gether with the comparison of the effects of GBR-12909 pear to partially depend on tonic DAergic and and cocaine (which indicate a decrease of DA-stimulated glutamatergic activity. This dependence is reflected in multisecond spectral power), the results suggest a ‘nor- decrease in oscillatory power after malizing’ effect of 5-HT or NE release on the DAergic %15ف the significant treatment with combined D1/D2 receptor antagonists or modulation of slow oscillatory power. This effect of a NMDA receptor antagonist. Interestingly, although 5-HT or NE appears to depend on tonic NMDA recep- these treatments blocked the effects of cocaine on oscil- tor activity, since there is no increase in spectral power latory period, they did not affect oscillatory period after cocaine injection after prior injection of MK-801. when given alone (similarly, oscillatory period in the Multisecond periodicities have been noted in blood subthalamic nucleus is not affected by decreased DAer- pressure (termed Mayer waves) and heart rate (Barnes gic transmission due to lesion of midbrain DA neurons and Burnham 1969; Mautner-Huppert et al. 1989). It is (Allers et al. 2000)). Since spectral power reflects oscilla- possible that these peripheral oscillations might some- tory regularity, the results suggest that tonic DAergic how drive central multisecond oscillations. However, it and glutamatergic (NMDA) tone partially supports the has recently been reported that desipramine, adminis- regularity of ongoing slow oscillations. The level of tered i.v. to awake rats at one of the presently tested DAergic tone in these immobilized rats is not likely to doses (2.0 mg/kg), induces particularly strong arterial be higher than normal, since firing rates of substantia pressure oscillations in the 10-s range (Bertram et al. nigra pars compacta DA neurons are not significantly 1999). Since, in the present study, desipramine pro- increased in immobilized rats compared to anesthe- duced (at best) inconsistent effects on oscillatory period tized rats (Melis et al. 1998), and since, regarding multi- and power, it seems probable that the multisecond os- second oscillations, the effects of DA antagonists alone cillations in activity in the basal ganglia are not simply (no change in period, small-magnitude power decrease) secondary to peripheral cardiovascular oscillations. In NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 1 Dopamine Effects on Pallidal Oscillations 37

addition, the DA receptors that modulate basal ganglia latory activity, as spatially distant basal ganglia neu- multisecond oscillations are located centrally, not pe- rons can have similar periods with constant phase rela- ripherally (Ruskin et al. 1999a; Ruskin et al. 1999c). tionships (Allers et al. 1999; Ruskin et al. 2000). In terms of mechanisms of the DAergic modulation Although wavelet analysis has been increasingly uti- of slow oscillations, it is important to note that drug ef- lized for analysis of electroencephalographic signals, fects on oscillatory period were not related to drug ef- fewer studies have used this technique for analysis of fects on overall firing rate. In other neuronal systems single unit data. Many of these latter studies have uti- and frequency ranges, the rate of oscillatory spiking ac- lized wavelets for spike sorting (Zouridakis and Tam tivity or the rate of periodic bursting is positively corre- 1997) or denoising (Koshiya and Smith 1999) applica- lated with the level of depolarization (Leresche et al. tions, rather than for analyzing neuronal spiking in the 1991; Beurrier et al. 1999; Koshiya and Smith 1999), im- time-frequency domain (Przybyszewski 1991; Lewalle et plying a voltage-dependent mechanism. Such a rela- al. 1995). Here, wavelet analysis successfully revealed tionship is not apparent for multisecond periodicities in multisecond periodicities in GP spiking activity, and the GP. Although treatments that increased oscillatory complemented our standard spectral analysis technique, frequency also increased mean firing rate in a majority the Lomb periodogram. Apart from the obvious differ- of neurons, some neurons demonstrated an increased ences in the methodologies (producing time information oscillatory frequency simultaneously with a decreased in the wavelet scalogram, and statistical information in mean firing rate. Additionally, in an earlier study of the Lomb periodogram), these two techniques routinely multisecond oscillations in the GP (Ruskin et al. 1999c), indicated similar oscillatory activity for a given data

