Unilateral dopamine depletions attenuate the response of striatal neurons to systemic amphetamine in both hemispheres

0306-4522/8553.00+ 0.00 Pergamon Press Ltd 0 1985IBRO

NeuroscienceVol. 16, No. 4, pp. 845-850, 1985 Printed in Great Britain

UNILATERAL DOPAMINE DEPLETIONS ATTENUATE THE RESPONSE OF STRIATAL NEURONS TO SYSTEMIC AMPHETAMINE IN BOTH HEMISPHERES A. E. BASSE-TOMUSKand G. V. REBEC* Department of Psychology, Indiana University, Bloomington, IN 47405, U.S.A.

Abstract-Neuronal activity was recorded bilaterally from the striatum of intact control animals and rats pretreated l&l5 days earlier with a unilateral intranigral injection of 6-hydroxydopamine. Following isolation of single unit discharges, each group was challenged with intravenous injections of 0.2 mg kg-’ d-amphetamine administered at 2-min intervals. Striatal neurons from intact control animals responded to amphetamine with equal numbers of inhibitions and excitations. In contrast, the predominant response in the animals with lesions was no response at all even with a total cumulative dose of

2.0 mg kg-‘. Approximately 50% of the neurons in each striatum of the rats with unilateral lesions failed to respond to amphetamine despite a greater than 98% difference in dopamine levels between hemispheres. The remaining neurons in these animals responded as in intact controls. These results suggest that some functional change occurs following unilateral dopamine depletion that acts to decrease the response of neurons to amphetamine in both the intact and the dopamine-depleted striatum.

(DA) from nerve terminals in one striatum is regulated, at least in part, by the extent of DA release in the other. Nieoullon et a[.” reported that unilateral electrocoagulation of the nigrostriatal bundle, which abolished DA release on the side of the lesion, caused a simultaneous increase in DA release in the contralateral structure. A similar hemispheric interaction was seen during unilateral intranigral infusions of amphetamine or benztropine.” These drugs, which cause a decrease in striatal DA release in the hemisphere ipsilateral to the infusion, also cause an increase in the contralateral striatum. Conversely, activation of striatal DA release by nigral application of neuroleptics produces the opposite effect.” Thus, despite an ipsilateral DA projection from the substantia nigra pars compacta to the striatum, a unilateral change in DA release causes a reciprocal change in the contralateral striatum. This phenomenon is accompanied by parallel changes in the activity of striatal neurons. We have shown, for example, that a unilateral infusion of amphetamine into the substantia nigra pars compacta accelerates the firing rate of neurons in the ipsilateral striatum, I’ but exerts the opposite effect on the contralateral side.j’ To the extent that DA acts as an inhibitory transmitter, 3othese results further support a reciprocal interaction between hemispheric DA release. To shed further light on this interaction, we administered amphetamine systemically and recorded neuronal activity bilaterally in the striatum of rats -_

that sustained a unilateral DA-depleting lesion and in intact controls.

The release of dopamine

DA, dopamine; DHBA, dihydroxybenzylamine. *To whom correspondence should be addressed.

Abbreviafions:

EXPERIMENTAL PROCEDURES Data were obtained from male, Sprague-Dawley rats (Harlan Industries, Indianapolis, Indiana) weighing between 300 and 500g and housed individually under standard laboratory conditions. One group of animals was anesthetized with chloral hydrate and pentobarbital (Chloropent, Fort Dodge), supplemented with 10.0 mg kg-’ atropine (Sigma) and mounted in a stereotaxic frame. Following exposure of the calvarium, a burr hole was drilled overlying the left substantia nigra pars compacta (approximately I.7 mm lateral and 2.8 mm anterior to lambda). A stainless steel infusion cannula (26-gauge) connected to a programmable infusion pump was lowered 7.6mm ventral to the dural surface. We infused 8.0~8 6-hydroxydopamine hydrobromide (Sigma) and 3 fig ascorbic acid in a total volume of 4~1 normal saline over a IO-min period. To minimize diffusion up the cannula track, five additional minutes were allowed to elapse before the cannula was removed. Upon completion of the surgery, 100,000 units benzathine penicillin (Bicillin; Wyeth) were administered intramuscularly to prevent infection. Following a recovery period of 5-8 days, the animals were tested for circling behavior to assess the extent of the lesion. preliminary data from our laboratory and elsewhere’,” indicate that a unilateral DA depletion in the striatum of 90% or more is associated with at least 50 net contralateral turns within a 5-min period following a subcutaneous injection of 0.25 mg kg~-’ (free-base) apomorphine hydrochloride (Merck). Rats with lesions that did not meet this criterion were excluded from further analysis. Between 2 to I5 days later, both the rats with lesions and a group of intact animals were prepared for single unit recording, as described previously.‘.‘4.‘h Approximately half of the intact control animals had been pretreated 4--8 days earlier with 0.25 mg kg-’ apomorphine to control for any residual effects that might have been introduced by this treatment during the turning test. The animals were mounted in a stereotaxic frame under ether anesthesia and holes were drilled bilaterally over the striatum (I .Omm anterior

