STUDIES ON THE LOCOMOTOR ACTIVITY PRODUCED BY INJECTION OF DIBUTYRYL CYCLIC 3’5’AMP INTO

THE NUCLEUS ACCUMBENS OF RATS

D. J. HEAL, A. G. PHILLIPS* and A. R. GREEN

MRC Unit and University Department of Clinical Pharmacology. Radcliffe Infirmary. Oxford OX2 6HE. England

(Accepted 19 October 1977)

Summary--Bilateral injection of dibutyryl cyclic AMP (S-25 pg) intracerebrally into the nucleus accumbens of rats produces an increase in co-ordinated locomotor activity lasting about 90 min. and behavioural changes similar to those produced by injection of dopamine. Haloperidol injection (2.5 pg bilaterally) into the n. accumbens I5 min before dibutyryl cyclic AMP (8pg bilaterally) had no effect on the locomotor response but totally abolished the locomotor response to dopamine (5 peg bilaterally) in rats pretreated with tranylcypromine (10 mg/kg i.p.. 30 min before dopamine). The observations are compatible with the hypothesis that dibutyryl cyclic AMP acts “beyond” the dopamine receptor.

Haloperidol (0.05 mg/kg i.p.) inhibited the locomotor response produced by dibutyryl cyclic AMP (12.5 pg bilaterally) injected into the n. accumbens I5 min later. z-Methyl-p-tyrosine (200 mg/kg Lp.) 3 hr before dibutyryl cyclic AMP (12.5 pg bilaterally) also inhibited the locomotor response. These experiments suggest the existence of a dopaminergic system post-synaptic to the n. accumbens.

Injection of p-chlorophenylalanine (200 mg/kg i.p. daily for 2 days) had no effect on the locomotor response to dibutyryl cyclic AMP 24 hr later.

Amino-oxyacetic acid (25 mg/kg) produced an inhibition of the dibutyryl cyclic AMP locomotor activity 90 min later. in agreement with other reports suggesting a possible inhibitory influence of GABA on brain dopaminergic systems.

Injection into the nucleus accumbens of rats of ergo- metrine (Pijnenburg, Woodruff and Van Rossum, 1973) or dopamine. usually after pretreatment with a monoamine oxidase inhibitor (Pijnenburg and Van Rossum, 1973; Jackson, Andkn and Dahlstriim, 1975;

Costa11 and Naylor, 1976), results in an increase in locomotor activity. Recently Miller and Kelly (1975) demonstrated that injection of cholera toxin into this region also produced a long-lasting increase in loco- motor activity which appeared to be due to the toxin producing a large irreversible increase in post-synap- tic dopamine-sensitive adenylate cyclase activity.

The locomotor activity following intracranial injec- tion of dibutyryl cyclic AMP bilaterally into the nu- cleus accumbens as now been studied. This procedure has the advantage of producing a change in activity of fairly short duration, and one which is repeatable for a period of several weeks. Given the similarity between the behaviour observed following dibutyryl cyclic AMP injection and that accompanying enhanced activity in the mesolimbic dopamine system after injection of dopamine, this paradigm may be used to study further post-synaptic mechanisms in a known dopaminergic system. Furthermore, this approach as made it possible to study the influence of other neurotransmitter systems on these dopamine- related events.

* Permanent address: Department of Psychology, The University of British Columbia, 2075 Wesbrook Mall, Van- couver, B.C., Canada V6T IW5.

METHODS

Animals and drugs

Adult male Sprague-Dawley rats weighing about 300g at the time of operation (Anglia Laboratory

Animals, Alconbury, Huntingdon) were used. Drugs were obtained from the following sources: dibutyryl

cyclic AMP, p-chlorophenylalanine, amino-oxyacetic

acid, DL-a-methyl p-tyrosine, dopamine hydrochloride (Sigma, London), haloperidol (“Serenace”, Searle, High Wycombe). Dopamine, dibutyryl cyclic AMP,

haloperidol and amino-oxyacetic acid were dissolved in 0.99; NaCl (saline) while p-chlorophenylalanine and r-methyl-p-tyrosine were suspended in saline con-

taining 1% carboxymethyl cellulose.

