RECEPTOR LIGANDS ON THE AMPHETAMINE- -INDUCED LOCOMOTOR HYPERACTIVITY IN RATS

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EFFECT OF INTRA-TEGMENTAL MICROINJECTIONS OF 5-HT

_1B

RECEPTOR LIGANDS ON THE AMPHETAMINE- -INDUCED LOCOMOTOR HYPERACTIVITY IN RATS

Iwona Papla, Ma³gorzata Filip, Edmund Przegaliñski

Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland

Effect of intra-tegmental microinjections of 5-HT_* receptor ligands on the amphetamine-induced locomotor hyperactivity in rats. I. PAPLA, M. FILIP, E. PRZEGALIÑSKI. Pol. J. Pharmacol., 2002, 54, 351–357.

Previous research demonstrated that the mesoaccumbens dopamine (DA) pathway played a critical role in the behavioral effects of amphetamine in rodents. Nonetheless, recent findings have also indicated involvement of 5-hydroxytryptamine (5-HT, serotonin) transmission in these effects. In the present study, we investigated the role of 5-HT_1B receptors located in the ventral tegmental area (VTA) in the amphetamine-induced locomotor hyperactivity in rats. Male Wistar rats, implanted bilaterally with cannulae in the VTA were infused with saline (0.2 ml/side), GR 55562 (an antagonist of 5-HT_1Breceptors; 0.1–1mg/side) or CP 93129 (an agonist of 5-HT_1Brecep- tors; 0.003–0.03 mg/side) immediately prior to the injection of saline (1 ml/kg, ip) or amphetamine (0.5 mg/kg, ip). The monitoring of locomotor activity in photobeam chambers began at once and proceeded for 60 min.

Neither GR 55562 nor CP 93129 affected basal locomotor activity. Pretreat- ment with GR 55562 (0.1–1mg/side) did not affect the locomotor hyperactivity evoked by amphetamine. On the other hand, microinjections of CP 93129 (0.01–0.03mg/side) enhanced the amphetamine-induced hyperlocomotor activity. GR 55562 (1mg/side) markedly reduced the enhancing effects of CP 93129 (0.01mg/side) on the amphetamine-induced hyperactivity.

These findings indicate that 5-HT_1Breceptors located in the VTA do not play a major role in the hyperlocomotion elicited by amphetamine, whereas their activation may modulate the behavioral response to the psychostimulant.

Key words: 5-HT_*receptors, amphetamine, CP 93129, GR 55562, loco- motor activation, rats

Polish Academy of Sciences Pol. J. Pharmacol., 2002, 54, 351357

ISSN 1230-6002

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INTRODUCTION

The psychostimulant amphetamine produces numerous behavioral responses, including locomotor hyperactivity, an effect depending on the release of dopamine (DA) and inhibition of its reuptake [28], especially within the mesoaccumbens pathway [14]. This pathway consists of the ventral tegmental area (VTA), containing DA cell bodies, and the nucleus accumbens (NAc) where DA terminals are located [6].

Mesoaccumbal DA neurons, which receive 5-hydroxytryptamine (5-HT) projections from the mid- brain raphe nuclei [21], have been shown to be in- hibited by 5-HT neurons. At the behavioral level, this is manifested by e.g. modulation of the amphetamine-induced hyperlocomotion following manipulation of the 5-HT system. In fact, agents re- ducing 5-HT input (non-selective 5-HT antago- nists, 5-HT neurotoxins, 5-HT synthesis inhibitors) have been reported to potentiate the locomotor response to the psychostimulant [2, 12, 17, 31], whereas 5-HT itself (microinjected intracerebrally) or its precursors have been demonstrated to inhibit amphetamine hyperlocomotion [4, 5, 12, 34].

Recently the examination of interactions between the 5-HT system and the amphetamine- or cocaine (another psychostimulant)-induced hyperactivity has been based on modulation of the behavioral response by selective ligands of numerous 5-HT receptor subtypes [8, 16, 26]. Among these receptors, 5-HT_1Bones deserve special attention in this respect as indicated by the following data:

1) 5-HT_1Breceptors and their mRNA are located in different brain structures, including the VTA and the NAc [3, 23]; 2) 5-HT_1B receptors act not only as autoreceptors which inhibit 5-HT release [11, 32], but also as heteroreceptors on different neuro- transmitter nerve terminals, including DA ones [29]; 3) activation of 5-HT_1Breceptors inhibits DA release in vitro [29, 30], but increases the basal or the cocaine-stimulated extracellular DA concentra- tion in vivo [1, 10, 22, 35]; 4) peripheral admini- stration of 5-HT_1B receptor ligands modulates the hyperlocomotor response to amphetamine or cocaine in mice [27] and rats [25], respectively.

