Specific modulation of brain stimulation reward by haloperidol

Pharmacology Btochemtstry& Behavtor, Vol 10, pp. 93%940 Printed in the U S.A

Specific Modulation of Brain Stimulation Reward by Haloperidol I RALPH UMBERTO

E S P O S I T O 2, W I L L I A M

FAULKNER

AND CONAN KORNETSKY 3

Laboratory. of Behavioral Pharmacology, Boston University School of Medicine, Boston MA 02118 ( R e c e i v e d 31 M a r c h 1979) ESPOSITO, R. U., W. F A U L K N E R AND C. KORNETSKY. Spectfic rnodulatton of brain sttrnulaoon reward by halopertdol. PHARMAC. BIOCHEM. BEHAV. 10(6)937-940, 1979.--Low doses of haloperidol (3-18 p,g/kg) caused dose related increases in reinforcing thresholds for self-stimulation to the medial forebrain bundle in rats. These effects, which were demonstrated completely independent of performance variables, indicate a direct modulation of central reinforcement processes by this drug, at doses which have highly selective action on dopaminerglc neurotransmlssion.

Haloperidol

Self-stimulation

Reinforcement thresholds

S E V E R A L converging lines o f research (i.e., anatomical, lesion, pharmacological) have rendered support to the hypothesis that the catecholamines are somehow critically involved in the phenomenon of brain stimulation reward [8,11]. Although there is widespread agreement that pharmacological interference with central dopamine systems will result in a general suppression of self-stimulation behavior, a remaining critical question is whether such suppression is due to an alteration of the rewarding value of the stimulation itself or alternatively to an impaired ability of the organism to perform the necessary operant response required to receive such stimulation. Evidence in favor of the specific reward explanation has recently been summarized by Wise [24]. Although cogent, this evidence is largely inferential (i.e. analysis of "extinction" patterns after drug administration), and to date there is no direct evidence demonstrating a neuroleptic induced alteration of self-stimulation behavior completely independent of motor impairment. After critically reviewing the evidence bearing on this issue, Fibiger [ I0] has concluded that resolution of the question will require techniques that clearly differentiate between the effects of drugs on motor function and central reinforcement processes. We presently report data demonstrating haloperidol induced increases in reinforcing thresholds for brain stimulation reward, completely independent of motor involvement. METHOD

Animals and Apparatus F o u r male a l b i n o F i s c h e r rats (Charles R i v e r Breeding Laboratories), weighing approximately 300 g, were stereotaxically implanted with bipolar stainless steel electrodes (0.0127 cm in dia. and insulated except at the tips).

Dopamine

The electrodes were aimed at the M F B - L H . Prior to surgery all animals were anesthetized with Equi-Thesin (0.3 ml/100 g body weight). Coordinates from bregma were - 4 . 0 mm, anterior-posterior; _+ 1.4 mm, lateral from the midline suture; and - 8 . 5 mm, dorsal-ventral from the skull surface. The skull surface was levelled between bregma and lambda. The animals were trained on a threshold procedure in a Plexiglas chamber (20x20 cm). Mounted in an opening in one wall of the chamber was a wheel manipulandum which was 15 cm long and 7.5 cm in diameter. Four equally spaced cams were positioned on one of the end plates such that they operated a microswitch when the wheel was rotated. Reinforcement was obtained only after closure of the microswitch (1/4 wheel turn). A constant current stimulator was used to deliver the stimuli which consisted of half-second trains of biphasic symmetrical pulses. Each train occurred at a frequency of 160 Hertz, with a pulse width of 0.2 msec, and a delay of 0.2 msec between the positive and negative pulses. Pulse amplitude was varied according to the procedural requirements for threshold determination.