Preparation and injection of the animals

Rats were anaesthetized with Equithesin (Jensen-. Salsbery Labs) and positioned in the stereotaxic

apparatus. After exposure of the skull, two 23-gauge stainless-steel cannulae were simultaneously im- planted with their tips in the n. accumbens using the co-ordinates of + 3.4; + 1.7; -7.1, according to the atlas of Pellegrino and Cushman (1967). This was achieved by supporting the cannulae on an inverted U-shaped wire carrier. The distance between the 2 upright parallels of the wire carrier was 3.4 mm, equivalent to 1.7mm either side of the midline. The cannulae were kept patent with 3S-gauge stainless-. steel wire stylets. The rats were allowed to recover for one week before testing.

265

266 D. J. HEAL, A. G. PHILLIPS and A. R. GREEN

\ ' I '

. . 'I

hi

Fig. 1. A vertical section through the rat forebrain is shown. The stars indicate the location in the ventral aspect of the nucleus accumbens septi (ACB) of the cannulae from 6 rats which all showed increased locomotor responses after injection of dibutyryl cyclic AMP. The cannulae were implanted using the co-ordinates of + 3.4: + 1.7; - 7.1 according to the atlas of Pellegrino and Cushman

(I 967tsee Methods.

Drugs were injected bilaterally into the n. accumbens through a 30-gauge needle passed down the cannulae. This needle had a collar at the top

which allowed a projection of 0.1 mm beyond the end of the cannulae into the brain. The rats were lightly anaesthetized with halothane and then dibutyryl cyc-

lic AMP and other drugs (all concentrations were dis- solved in 1~1 of saline) were injected at a rate of 1 ~1 in 0.5 min. In initial experiments 12.5 pg of dibu- tyryl cyclic AMP was injected bilaterally into the n. accumbens but in later experiments this dose was reduced to 8pg bilaterally as this did not markedly reduce the locomotor response but avoided any tend-

ency towards convulsions in the rats. A group of animals which had shown the locomo-

tor response and behavioural changes following injec- tion of dibutyryl cyclic AMP were killed, and the pos- itions of the cannulae tips were examined. These were all found to be located in the n. accumbens of the rats (Fig. 1).

Measurement of activity

Following injection, the rat was placed in a cage on an LKB Animex activity meter (sensitivity and tuning: 30 PA) and activity measured. Counts for the

600

500

101

0 1 15 25 35 45 55 65

Saline

TIME AFTER INJECTION IminI first 5 min after injection were discarded as the animal was still recovering from the anaesthetic. Movements/

Fig. 2. Rats were briefly anaesthetized with halothane and then iniected bilaterallv with various concentrations of

min were then recorded and results plotted as total m&ements/lb r?%. this the 15 min value &ws the

dibutyril cyclic AMP into the nucleus accumbens-see Methods. The activity (total movements/IO-min period) is

movements in the period 5-15 min after injection. shown plotted against time after injection (min). The

Results are plotted as mean + S.E.M. with the counts for the first 5-min period were discounted because

number of observations (on different animals) noted. the rats were still recovering from the effects of the anaes- thesia. The results are plotted as the mean + S.E.M. for

While there was a large variation between individual the locomotor respinses from 4 different animals.

N. accumbens, dibutyryl cyclic AMP and locomotion 267

rats as is shown in the results reported in Figure 2 the variation of any individual animal was not greater

than lo”;, from experiment to experiment after the first 3 injections (see below).

For statistical evaluations of drug effects a Stu- dent’s paired t-test was used, the rats acting as their own control.