Moreover, we have recently found that the cocaine-induced hyperlocomotion in rats is differently modulated by 5-HT_1B receptor ligands microinjected into the VTA [Przegaliñski et al., in preparation] or the NAc subregions [24].

In the present paper, we investigated the role of 5-HT_1B receptors located in the VTA in the amphetamine-induced locomotor hyperactivity in rats.

To this end, effects of intra-tegmental microinjections of GR 55562 (an antagonist of 5-HT_1Brecep- tors, [15]) and CP 93129 (an agonist of 5-HT_1Bre- ceptors, [18]) on the behavioral response to the psychostimulant were examined.

MATERIALS and METHODS

Animals

The experiment was performed on male Wistar rats (280–300 g). The animals had free access to food (Labofeed pellets) and water, and were kept at a room temperature of 20 ± 1°C on a 12-h light/dark cycle (the light on between 6.00–18.00 h). All the experiments were approved by the Committee for Laboratory Animal Welfare and Ethics and met the International Animal Guide for the Care and Use of Laboratory Animals.

Drugs

The following drugs were used (in parentheses:

pre-session injection times, suppliers): D-amphetamine sulfate (–5 min; Sigma, USA), 1,4-dihydro- 3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrolo[3,2- -b]pyridin-5-one (CP 93129; –10 min; Tocris, UK) and 3-[3-(dimethylamino)propyl]-4-hydroxy-N-[4- -(4-pyridinyl)phenyl]benzamide dihydrochloride (GR 55562; –20 min; Tocris, UK). All the drugs were dissolved in sterile saline (0.9% NaCl). D-amphet- amine was injected intraperitoneally (ip) in a volu- me of 1 ml/kg. CP 93129 or GR 55562 were injected intracerebrally in a volume of 0.2ml/side.

Locomotor activity measurements

Locomotor activity was recorded individually for each animal in Opto-Varimex cages (Columbus Instruments, USA) linked on-line to a compatible IBM-PC. Each cage (43 × 44 cm) was equipped with 15 infra-red emitters located on the x and y axes, and with the same number of receivers on the opposite walls of the cage. The rats’ behavior was analyzed using Auto-track software (Columbus In- struments, USA). Locomotor activity associated with horizontal locomotion was defined as a tres- pass of three consecutive photo-beams.

Before recording locomotor activity, the animals were allowed a 60-min habituation period af-

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ter which they were taken out, injected with the drugs, and placed back in the cages. Locomotor activity was recorded for 60 min. Seven or eight animals per group were used.

Implantation of intra-tegmental cannulae

Rats were anesthetized with an intramuscular (im) injection of 100 mg/kg of ketamine and 65 mg/kg of xylazine in 0.9% NaCl. With the tooth bar of a Kopf stereotaxic instrument positioned at –3.3 mm below the interaural line and using the inter- section of the bregma and the longitudinal sutures as the origins, rats were implanted bilaterally with stainless steel guide cannulae (9 mm long, 0.4 mm od, 0.3 mm id) 2 mm above the VTA (AP = –5.8 mm from the bregma, ML = ± 0.5 mm, DV = –6 mm). The guide cannulae were fastened to the skull with stainless steel screws and cranioplastic ce- ment. Rats were allowed a 1-week recovery period during which they were handled and weighed daily.

Microinjections

Following recovery, the rats were habituated to a intracranial microinjection technique. During each microinjection, the obturators were replaced by two stainless steel bilateral internal cannulae (11 mm long, 0.3 mm od) which were positioned 2 mm be- low the bilateral guide cannula tips. A programma- ble controller (Bee Hive Controller, BAS) drove two 5-ml Hamilton syringes attached by the poly- ethylene tubing to the bilateral internal cannulae.

The volume of infusion was 0.2 ml/side at a con- stant rate of 0.1 ml/min. Injection cannulae re- mained in place for another 1 min to allow for dif- fusion away from the cannulae tips.

Histology

At the completion of the study, the rats were overdosed with chloral hydrate (800 mg/kg, ip) their brains were removed and stored in a 20% sucrose- -10% formalin solution. Three days later, the brains were cut into 50-mm sections which were later mounted on gelatin-coated glass slides. The brain sections were defatted, stained with cresyl violet, cleared with xylene and cover-slipped. The cannula placements were verified using a light microscope.