Procedure Determination of the threshold involved a discrete trial procedure identical in part to that used previously [9]. A trial began with the delivery of a noncontingent 0.5 see pulse train. A response within 7.5 sec of this stimulus resulted in immediate delivery of a contingent stimulus, identical in all parameters to the noncontingent stimulus, and terminated the trial. Failure to respond has no scheduled consequences, and the trial terminated after 7.5 sec. Intervals between trials varied, with an average of 15 sec. Responses during the inter-trial interval resulted in a 15-sec delay before the start of the next trial. The initial noncontingent stimulation thus

tWork supported by NIMH Grant MH 12568

2Fellow, NSRA B~ological Science Training Program MH 15189 3NIMH Research Scientist Awardee, MH 1759

C o p y r i g h t © 1979 A N K H O

I n t e r n a t i o n a l Inc.--0091-3057/79/060937-04500.90/0

938

ESPOSITO, F A U L K N E R AND KORNETSKY

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20

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Saline

3

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18 Pg/kg

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FIG. 1. Dose response data for all ammals. The vertical bars to the left indicate the mean and standard deviation of percentage change value for a number (8-10) of sahne control days Doses of drug admimstered are expressed in microgram/kilogram values, and plotted on a logarithmic scale on the abossa. All injections were via the subcutaneous route. The arrows for animals 336 and 339, at the 18/xg/kg dose, indicate a lack of responding up to a level of 250/xa, the highest mtenstty employed. These ammals, however, showed no gross mgns of sedation at this dose level.

served both as a discriminative stimulus indicating availability of response-contingent stimulation, and as a comparative stimulus in the sense that it was a predictor of the parameters of the contingent stimulus. The latency to respond (time interval between the non-contingent stimulus and wheelturning) was determined for each trial in which the animals responded. Total inter-trial or error responses were also calculated. These measures allowed for an assessment of behavioral impairment or disruptive responding. Stimulus intensities for the threshold determinations were varied according to the classical method of limits with slight modification. Stimuli were presented in alternating descending and ascending series with a step size of 10/.tA. Ten trials were given in succession at each step size or interval. A descending series was initiated at a previously determined intensity which invariably yielded a contingent response in at least nine out of ten trials, and then ten more successive trials were conducted at the next lowest interval and so on. Five or more responses at a particular intensity were arbitrarily scored as a plus for the interval, while less than five responses were scored as a minus for the interval. Descending series were conducted until minus scores were achieved in two successive intervals. An ascending series was started at one step size below the lowest intensity in the descending series, and continued until plus scores were achieved in two successive intervals, whereupon a descending series would

be initiated at one interval above the last mtensity used in the ascending series. Threshold was determined by calculating the arithmetic mean (~) in microampers of the midpoints between the intervals in which the animal made greater than five responses (a plus score) and less than five responses (a minus score). Each day the animals were given four test series (Session 1) before, and four test series (Session 2) after they were injected. After Session 1, the animals were injected subcutaneously with either saline or the drug, and then allowed 10 minutes to rest in the chamber before Session 2 was begun. The time needed to complete Session 1 or Session 2 varied from 60-90 minutes. The critical dependent measure was the percentage change in threshold from Session 1 to Session 2. (The percentage change was calculated as the Session 2 threshold minus the Session 1 threshold x 100 divided by the Session 1 threshold.J The animals were trained until their thresholds stabilized and then were run for at least 4 days to determine the extent of the changes that occurred between Sessions I and 2 when the animals were injected with saline. They were then injected subcutaneously on test days with various single doses of haloperidol. Haloperidol was dissolved in 0.1 molar tartaric acid, diluted with isotonic saline and buffered with sodium hydroxide (pH=5.6). In between drug test days the animals were again tested after saline injections.

HALOPERIDOL

AND BRAIN STIMULATION

939

REWARD TABLE 1

LATENCY* OF RESPONSE IN SECONDS AT THRESHOLD, PRE AND POST, AT DOSES OF 6, 12.5, AND 18 g.G/KG DOSES OF HALOPERIDOL Animal

Dose gg/kg

Pre

Post

t

962

6 12.5 18

4.59 ± 0.23 4.82 ± 0.33 5.57 _+0.38

4.51 ± 0.20 4.83 ± 0.59 4.59 ± 0.35

0.26 -0.01 1.90

337

6 12.5 18

4.33 ± 0.30 4.95 -+ 0.32 3.09 ± 0.42

4.80 ± 0.40 4.14 ± 0.23 5.02 ± 0.39

- 0 94 2.06 -3.37

336

6 12 5 18

4.77 ± 0.38 3.74 ± 0.31 ?