RESULTS

Effect of dihutyryl cyclic AMP in the II. accumhens

Injection of dibutyryl cyclic AMP (5 pg-25 pg bila- terally) produced an increase in co-ordinated locomo- tor activity (Fig. 2). While the locomotor activity looked rather like that produced by low doses of methamphetamine (l-2 mg/kg i.p.) to normal rats, various other behavioural changes were also noted. The activity was not continuous but was seen as periods of activity around the cage followed by periods of immobility. When a rat was walking it

generally did this with an arched back and the head down. During the periods of immobility licking, chewing movements of the mouth, grooming the face, and salivation were occasionally noticed. At 12.5 peg bilaterally the rats occasionally sat on their rear haunches with front feet held up and jerking of the body was seen. This would only last for about 30 set, however, and none of the animals-actually con- vulsed. These effects became more pronounced at 25 pg bilaterally and resulted in a reduction of co- ordinated locomotor activity in the animals.

The locomotor response produced by injection of dibutyryl cyclic AMP increased following the 2 initial

injections but was constant after the third injection. Pijnenburg, Honig, Struyker Boudier, Cools, Van der

Heyden and Van Rossum (1976) and &heel-Kruger, Cools and Honig (1977) reported a similar effect when injecting ergometrine into the n. accumbens.

Pretreatment of rats with haloperidol before dihutyryl cyclic AMP or dopamine

When rats were injected with haloperidol (2.5 pg

bilaterally) into the n. accumbens followed by saline

(1 ~1, bilaterally) I5 min later, the haloperidol caused

no inhibition of the spontaneous locomotor activity

in the 60-min period following the saline injection, when compared to rats injected with saline (1 ~1 bila- terally) twice (Table 1). When rats were injected with haloperidol (2.5 pg bilaterally) and 15 min later with dibutyryl cyclic AMP (8 pg bilaterally) they showed the same locomotor response as those injected with saline (1 ~1 bilaterally) in place of haloperidol (Table 1). However haloperidol (2.5 pg bilaterally) markedly inhibited the locomotor activity produced by injec- tion of dopamine (5 pg bilaterally) to tranylcypromine pretreated rats (10 mg/kg 60 min before dopamine)

(Table 1). This is in accord with the fact that dibutyryl cyclic AMP is suggested to work “beyond” the post-

synaptic receptor and is not thought to release dopa- mine (Patrick and Barchas, 1976: Satoh, Satoh,

Honda and Notsu, 1976). When rats were pretreated with haloperidol (0.05

mg/kg) given intraperitoneally, then the locomotor response following injection of dibutyryl cyclic AMP (12.5 pg bilaterally) into the n. accumbens was totally abolished (Fig. 3). This did not appear to be due to any sedative action of the drug as the animals were very alert following this low dose of haloperidol. After

a further 48 hr these animals were again tested with dibutyryl cyclic AMP, at which time they again showed a normal response to the drug. This result suggested strongly therefore that we were blocking

another dopaminergic system that lay post-synaptic to the n. accumbens receptors initiating the hyperacti- vity response. This was examined further in the next experiment reported.

Effect of pretreatment of rats with r-methyl-p-tyrosine

Rats were pretreated with r-methyl-p-tyrosine (200 mg/kg i.p.). Three hours later dibutyryl cyclic AMP (12.5 pg bilaterally) was injected into the n. accumbens. The hyperactivity was totally abolished (Fig. 3).

Table I. The effects of injection of haloperidol into the nucleus accumbens of rats on the locomotor activity produced by injection of dibutyryl cyclic AMP or dopamine at the same site I5 min later

Second injection

Saline Dibutyryl cyclic AMP (8 ng bilaterally)

Dopamine (5 fig bilaterally, 60 min after tranylcypromine 10 mg/kg i.p.)

First injection Haloperidol

Saline (2.5 pg bilaterally)

1057 k I65 (3)* 930 * 200 (3); 2571 k 709 (4)** 2206 f 573 (4)**

3281 + 978 (4)t 1462 f 492 (4)t

The results are the mean k S.E.M. of the total number of movements in the 60 min following injection of dibutyryl cyclic AMP or dopamine after discounting the first 5-min period. The number of observations are shown in parentheses. Paired observations are as follows: * not significantly different; ** P > 0.01.

not significantly different; t significantly different

268 D. J. HEAL, A. G. PHILLIPS and A. R. GREEN

Fig. 3. Rats were briefly anaesthetized with halothane and then injected with dibutyryl cyclic AMP (12Spg bilaterally) into the nucleus accumbens. Haloperidol (0.05 mg,kg i.p.) or a-methyl p-tyrosine (200 mg,kg Lp.) were injected at 15 and 180 min respectively before dibutyryl cyclic AMP. The results

are plotted as mean k S.E.M. for the locomotor responses of 4 different animals.