845

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A. E. BAW-TOMUSK and G. V. REBIX

and 2.0mm lateral to bregma).‘” All surgical and stereotaxic contact points were thoroughly intiltrated with local anesthetics, the ether was withdrawn. and c/-tubocurarine hydrochloride (Lilly) was administered via an intravenous (i.v.) femoral catheter to relax all skeletal muscles. Positivcpressure artificial respiration was maintained at a rate and stroke volume that produced end-tidal carbon dioxide levels of 4.0 (iO.5)“/,. Tungsten microelectrodes with impedences ranging from 7 to 10 MR were lowered bilaterally into the anteromedial striatum. Spontaneously active single unit discharges were amplified, filtered (band pass: 0.3 IO kHz), and displayed by conventional means. Neuronal tiring rate was counted on a minute-by-minute basis using a high speed printercounter (Digitec) in conjunction with a neuronal spike analyzer (Mentor). Window discriminators were set to record the activity of a single neuron isolated to a signalto-noise ratio of 3:1 or more as described and illustrated elsewhere.““,” Spontaneously active units typically showed both regular and bursting patterns of activity. Consistent with previous reports,“,‘j,‘“” striatal neurons generated action potentials that were approximately 500 /(V in amplitude and 0.8 ms in duration. Neuronal activity was recorded for IO min to establish a stable baseline which was defined in each case as 100% Animals were then challenged with 0.2 mg kg~ ’ (free-base) d-amphetamine sulfate (Smith. Kline & French) every 2 min for a total of IO i.v. injections. Drug-induced changes in firing rate were calculated for every 2-min injection interval as a percentage change from the 100% baseline. To verify that changes in neuronal activity were not due to cell loss or other non-drug factors. 5.0 mg kg ’ clozapine (Sandoz). which has been shown to reverse the amphetamine response in the striatum.“‘h was administered after the last amphetamine injection. Neuronal activity that failed to return to within 50% of baseline was excluded from data analysis. Upon completion of the experiment. ammals in the control group were given a lethal dose of sodium pentobarbital. Lesions were made at both recording sites bb passing a 5 mA current for 20 s. Following a transcardial perfusion with normal saline and 10% formalin, brains were frozen. sectioned and stained with cresyl violet for histological analysis. The animals with unilateral DAdepleting lesions were decapitated and each striatum removed for analysis of DA levels by liquid chromatography with electrochemical detection. Bilateral tissue plugs were placed in a centrifuge tube containing 200 {tl perchloric acid (HCIO,) and iOO@l 2.0 x IO ‘M dihydroxybenzylamine (DHBA). After sonication of each sample, I ml of 0.5 Tris buffer (pH 8.6) and IO mg of acid-washed alumina were added. Following I5 min of hand inversion and subsequent aspiration of the liquid phase, the alumina was washed th;ee times with I &I aliquots of a solution consisting of 500 ml distilled water. 0.5 ml I.0 M NaHSO, and 5.0 mi 0.5 Tris bufrcr (pH 8.6). After the final wash. the alumina was aspirated dry. To release the catecholamines from the 200111 of 0.2 M perchloric acid (HCIO,) was alumina. added and the solution swirled for 5 min. The supernatant was then injected onto the column. Neurochemical levels were determined according to the following equation:” S = (SH;DHBAH)

x (mol DHBAXissue

mass) x K.

where S represents molts of sample/g brain tissue. SH is the sample height in cm. DHBAH is the height of the internal standard DHBA in cm. moles of DHBA represent the

Table

molar value of the internal standard, and rc’ IS the ratlo 01 heights of equimolar solutions of DHBA and sample. Only those animals showing greater than 9X”+ DA deplc!ion,, were included in the data analyjls