D1 agonists were found to increase oscillatory fre- segment. For instance, in Figure 2, Panel A, center, both -s after co 12ف quency without having consistent effects on mean fir- techniques indicate a strong oscillation of ing rate, while D2 agonists modestly increased firing caine injection, while in the baseline epoch depicted in rate without having consistent effects on oscillations. Figure 2, Panel B, left, both methods indicate a lack of Therefore, oscillatory period does not appear to be volt- substantial multisecond oscillatory activity. Yet there age-related for GP neurons when considered as a single are subtle differences between the two methods, such as population. Similar conclusions have been made about the more sensitive detection of the 25-s periodicity by neurons in the entopeduncular nucleus and substantia the Lomb periodogram in Figure 2, Panel A, left. Possi- nigra pars reticulata (Ruskin et al. 1999a). Oscillatory bly the most enlightening use of the wavelet scalogram frequency might be positively linked to depolarization for the present data is to reveal the nature of the multi- in the predominant subpopulation of GP neurons that ple, statistically significant spectral peaks which are increase average firing rate after combined D1/D2 represent in the Lomb periodogram in some cases. In Fig- ceptor activation, and these neurons might drive (via ure 2, Panel B, middle, the Lomb spectrum of a post-co- local axon collaterals) other GP neurons to oscillate at a caine epoch shows a number of spectral peaks with peri- similar speed. However, this scenario seems unlikely, ods ranging from 3.7 to 6.6 s centered on a powerful since there is no correlation between oscillation fre- main peak of 4.9 s. Inspection of the corresponding quency and net firing rate (either absolute or percent of scalogram reveals that the period of the neuron’s strong baseline) after cocaine or GBR-12909 treatment in the oscillatory activity was continuously shifting within the subpopulation with increases in average firing rate analyzed time, with an overall decrease in period. (data not shown). If oscillatory period in the GP is not Hence, in this case the multiple peaks in the Lomb spec- related to membrane voltage, then the mechanisms by trum arise from the period variation of the predominant which DA modulates net firing rate and oscillatory pe- oscillation over time. Alternatively, concerning the riod in the GP must differ. weaker oscillatory activity present in Figure 2, Panel B, Regarding the mechanism of generation of slow oscil- right, the Lomb periodogram indicates three spectral lations, if these oscillations (regardless of period) can peaks of nearly equal strength, at 7.7, 14, and 33 s. The occur in the GP within a wide range of membrane volt- scalogram demonstrates that the 33 s oscillation was ages, then they are likely not generated by voltage- present throughout the analyzed segment, simulta- dependent mechanisms within the GP. Instead, they neously with the 7.7 and 14 s oscillations, which them- might be generated in afferent structures and transmit- selves were segregated to early and later parts of the ted synaptically to the GP, or they might arise from net- segment. Therefore, the presence of multiple spectral work mechanisms within the GP or between the GP peaks can indicate simultaneous oscillations and/or and other structures. There is some evidence for this shifts in oscillation period over time. last hypothesis, as reverberating oscillations have been Periodic oscillations in activity in the seconds-to- found in organotypic co-cultures of GP and subtha- minutes range have been noted in many biological sys- lamic nucleus, albeit at shorter periods (Plenz and Kitai tems, and have been attributed with various functions. 1999). Also, network mechanisms are clearly involved In particular, oscillatory fluctuations in intracellular in correlating (if not also generating) multisecond oscil- levels of the second-messenger calcium are more effi- 38 D.N. Ruskin et al. NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 1