Effect of p-chlorophenylalanine on the locomotor re- sponse to dihutyryl cyclic AMP

To determine whether a 5-hydroxytryptamine neur-

onal system was involved in the locomotor response following dibutyryl cyclic AMP injection (12.5 pg bilaterally), rats were injected with the tryptophan hy- droxylase inhibitor p-chlorophenylalanine (200 mg/kg) on day 1 and day 2. On day 3, 24 hr after the second dose when brain 5-HT concentrations would have been decreased by 707” (Green and Kelly, 1976) the rats were injected with dibutyryl cyclic AMP into the n. accumbens. No alteration in the size of the locomotor response was observed (Table

2).

EJJct of amino-o.uyacetic acid on the locomotor re- sponse to dihutyryl cyclic AMP

Previous studies have suggested an involvement of

the neurotransmitter y-aminobutyric acid (GABA)

with brain dopaminergic systems both in the nigro- - striatal region (And&n and Stock, 1973; Kim, Bak.- Hassler and Okada, 1971) and the mesolimbic area (Fuxe, Hiikfelt, Ljungdahl, Agnati, Johansson and Perez de la Mora, 1975). It has also been shown that raising the brain GABA concentration by injecting amino-oxyacetic acid results in inhibition of the loco- motor activity produced by injection of tranylcypro- mine and L-dopa (Green, Tordoff and Bloomfield, 1976). The possibility that GABA played an inhibi- tory role in the locomotor activity produced by the dibutyryl cyclic AMP injection was therefore exam- ined.

Rats were injected with amino-oxyacetic acid (25 mg/kg i.p.) which produced little sedation. Ninety minutes later they were injected with dibutyryl cyclic

AMP (12.5 pg bilaterally) into the n. accumbens. The

Table 2. The effects of p-chlorophenylalanine or amino-oxyacetic acid on the locomotor activity produced by injection of dibutyryl cyclic AMP into the nucleus accumbens

Dibutyryl cyclic AMP (12.5 pg bilaterally)

Control 2712 + 341 (5)*

p-cblorophenylalanine 2462 + 406 (5)

Amino-oxyacetic acid 904 + 139 (4)*

Rats were injected with dibutyryl cyclic AMP, p-chlorophenylalanine (200 mg/kg i.p.) on days 1 and 2, followed by dibutyryl cyclic AMP on day 3, 24 hr after the last injection. or amino-oxyacetic acid (25 mg/kg Lp.) followed by dibutyryl cyclic AMP 90 min later. Results are mean k S.E.M. of the total number of movements in the 60 min following injection of dibutyrylcyclic AMP after discounting the first 5-min period. The number of observations are shown in brackets.

* Result significantly different from control P > 0.01.

N. accumbens, dibutyryl cyclic AMP and locomotion 269

locomotor response was abolished by the amino- cyclic AMP and therefore blocked by peripheral in-

oxyacetic acid pretreatment (Table 2). jections of haloperidol.

DISCUSSION

There have been relatively few studies on the be- havioural effects of dibutyryl cyclic AMP. Intraventri- cular injection was shown to cause locomotor activity

and convulsions in rats (Herman, 1973; Brus, Herman and Kostman. 1974) and cats (Gessa. Krishna. Forn. Tagliamonte and Brodie, 1970). Jackson et al. (1975) injected dibutyryl cyclic AMP into the n. accumbens

at a dose of 50 pg bilaterally and observed body leaps and jerks and sometimes generalized convulsions. Using lower doses we have now shown increased locomotor activity following this drug. The period of increased activity was generally around 90 min and was reproducible over several weeks. The duration of action and repeatability of the dibutyryl cyclic AMP technique therefore make it a useful tool for studying dopaminergic function in the n. accumbens. When this technique is combined with that of inject- ing dopamine into the nucleus accumbens the result- ing method appears to provide a convenient way of

distinguishing between receptor and post-receptor mediated events with respect to the influence of drugs and other neuronal pathways.