HESUI,TS

Histological analysis of the animals without lesions revealed that all electrode placements were located in the anteromedial striatum between 7.0 and 8.6mm anterior to stereotaxic zeroi and approximately 3.5 to 5.5 mm ventral to the dural surface. Because the striata from the animals with lesions were used for neurochemical analysis (and thus, were not available for histological examination), the same stereotaxic parameters were used for recordings from these rats to insure comparable electrode placements. As shown in Table 1, spontaneous firing rates were slow and irregular in all groups. Note that although neuronal activity in both striata of the animals with unilateral lesions was elevated above that in the intact controls, this effect was not statistically significant (P > 0.05). As shown in Fig. I. intact controls responded to repeated injections of 0.2 mg kg ’ d-amphetamine (i.v.) with increases or decreases in firing rate that in each case exceeded a 40% change from the baseline rate for at least two consecutive injection intervals. Note that these responses were recorded from both untreated controls (n = IO) and from controls pretreated with 0.25 mg kg- ’ apomorphine (n = 1I). In fact, a Fisher Exact Test indicated no significant difference (P > 0.28) in the distribution of increases and decreases in response to amphetamine between these two groups. Moreover. a repeated measures analysis of variance revealed no significant difference in the magnitude of the decreases (P > 0.10) or increases (P > 0.05) exhibited by these different animals. Therefore, the data from both control groups were pooled for all analyses. Unlike the control animals, however, rats with unilateral lesions showed significantly fewer responses to amphetamine and this effect occurred in both hemispheres. A Chi Square test revealed a significant relationship between groups and the distribution of neuronal responses (P < 0.025). Note that approximately half of the neurons in both the intact (n = 14) and the DA-depleted (n = 14) striata of these animals were unresponsive to amphetamine. This occurred despite a vigorous response in the apomorphine turning test that suggested at least a 90% depletion of DA in only one striatum. In fact, subsequent neurochemical analysis using liquid chromatography with electrochemical detection indicated a greater

I. Mean spontaneous

Intact control group Lesioned group-nonlesioned Lesioned group-DA-depleted

striata striata

baseline

firing rates

,1

Spikesmin-’

21 I4 14

(SEM)

86.8 (Ifr 39.6) 148.7 (F40.6) 122.4 ( + 34.6)

Dopamine and hemispheric interactions

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Fig. 1. Percentage of neurons that responded with an increase, decrease or no change in firing rate during iv. challenge with a cumulative dose of 2.0 mg kg-’ amphetamine. Note the increase in the number of unresponsive neurons in both hemispheres following unilateral depletion of DA. APO, apomorphine.

than 98% difference in DA levels between the two striata. This shift toward unresponsiveness in both hemispheres appeared to develop mainly at the expense of amphetamine-induced excitations since the frequency of this response, but not the amphetamineinduced depressions, was attenuated in the animals with lesions. Individual examples of the neuronal response to amphetamine are shown for each group in Fig. 2. Note that in control rats, both the depression (2A) and excitation (2B) began with a cumulative i.v. dose of 0.8 mg kg-’ and became progressively more pronounced as the dose was increased. Note also that a subsequent injection of 5.0 mg kg-’ clozapine reversed these responses. Neurons that were unresponsive to amphetamine were found only in rats with unilateral lesions and this effect was observed in both the intact (2C) and the DA-depleted (2D) striatum. In each case, a total cumulative dose of failed to produce a 2.0 mg kg-’ amphetamine consistent change from the baseline rate. Among those neurons that did respond to amphetamine in the rats with lesions, neither the excitations

Table 2. Maximum

increases expressed

nor the inhibitions were different from the control responses, as shown in Table 2. In all cases, the inhibitions were characterized by at least a 40% reduction in activity from the preinjection baseline rate. The magnitude of the excitations also was comparable in all groups, although in the DA-depleted striatum only one neuron showed this response. DISCUSSION

A large body of evidence indicates that a reduction in DA release in one striatum is accompanied by a corresponding increase in the other.3.4.‘7.‘8.‘9This imbalance, however, does not appear to extend to postsynaptic neurons. At this level, our results suggest that the two striata are remarkably similar. Thus, the neuronal response to amphetamine in the intact striatum of animals with unilateral lesions compares favorably with that obtained from the DA-depleted striatum. In fact, in comparison to its effects in control rats, amphetamine elicits significantly fewer responses in both hemispheres despite a greater than 98% difference in DA levels. Moreover, it is unlikely

and decreases in firing rate in response as a percentage of the baseline rate Mean decrease (SEW

Intact control group (n = 21) Lesioned group-nonlesioned striata (n = 14) Lesioned grouyDA-depleted striata (n = 14)

11.6(f4.2) 14.6 ( + 5.0) 18.3(&6.l)

to amphetamine Mean increase (SEW 413.0(+62.3) 366.4 (k62.9) 188.9(&0.0)

A. E. BASE-TOMUSK and G. V.

848

REBEC

' 0:4 ' 0:s ' 1:2 ' 1:6 ' 2:0 ' CUHULATIVE

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CUHULATIVE

lmg/kgl

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' '

(mg/kgl

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w v,

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(mg/kgl

1 0:2 O:, 0:6 0:6 110 1:2 1:4 I:6 I:6 i CUMULATIVE

AMPH

lmg/kgl

Fig. 2. Illustrative examples of the response of individual neurons in each group. Each animal received 0.2 mg kg-’ d-amphetamine (AMPH) every 2 min. Responses are plotted as a percentage change from the 100% baseline for each 2-min injection interval. A and B show typical responses seen in both the non-pretreated control group and the control group pretreated with 0.25mg kg-’ apomorphine, respectively. Note again the shift toward unresponsiveness in both the inact (C), and DA-depleted (D) striatum of the animals with lesions compared to the responses obtained in the rats without lesions.