cient than simple changes in mean calcium level for in- Allers KA, Kreiss DS, Walters JR (2000): Multisecond oscilla- ducing gene expression, enzymatic activity and hor- tions in the subthalamic nucleus: effects of apomor- mone secretion in some in vitro systems (Holl et al. phine and dopamine cell lesion. Synapse 38:38–50 1988; Matozaki et al. 1990; Dolmetsch et al. 1998; De Allers KA, Ruskin DN, Bergstrom DA, Molnar LR, Walters Koninck and Schulman 1998; Li et al. 1998; Charles et al. JR (1999): Correlations of multisecond oscillations in firing rate in pairs of basal ganglia neurons. Soc Neurosci ´ 1999; Narenjkar et al. 1999; Tomic et al. 1999). Further- Abstr 25:1929 more, it was hypothesized in some of these studies that the calcium-mediated influence on effector systems is Baek D, Ruskin DN, Bergstrom DA, Walters JR (1999): D-amphetamine (AMPH) and cocaine increase the related to oscillatory frequency. The oscillations in neu- speed of multisecond oscillations in globus pallidus ronal firing rate in the present study presumably drive (GP) unit activity. Soc Neurosci Abstr 25:1819 slow variations in intracellular calcium concentration Barbieri EJ, Ferko AP, DeGregorio GJ, Ruch EK (1992): The which might be functionally significant; however, they presence of cocaine and benzoylecgonine in rat cere- are likely to have effects beyond signal transduction, brospinal fluid after the intravenous administration of namely at systems and behavioral levels. Such promi- cocaine. Life Sci 51:1739–1746 nent temporal patterning in basal ganglia spiking activ- Barnes CD, Burnham E (1969): The reflection of third order ity is likely to be associated with corresponding pat- blood pressure waves in the lumbar monosynaptic terning in activity of other forebrain regions (via the reflex. Brain Res 13:183–186 basal ganglia ouput pathways), and so to modulation of Baumann MH, Char GU, De Costa BR, Rice KC, Rothman cognition and behavior. Cocaine and GBR-12909 (as RB (1994): GBR12909 attenuates cocaine-induced activa- well as D-amphetamine and methylphenidate) induce tion of mesolimbic dopamine neurons in the rat. J Phar- macol Exp Ther 271:1216–1222 stereotyped sniffing and oral movements, stereotyped locomotion, and perseveration during the execution of Bergman J, Madras BK, Johnson SE, Spealman RD (1989): learned motor behaviors (Kokkinidis and Anisman Effects of cocaine and related drugs in nonhuman primates. III. Self-administration by squirrel monkeys. J 1976; Ridley et al. 1981; Mueller et al. 1989; Paulus et al. Pharmacol Exp Ther 251:150–155 1993; Rosenzweig-Lipson et al. 1994; present results) in Bergstrom DA, Walters JR (1981): Neuronal responses of the rodents and non-human primates. Cocaine or amphet- globus pallidus to systemic administration of d-amphetamine intoxication in humans can lead to similar be- amine: investigation of the involvement of dopamine, haviors (reviewed in Lyon and Robbins 1975). GP neu- norepinephrine, and serotonin. J Neurosci 1:292–299 rons are well-characterized as having alterations in Bertram D, Barrès C, Julien C (1999): Effect of desipramine firing rate in relation to movement, so that multisecond on spontaneous arterial pressure oscillations in the rat. oscillations in pallidal firing rate might relate to some Eur J Pharmacol 378:265–271 specific periodicity of limb or body movement, or mo- Beurrier C, Congar P, Bioulac B, Hammond C (1999): Sub- tor state. Such relationships will need to be character- thalamic nucleus neurons switch from single-spike ized in studies of freely-moving animals. In addition to activity to burst-firing mode. J Neurosci 19:599–609 motor effects, cocaine, amphetamine and methylpheni- Charles AC, Piros ET, Evans CJ, Hales TG (1999): L-type ϩ ϩ date all produce a ‘high’ or ‘rush’ at sufficient doses in Ca2 channels and K channels specifically modulate 2ϩ humans, and continued usage typically leads to addic- the frequency and amplitude of spontaneous Ca oscil- tion. In studies of rodents and non-human primates, all lations and have distinct roles in prolactin release in GH cells. J Biol Chem 274:7508–7515 these stimulants as well as GBR-12909 (Bergman et al. 3 1989; Roberts 1993) support self-administration. The Church WH, Justice Jr JB, Byrd LD (1987): Extracellular dopamine in rat striatum following uptake inhibition similarity of the effects of these drugs on basal ganglia by cocaine, nomifensine and benztropine. Eur J Phar- multisecond