4.16 ± 0.38 2.67 ± 0.43 ~"

1.14 2.02

339

6 12.5 18

4.55 _+0 36 4.76 ± 0.42

4.59 ± 0.60 3.38 ± 0.44

-0.06 2.27

t

t

(p<0.05) (p<0 01)

(p<0.05)

*Latency represents the average value at threshold intensity. When the threshold value did not fall on one of the 10 #A intervals, the value was rounded off to the nearest interval, and the latency value based on that interval. Latency values are presented as the mean (+- ISEM). tlndicates that too few responses were made m the postsession to make a meaningful comparison.

TABLE 2

RESULTS

NUMBER OF INTER-TRIAL (ERROR) RESPONSES, PRE AND POST, FOR ALL ANIMALS AT THE DOSES OF 6, 12.5, AND 18 p.G/KG OF HALOPERIDOL BOTH PRE A N D POSTSESSIONS CONSISTED OF APPROXIMATELY 200 TRIALS.

T h e effects of h a l o p e r i d o l o n self-stimulation t h r e s h o l d s are illustrated in Fig. 1. A s c a n be seen, t h r o u g h t h e d o s e r a n g e o f 6-18 /~g/kg, t h e r e w e r e c l e a r - c u t i n c r e a s e s in the r e i n f o r c i n g t h r e s h o l d s . It is o f i n t e r e s t to n o t e t h a t t h e s e d o s e s o f h a l o p e r i d o l are significantly b e l o w t h o s e f o u n d to c a u s e rate s u p p r e s s i o n in studies i n v o l v i n g l e v e r - p r e s s i n g for b r a i n s t i m u l a t i o n r e w a r d (e.g. [23]). T h e p a t t e r n o f r e s p o n d i n g a f t e r drug a d m i n i s t r a t i o n s u g g e s t e d a n ' e x t i n c t i o n p a t t e r n r a t h e r t h a n a failure to d e t e c t the b r a i n s t i m u l a t i o n . Typically, o n a d e s c e n d i n g series, t h e a n i m a l s w o u l d give a few r e s p o n s e s at the s u b - t h r e s h o l d intensity, a n d t h e n c e a s e to r e s p o n d entirely. T h r e s h o l d i n c r e a s e s w e r e u n a c c o m p a n i e d b y i n c r e a s e s in r e s p o n s e l a t e n c i e s ( T a b l e 1). In fact, t h e r e w e r e i n s t a n c e s o f significant t h r e s h o l d i n c r e a s e s with c o n c o m i t a n t d e c r e a s e s in r e s p o n s e latencies. L i k e w i s e the drug h a d n o c o n s i s t e n t effect o n inter-trial or e r r o r r e s p o n d i n g ( T a b l e 2), a n d u p o n o b s e r v a t i o n t h e a n i m a l s r e v e a l e d n o o v e r t signs o f s e d a t i o n .

Animal

Dose ~tg/kg

Pre

Post

962

6 125 18

11 7 4

15 10 29

337

6 12.5 18

10 5 18

5 5 12

336

6 12.5 18

12 7 *

5 10 *

339

6 12.5 18

2 6 *

7 5 *

*Indicates that too few responses were made m the postsession to make a meaningful comparison

F o l l o w i n g t e s t i n g the a n i m a l s w e r e sacrificed a n d perf u s e d i n t r a c a r d i a l l y with saline a n d t h e n formalin. T h e b r a i n s w e r e s u b s e q u e n t l y r e m o v e d f r o m the skull, fixed, e m b e d d e d , a n d sliced at 4 0 / z . M o u n t e d s e c t i o n s w e r e s t a i n e d with cresyl violet a n d luxol blue a n d e x a m i n e d u n d e r a light m i c r o s c o p e . T h e e l e c t r o d e tips w e r e l o c a t e d w i t h i n the M F B at t h e level o f the L H .