that our results in the animals with lesions could be explained by the administration of apomorphine during the turning test since pretreatment with this drug in intact controls failed to alter the neuronal response to amphetamine. Although the number of neurons responding to amphetamine was reduced in both the intact and the DA-depleted striata, the mechanisms responsible for this effect may be different in each case. Thus, whereas a lack of DA presumably mediates the unresponsiveness in the DA-depleted striatum, DA release is actually enhanced in the opposite hemisphere.” Such an effect, however, may reduce the sensitivity of postsynaptic DA receptors and, in that way, reduce the amphetamine response in the intact striatum. Consistent with this view, Costall et al.’ found that while a unilateral infusion of DA into the striatum of normal rats elicited circling behavior, similar infusions into the intact striatum of unilaterally DA-depleted rats failed to cause any turning. Thus, an increased release of DA in the intact striatum may “down-regulate” DA receptors in this site and, as a result, reduce the imbalance in output between each striatum. That increased DA release could produce hyposensitive DA receptors is sup-

ported by evidence that long-term amphetamine treatment, which produces a progressive increase in DA release,*’ reduces the response of striatal neurons to iontophoretic DA.14 Thus, whereas too little DA may account for our results in the lesioned striatum, too much DA associated with postsynaptic receptor subsensitivity may explain our results in the opposite hemisphere. It is impossible, however, to rule out non-DA factors. Schneider et al., 29 for example, failed to detect a change in [3H]spiroperidol binding in the intact striatum of rats that received a unilateral 6-hydroxydopamine lesion. Moreover, several studies have implicated a polysynaptic pathway that may involve thalamic3.4,2” and cortical” structures in the reciprocal control of striatal DA afferents. In addition, striatal neurons are responsive to a wide range of endogenous compounds, many of which are released by amphetamine7,9 and which may be altered by a unilateral DA depletion. Although further research is required to distinguish among these alternatives, it seems clear that the intact striatum of a rat with a unilateral lesion does not function in the same way as the striatum of a naive animal. Thus, the common practice of using the opposite hemisphere as

Dopamine and hemispheric interactions

the only control to study striatal function in rats unilaterally depleted of DA may lead to unwarranted conclusions. Surprisingly, our results also indicate that even a near-total DA depletion in the striatum dose not abolish the amphetamine response completely. In fact, over half the neurons continued to respond to the drug and, when it occurred, this response was comparable in magnitude to that obtained from rats without lesions. These data emphasize the point that conclusions based on the effects of systemic drug injections must be interpreted cautiously. Thus, although it is conceivable that in our rats the small amount of DA remaining after the lesion is acting on supersensitive DA receptors to elicit a full-blown response to amphetamine, or that the drug is acting directly on postsynaptic DA receptors,* it seems equally likely that our results can be explained by an action of amphetamine on systems remote from the striatum. When injected systemically, for example, amphetamine has been reported to alter the firing rate of neurons in the dorsal raphe nucleus,23 the mesencephalic reticular formation,24 medial thalamus’ and the- cerebral cortex,’ all of which modulate striatal firing rate. Moreover, within the striatum, amphetamine increases the release of serotonin’ and ascorbic acid,‘.” and these compounds are known to act directly on striatal neurons.7.‘o.20,2’The changes that occur in striatal activity following systemic amphetamine injections, therefore, may reflect a combination of several neuronal and neurochemical events, only one of which may involve striatal DA.

849

It also is interesting to note that whereas amphetamine-induced decreases in firing rate were similar in number and magnitude in both the rats with and without lesions, the number of excitations was reduced markedly in the animals with lesions, especially in the DA-depleted striatum. In previous recordings from intact animals, we have reported both increases and decreases in striatal activity following amphetamine’~22~26and both types of responses have been blocked by DA antagonists.22.26 That 6-hydroxydopamine appeared to reduce the excitations selectively may indicate a more direct role for DA in this response, although again other interpretations cannot be ruled out. The similarity of the neuronal response to amphetamine in each striatum of rats unilaterally depleted of DA suggests that powerful compensatory mechanisms are at work to insure a balanced striatal output. Further understanding of the mechanisms involved in achieving this balance may shed new light on the operation of the striatum in Parkinson’s disease and other abnormal conditions that involve DA dysfunction.

Acknowledgements-This research was supported by U.S.P.H.S. Grants DA 02451 and SO7 RR07031 (Biomedical Research Support Grant). We wish to thank Dr James Bigelow for helping with the liquid chromatography and Mrs Doris Batson for preparing the histologies. We also acknowledge Smith, Kline & French, and Sandoz Pharmaceuticals for providing the d-amphetamine sulfate and clozapine, respectively.

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V RER~(

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