oscillations, and their common effects on macol 139:345–348 these behaviors, suggests that abnormal multisecond De Koninck P, Schulman H (1998): Sensitivity of CaM kinase II patterning in the forebrain (with shifted frequency to the frequency of Ca2ϩ oscillations. Science 279:227–230 range and/or increased power) might relate to the Dolmetsch RE, Xu K, Lewis RS (1998): Calcium oscillations acute motor and affective/cognitive effects of stimulant increase the efficiency and specificity of gene expres- treatment, and might represent a state of brain activity sion. Nature 392:933–936 which induces or augments addictive processes. Engberg G, Elverfors A, Jonason J, Nissbrandt H (1997): Inhibition of dopamine re-uptake: significance for nigral dopamine neuron activity. Synapse 25:215–226 REFERENCES Fink-Jensen A, Ingwersen SH, Nielsen PG, Hansen L, Nielsen EB, Hansen AJ (1994): Halothane anesthesia enhances the effect of dopamine uptake inhibition on Allers KA, Kreiss DS, Twery MJ, Juncos JL, Walters JR (1996): interstitial levels of striatal dopamine. Naunyn The role of glutamate in D1 agonist induced increases of Schmeidebergs Arch Pharmacol 350:239–244 subthalamic nucleus neuronal firing rate: normal vs. 6-OHDA lesioned rats. Soc Neurosci Abstr 22:1200 Fox SH, Brotchie JM (1996): Normethylclozapine potentiates NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 1 Dopamine Effects on Pallidal Oscillations 39

the action of quinpirole in the 6-hydroxydopamine catecholamine-induced behavioral arousal. Brain Res lesioned rat. Eur J Pharmacol 301:27–30 49:381–391

Fox SH, Brotchie JM (2000): 5-HT2C receptor antagonists Matozaki T, Göke B, Tsunoda Y, Rodriguez M, Martinez J, enhance the behavioural response to dopamine D1 Williams JA (1990): Two functionally distinct cholecys- receptor agonists in the 6-hydroxydopamine-lesioned tokinin receptors show different modes of actions on rat. Eur J Pharmacol 398:59–64 Ca2ϩ mobilization and phospholipid hydrolysis in iso- Gainetdinov RR, Wetsel WC, Jones SR, Levin ED, Jaber M, lated rat pancreatic acini. J Biol Chem 265:6247–6254 Caron MG (1999): Role of serotonin in the paradoxical Mautner-Huppert D, Haberl RL, Dirnagl U, Villringer A, calming effects of psychostimulants on hyperactivity. Schmiedek P, Einhäupl K (1989): B-waves in healthy Science 283:397–401 persons. Neurol Res 11:194–196 Grabowska M (1976): The involvement of serotonin in the Melis M, Mereu G, Lilliu V, Quartu M, Diana M, Gessa GL mechanism of central action of apomorphine. Pol J (1998): Haloperidol does not produce dopamine cell Pharmacol Pharm 28:389–394 depolarization-block in paralyzed, unanesthetized rats. Henry B, Crossman AR, Brotchie JM (1998): Characterization Brain Res 783:127–132 of enhanced behavioral responses to L-DOPA following Mueller K, Hollingsworth EM, Cross DR (1989): Another repeated administration in the 6-hydroxydopamine- look at amphetamine-induced stereotyped locomotor lesioned rat model of Parkinson’s disease. Exp Neurol activity in rats using a new statistic to measure locomo- 151:334–342 tor stereotypy. Psychopharmacology 97:74–79 Holl RW, Thorner MO, Mandell GL, Sullivan JA, Sinha YM, Narenjkar J, Marsh SJ, Assem ESK (1999): The characteriza- Leong DA (1988): Spontaneous oscillations of intracel- tion and quantification of antigen-induced Ca2ϩ oscilla- lular calcium and growth hormone secretion. J Biol tions in a rat basophilic leukaemia cell line (RBL-2H3). Chem 263:9682–9685 Cell Calcium 26:261–269 Huang K-X, Bergstrom DA, Ruskin DN, Walters JR (1998): Paulus MP, Callaway CW, Geyer MA (1993): Quantitative N-methyl-D-aspartate receptor blockade attenuates D1 assessment of the microstructure of rat behavior: II. Dis- dopamine receptor modulation of neuronal activity in tinctive effects of dopamine releasers and uptake inhibi- rat substantia nigra. Synapse 30:18–29 tors. Psychopharmacology 113:187–198 Kaneoke Y, Vitek JL (1996): Burst and oscillation as dispar- Plenz D, Kitai ST (1999): A basal ganglia pacemaker formed ate neuronal properties. J Neurosci Meth 68:211–223 by the subthalamic nucleus and external globus palli- Kelland MD, Soltis RP, Anderson LA, Bergstrom DA, dus. Nature 400:677–682 Walters JR (1995): In vivo characterization of two cell Przybyszewski AW (1991): An analysis of the oscillatory types in the rat globus pallidus which have opposite patterns in the central