Only the animals whose cannulae were within the VTA were chosen for a statistical analysis.

Statistical analysis

A one-way ANOVA, followed by a post hoc Newman-Keuls test, were applied to evaluate the treatment group effect.

RESULTS

Figure 1 shows the representative distribution of injection sites within the VTA (cannula placements extended between 5.8–6.3 mm to bregma;

Fig. 1). The rats, whose cannula placements were found outside this brain area were discarded. No significant tissue damage was observed during the histological examination of sections.

Effects of 5-HT

_1B

receptor ligands, micro- injected into the VTA, on basal locomotor activation

Following intra-tegmental injection of GR 55562 (0.1–1 mg/side) or CP 93129 (0.003–0.03 mg/side), no significant changes in basal locomotor activity were observed (Fig. 2).

Effects of 5-HT

_1B

receptor ligands, microinjected into the VTA, on the amphetamine-induced locomotor hyperactivity

Amphetamine (0.5 mg/kg, ip) induced a 340–

350% enhancement of locomotor activity in rats (Figs. 3–5).

-5.80 -6.04 -6.30

Fig. 1. A schematic diagram of the representative sites of intra- VTA cannula placements. The numbers beside the plates denote the distance from the bregma in mm

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Intra-VTA pretreatment with GR 55562 (0.1–1 mg/side) did not affect the amphetamine (0.5 mg/kg, ip)-induced hyperactivation (Fig. 3).

Following local microinjections of CP 93129 (0.003–0.03 mg/side) into the VTA, enhancement of amphetamine (0.5 mg/kg, ip) locomotor hyper- activity was observed; the maximum increasing effect (ca. 100%) was found after CP 93129 at 0.01 mg/side (Fig. 4).

When given into the VTA, GR 55562 (1mg/side) markedly reduced the enhancing effect of CP 93129 (0.01mg/side) on the amphetamine (0.5 mg/kg, ip)- induced hyperlocomotion (Fig. 5).

(µg/side)

GR 55562 0 0.1 0.3 1 0 0.003 0.01 0.03

SALINE (ip)

SALINE (ip) 0

200 400 600 800 1000

CP 93129 (µg/side)

DistanceTraveled[cm]/ 60min

Fig. 2. Effects of the 5-HT_1Breceptor antagonist GR 55562 (0.1–1mg/side; left panel) and agonist CP 93129 (0.003–0.03 mg/side; right panel), microinjected to the VTA, on basal loco- motor activity in rats. There was no main effects of CP 93129 (F_(3,25)= 0.5, p > 0.05) or GR 55562 (F_(3,25)= 0.7, p > 0.05) treatment

0 2000 4000 6000

(µg/side)

GR 55562 ⁰ ⁰ ^0.1 ^0.3 ¹

AMPHETAMINE (0.5 mg/kg,ip) SALINE

* *

*

Fig. 3. Effects of the 5-HT_1Breceptor antagonist GR 55562 (0.1–1mg/side), microinjected into the VTA, on the ampheta- mine (0.5 mg/kg, ip)-induced locomotor hyperactivity in rats.

An ANOVA showed a significant treatment effect, F_(4,31) = 4.55, p < 0.05. * p < 0.01 vs. saline

0 2000 4000 6000

CP 93129 (µg/side)

0 0 0.003 0.01 0.03

*

^#

*

^#

Fig. 4. Effects of the 5-HT_1B receptor agonist CP 93129 (0.003–0.03mg/side), microinjected into the VTA, on the am- phetamine (0.5 mg/kg, ip)-induced locomotor hyperactivity in rats. An ANOVA showed a significant treatment effect, F_(4,30)= 8.16, p < 0.05. * p < 0.05 vs. saline,^#p < 0.05 vs. amphetamine

0 2000 4000 6000

GR 55562(µg/side) 0

0.01 0.01

0 1

*

^#

CP 93129(µg/side) 0 0

0

* ^

Fig. 5. The effect of the 5-HT_1Breceptor antagonist GR 55562 (1 mg/side), microinjected into the VTA, on the intra-VTA 5-HT_1Breceptor agonist CP 93129 (0.01mg/side)-induced en- hancement of amphetamine (0.5 mg/kg, ip) hyperactivation in rats. An ANOVA showed a significant treatment effect, F_(3,25)= 7.12, p < 0.05. * p < 0.01 vs. saline,^#p < 0.01 vs. amphetamine,