DISCUSSION T h e specific n a t u r e o f t h e s e effects was m a d e e v i d e n t b y t h e o c c u r r e n c e o f t h r e s h o l d i n c r e a s e s in t h e a b s e n c e o f conc u r r e n t i n c r e a s e s in r e s p o n s e l a t e n c i e s o r inter-trial res p o n s e s . T h e s e o b s e r v a t i o n s m a k e it u n t e n a b l e to e x p l a i n t h e s e results o n the b a s i s o f a general p e r f o r m a n c e impairment. T h e e x t r e m e l y low d o s e s o f h a l o p e r i d o l e m p l o y e d in this s t u d y h a v e b e e n s h o w n to h a v e highly s e l e c t i v e effects o n dopaminergic neurotransmission [1, 2, 4, 22]. Although possible n o r a d r e n e r g i c [21], a d r e n e r g i c [12,13], s e r o t o n e r g i c [16, 17, 18], a n d p e p t i d e r g i c [3] i n f l u e n c e s o n self-stimulation b e h a v ior c a n n o t b e e x c l u d e d , t h e p r e s e n t results a r g u e for a d i r e c t role for d o p a m i n e in t h e m o d u l a t i o n of b r a i n s t i m u l a t i o n re-

940

ESPOSITO, FAULKNER

w a r d , in a g r e e m e n t with earlier studies that h a d s u g g e s t e d such a p o s s i b d i t y [6,14]. A l t h o u g h the role t h a t d o p a m i n e m a y play in the r e i n f o r c e m e n t p r o c e s s r e m a i n s u n s p e c i f i e d , a n u m b e r of related findings p r o v i d e s o m e b a s i s for speculation. First, it is n o t e w o r t h y t h a t p r e v i o u s w o r k h a s f o u n d a strikingly high c o r r e l a t m n b e t w e e n t h e ED~0 v a l u e s for n e u r o l e p t i c i n d u c e d inhibition o f self-stimulation a n d ED~,, v a l u e s for r e v e r s a l o f a m p h e t a m i n e i n d u c e d s t e r e o t y p y [23]. F u r t h e r , t h e r e is e v i d e n c e w h i c h indicates a n i m p o r t a n t role for the nigostriatal d o p a m i n e s y s t e m in t h e m e d i a t i o n o f amp h e t a m i n e i n d u c e d s t e r e o t y p y (e.g. [5]). This d o p a m i n e syst e m is i n v o l v e d in s e n s o r y - m o t o r i n t e g r a t i o n [15], a n d also h a s b e e n implicated in self-stimulation o n the b a s i s o f mapping, a n a t o m i c a l , a n d lesion studies [7, 11, 19, 20]. T h u s ,

AND KORNETSKY

h a l o p e r i d o l m a y e l e v a t e s e l f - s t i m u l a t m n t h r e s h o l d s by subtly d i s r u p t i n g h i g h e r o r d e r s e n s o r y - m o t o r m t e g r a t i o n . As W a u q u i e r [23] h a s suggested, n e u r o l e p t i c t r e a t e d rats m a y be u n a b l e to relate b e h a v i o r with its c o n s e q u e n c e s in situations i n v o l v i n g relatively c o m p l e x b e h a v i o r s . In this s e n s e h a l o p e r i d o l m a y d i s r u p t the c o n t i n g e n c y b e t w e e n a n o p e r a n t a n d / o r i n s t r u m e n t a l r e s p o n s e a n d its c o n s e q u e n c e . A h i g h e r d e g r e e o f stimulus " v a l u e " ( i n c r e a s e d stimulus i n t e n s i t y in o u r e x p e r i m e n t ) w o u l d thus be r e q u i r e d in o r d e r to ree s t a b l i s h the r e l e v a n t s t i m u l u s - r e s p o n s e relationship. This a t t a c h m e n t o f stimulus " v a l u e " to a p p r o p r i a t e r e s p o n s e o u t p u t m a y also i n v o l v e o t h e r b r a i n d o p a m i n e s y s t e m s such as t h e m e s o - l i m b i c a n d / o r m e s o - c o r t i c a l fibers,

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