nervous system with the wavelet responses to dopamine receptor stimulation: compari- method. J Neurosci Meth 38:247–257 son of electrophysiological properties and responses to Ridley RM, Baker HF, Haystead TA (1981): Perseverative apomorphine, dizocilpine, and ketamine anesthesia. behaviour after amphetamine; dissociation of response Synapse 20:338–350 tendency from reward association. Psychopharmacol- Kelland Sr MD, Walters JR (1992): Apomorphine-induced ogy 75:283–286 changes in striatal and pallidal neuronal activity are Roberts DCS (1993): Self-administration of GBR-12909 on a modified by NMDA and muscarinic receptor blockade. fixed-ratio and progressive ratio schedule in rats. Psy- Life Sci 50:PL179–184 chopharmacology 111:202–206 Kokkinidis L, Anisman H (1976): Interaction between cho- Rocha BA, Scearce-Levie K, Lucas JJ, Hiroi N, Castanon N, linergic and catecholaminergic agents in a spontaneous Crabbe JC, Nestler EJ, Hen R (1998): Increased vulnera- alternation task. Psychopharmacology 48:261–270 bility to cocaine in mice lacking the serotonin-1B recep- Koshiya N, Smith JC (1999): Neuronal pacemaker for breath- tor. Nature 393:175–178 ing visualized in vitro. Nature 400:360–363 Rosenzweig-Lipson S, Hesterberg P, Bergman J (1994): Leresche N, Lightowler S, Soltesz I, Jassik-Gerschenfeld D, Observational studies of dopamine D1 and D2 agonists Crunelli V (1991): Low-frequency oscillatory activities in squirrel monkeys. Psychopharmacology 116:9–18 intrinsic to rat and cat thalamocortical cells. J Physiol Ruskin DN, Bergstrom DA, Kaneoke Y, Patel BN, Twery MJ, 441:155–174 Walters JR (1999a): Multisecond oscillations in firing Lewalle J, Peek FW, Murphy SJ (1995): Wavelet analysis of rate in the basal ganglia: Robust modulation by dopa- olfactory nerve response to stimulus. J Theor Biol mine receptor activation and anesthesia. J Neurophysiol 177:215–236 81:2046–2055 Li W-h, Llopis J, Whitney M, Zlokarnik G, Tsien RY (1998): Ruskin DN, Bergstrom DA, Shenker A, Freeman LE, Baek D, Cell-permeant caged InsP3 ester shows that Ca2ϩ spike Walters JR (2001): Drugs used in the treatment of atten- frequency can optimize gene expression. Nature tion-deficit/hyperactivity disorder affect postsynaptic 392:936–941 firing rate and oscillation without preferential dopa- Lyon M, Robbins T (1975): The action of central nervous sys- mine autoreceptor action. Biol Psychiatry, 49:340–350 tem stimulant drugs: a general theory concerning Ruskin DN, Bergstrom DA, Walters JR (1999b): Firing rates amphetamine effects. In Essman WB, Valzelli L (eds), and multisecond oscillations in the rodent entopedun- Current Developments in Psychopharmacology, Vol. 2. cular nucleus (EPN): effects of dopamine (DA) agonists New York, Spectrum Publications, Inc., pp 80–163 and nigrostriatal lesion. Soc Neurosci Abstr 25:1929 Mabry PD, Campbell BA (1973): Serotonergic inhibition of Ruskin DN, Bergstrom DA, Walters JR (1999c): Multisecond 40 D.N. Ruskin et al. NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 1

oscillations in firing rate in the globus pallidus: syner- Tomic´ M, Koshimizu T-a, Yuan D, Andric SA, Zivadinovic gistic modulation by D1 and D2 dopamine receptors. J D, Stojilkovic SS (1999): Characterization of a plasma Pharmacol Exp Ther 290:1493–1501 membrane calcium oscillator in rat pituitary somatotro- Ruskin DN, Bergstrom DA, Walters JR (2000): Spatially dis- phs. J Biol Chem 274:35693–35702 tant neurons in the basal ganglia can demonstrate corre- Ungerstedt U (1971): Striatal dopamine release after amphet- lated multisecond periodicities in firing rate in vivo. amine or nerve degeneration revealed by rotational Winter Conference on Brain Research; Breckenridge, behavior. Acta Physiol Scand Suppl 367:49–68 Colorado. Wichmann T, Bergman H, Kliem MA, Soares J, DeLong MR (1999): Low-frequency oscillatory discharge in the pri- Ruskin DN, Rawji SS, Walters JR (1998): Effects of full D1 dopamine receptor agonists on firing rates in the globus mate substantia nigra pars reticulata (SNr) in the nor- pallidus and substantia nigra pars compacta in vivo: mal and parkinsonian state. Soc Neurosci Abstr 25: 1928 tests for D1 receptor selectivity and comparisons in the partial agonist SKF 38393. J Pharmacol Exp Ther Zouridakis G, Tam DC (1997): Multi-unit spike discrimination 286:272–281 using wavelet transforms. Comput Biol Med 27:9–18