Recently Satoh ef al. (1976) examined the effect of intraventricular injection of dibutyryl cyclic AMP on rotational behaviour in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra. Satoh et al. (1976) proposed that in this system too dibutyryl cyclic AMP acts at a site beyond the dopa- mine receptor.

Haloperidol when injected directly into the nucleus accumbens blocked the dopamine-induced locomotor activity while being ineffective against that produced by dibutyryl cyclic AMP. Since dibutyryl cyclic AMP

is not thought to act by releasing dopamine (Patrick and Barchas, 1976; Satoh et al.. 1976) but is believed to mimic the action of cyclic AMP beyond the dopa- mine-receptor these findings are in agreement with the hypothesis that haloperidol acts in oiuo by block- ing brain dopamine receptors. Recently Heal, Green,

Bloomfield and Grahame-Smith (1978) have shown that haloperidol also inhibits the elevation of caudate nucleus cyclic AMP concentrations produced in rim

by injection of tranylcypromine and L-dopa. a pro- cedure which markedly elevates brain dopamine con- centrations. This again points towards the dopamine receptor as being a site of action for neuroleptic drugs in ~‘it.o. The fact that haloperidol when injected peri- pherally at low concentration inhibited the dibutyryl cyclic AMP-induced locomotor activity was surpris- ing. Since haloperidol inhibits the dopamine-mediated locomotor activity when injected directly into the nu- cleus accumbens. the most plausible explanation for the haloperidol inhibition is the involvement of a non-mesolimbic dopamine system, which is tran- synaptically activated following injections of dibutyryl

Mabry and Campbell (1973) and Breese, Cooper

and Mueller (1974) have both reported that p-chloro- phenylalanine enhances the Fmphetamine-induced locomotor activity although studies in this laboratory

(Green and Kelly. 1976) and by Jacobs, Wise and Taylor (1975) have failed to confirm these observa- tions. Kelly. Seviour and Iversen (1975) have sug- gested that the site of amphetamine-induced locomo- tor activity is the nucleus accumbens. The current

finding therefore that p-chlorophenylalanine does not affect the locomotor activity produced by injection of dibutyryl cyclic AMP into the n. accumbens is con-

sistent with the observations of Jacobs rt al. (1975) and Green and Kelly (1976). In contrast Costall. Nay- lor, Marsden and Pycock (1976) have suggested that 5-hydroxytryptamine modulates the dopaminergic re-

sponses from the n. accumbens and have shown that the locomotor activity produced by dopamine injec- tion into the n. accumbens is markedly decreased by injection of 5-hydroxytryptamine at the same site. At present no explanation for these apparently conflict- ing observations can be offered except for the differ- ences in experimental techniques used.

Similar to the previous study shcwing that 90 min

after administration of the GABA transaminase in- hibitor, amino-oxyacetic acid, the locomotor re- sponses to central dopaminergic stimulation were in- hibited (Green et al.. 1976) the present study has shown that administration of this drug also inhibits

the locomotor effects of dibutyryl cyclic AMP. This finding is consistent with the recent report of a selec- tive inhibitory influence of GABAergic drugs on the mesolimbic dopamine system (Fuxe rt al., 1975). Amino-oxyacetic acid also inhibits dopamine turn- over in the neostriatum (And& 1974; Westerink and Korf, 1975), therefore it would be of interest to exam-

ine the effects of b-(4-chlorophenyl)-GABA (Lioresal) which, at certain dose levels. has a selective influence on the mesolimbic dopamine system (Fuxe et al.,

1975). In conclusion therefore it is suggested that the loco-

motor activity following dibutyryl cyclic AMP injec- tion into the n. accumbens may provide a useful model for investigating mesolimbic dopaminergic function.

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