^ p < 0.05 vs. CP 93129 + amphetamine

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DISCUSSION

We showed recently that peripheral administration of the 5-HT_1Breceptor antagonist SB 216641B or GR 127935 prevented the locomotor hyperactivity response to a single dose of amphetamine in mice [27] or cocaine in rats [25], respectively. Moreover, we also found that the cocaine-induced hyperlocomotion in rats was antagonized by another 5-HT_1B receptor antagonist, GR 55562, microinjected into the NAc shell, but not into the NAc core [24] or VTA [Przegaliñski et al., in preparation]. The latter observation is supported by the results of the present study showing that intra-tegmental microinjections of GR 55562 at doses of 0.1–1 mg/side of which at least the highest one is sufficient to block the effect of the 5-HT_1B receptor agonist (see below), are without effect on the amphetamine-induced locomotor hyperactivity. Summing up, our earlier observations and the present results indicate that the 5-HT_1B receptors located in the VTA – in contrast to those in the NAc shell – do not play a major role in the hyperlocomotion induced by the psychostimulant amphetamine or cocaine. Such a conclusion seems to be in line with the observations that intra-accumbal [7, 9, 13, 33], but not intra-tegmental [13, 33], administrations of the psychostimulants elicits hyperlocomotion in rats.

At the same time, the results of the present paper demonstrate that the 5-HT_1B receptor agonist CP 93129 [18], microinjected into the VTA at doses of 0.01–0.03mg/side in which it does not af- fect per se the locomotor activity of drug-naive rats, enhances the hyperlocomotion induced by amphetamine. Moreover, the effect induced by CP 93129 0.01 mg/side is markedly reduced by GR 55562 (1 mg/side), which indicates that it is mediated by 5-HT_1Breceptors. The above effect of CP 93129 is corroborated by our earlier results which showed that another 5-HT_1B receptor agonist, CP 94,253, administered systemically enhanced the hyperlocomotion produced by amphetamine in mice [27] or cocaine in rats [25], and that local microinjections of CP 93129 into the NAc shell [24] or the VTA [Przegaliñski et al., in preparation] increased the cocaine-induced locomotor hyperactivity. It should be stressed, however, that in the case of intra-tegmental administration a con- siderably higher dose of CP 93129 (1mg/side) was necessary to increase the behavioral response to cocaine [Przegaliñski et al., in preparation], as com-

pared to those (0.01–0.03 mg/side) enhancing amphetamine hyperlocomotion (present study).

Moreover, the specificity of the effect of intra-VTA CP 93129 administration on the cocaine-induced hyperactivity is dubious, since the 5-HT_1Breceptor agonist microinjected at a dose 1mg/side or higher into this structure produces its own potent hyperlocomotor effect [Przegaliñski et al., in preparation].

In other words, 5-HT_1B receptors located in the VTA seem to play a modulatory role in relation to the locomotor hyperactivity induced by amphetamine, but not cocaine. The difference between the effects of intra-VTA administration of the 5-HT_1B receptor agonist on the amphetamine- or cocaine- induced hyperlocomotion may stem from a diverse local DA neurotransmission tone induced by either amphetamine or cocaine [19, 20].

As to the mechanism responsible for the effect of intra-VTA administration of CP 93129 on amphetamine hyperlocomotion, an interaction between 5-HT_1Breceptors and the DA mesoaccumbens system should be considered. In fact, it is well docu- mented that these receptors act not only as autoreceptors regulating 5-HT release [11, 32], but also as heteroreceptors modulating the release of other neurotransmitters including DA. For example, activation of 5-HT_1B receptors inhibits DA release from rat striatial synaptosomes in vitro [29, 30]. On the other hand, under in vivo conditions, systemic and local (intra-accumbal and/or intra-tegmental) administration of 5-HT_1B receptor agonists increases basal and the psychostimulant-stimulated extracellular DA concentrations in the NAc, this effect most probably stemming from the reduction of g-aminobutyric acid (GABA) release from GABA- -ergic afferents and consequent disinhibition of DA neurons [1, 10, 22, 35].

In summary, the results of the present study show that the amphetamine-induced locomotor hyperactivity is not affected by intra-VTA microinjection of the 5-HT_1B receptor antagonist GR 55562, but is enhanced after activation of these receptors by their agonist CP 93129 in this structure. In other words, the obtained data suggest that the 5-HT_1B receptors located in the VTA do not play a major role in the hyperlocomotion elicited by amphetamine, whereas their activation may modulate the behavioral response to the psychostimulant.

Acknowledgment. This work was supported by the grant no. 4P05A 122 18 from the State Committee for Sci- entific Research, Warszawa, Poland.

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Received: July 4, 2002; in revised form: July 18, 2002.