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Stereotyped behaviour and electrocortical changes after intracerebral microinfusion of dopamine and apomorphine in fowls
STEREOTYPED BEHAVIOUR AND ELECTROCORTICAL CHANGES AFTER INTRACEREBRAL MICROINFUSION DOPAMINE AND APOMORP~INE IN FOWLS
OF
G. NISTI~, D. ROTIROTI’ and J. D. STEPHENSON~ ‘Institute of Pharmacology. Faculty of Medicine, University of Messina, Italy and “Institute of Psychiatry, University of London. England (ArreptPd 1 Mnp 1980) Summary-The effects of dopamine and apomorphine, infused into the third cerebral ventricle, lateral ventricle or into several discrete areas of the CNS, on stereotyped behaviour, electrocortical activity and body temperature of adult fowls (Gallus domesticus) were studied. Dopamine infused into the lateral ventricle or hypothalamus of fowls, pretreated with an MAO inhibitor, evoked behavioural and electrocortical sleep with contralateral head-neck deviation and side to side stereotyped head-neck movements, repetitive preening and pecking associated with a fall in body temperature. Infusion of dopamine into the pnleostriatum augmentutum produced an intense pattern of stereotyped movements and contralateral head-neck deviation; sleep was not elicited. Dopamine, given into the right n. mesencephulicus prcfundus pars centralis in fowls pretreated with a MAO-inhibitor. produced behavioural and electrocortical sleep associated with ipsilateral sustained head-neck deviation on which repetitive head-neck movements were superimposed. Apomorphine given into the same sites produced an intense pattern of stereotyped movements. Behavioural and electrocortical sleep associated with stereotyped movements, similar to those elicited by dopamine, was obtained after infusing smaller doses (0.01 pmol) into the ventricles, hypothalamus or n. mese~~epha~ieus pro~uf~dus, whereas larger doses (0.05 and 0.1 pmol) produced behavioural and electrocortical arousal, vocalization and increase in locomotor activity. Haloperidol or spiroperidot prevented behavioural, electrocortical effects and stereotypies evoked by subsequent infusion of apomorphine into the cerebral ventricles or into the n. mesencephalicus profundus. Pretreatment of fowls for 5 consecutive days with haloperidol or spiroperidol significantly increased the number of head-neck stereotypies evoked by subsequent infusion of apomorphine into the paleostriurum uuymenratum or into the lateral ventricle.
Although much progress has been made in the last decade in understanding the functions of dopamine in the mammalian CNS (see Costa and Gessa, 1977), the literature concerning the role of dopaminergic mechanisms in avian species is still scanty (Nisticb and Stephenson, 1979). In young chicks dopamine, given systemically produces ~havioural and electrocortical sleep (Key and Marley, 1962; Dewhurst and Marley, 1965) whereas larger doses produce a biphasic response, i.e. an initial period of behavioural arousal followed after some 30 min by sleep (Spooner and Winters, 1966). In adult fowls dopamine, infused into the III cerebral ventricle or into the hypothalamus, produces behavioural and electrocortical sleep, lowers body temperature and evokes stereotyped head-neck movements (Marley and Nisticb, 1972). Stereotyped pecking occurs in pigeons (Koster, 1957; Cheng and Long, 1974; Saxena, Naresh Chawala and Johri Shama Iqbal, 1977) after systemic or intracerebroventricular administration of apomorphine, a dopamine receptor agonist. In addition, it has been reported that apomorphine, given systemically in young chicks, increases locomotor activity, produces pecking, vocalization (de Lanerolle and Youngren, 1978) and aggressive behaviour (Osuide and Adejoh, 1973). In adult fowls apomorphine, given
into the III cerebral ventricle or into the hypothalamus, produces stereotyped head-neck movements, behavioural and electrocortical arousal, vocalization and increases body temperature (Nisticb, 1976; Koc and Marley, 1977). Recently, it has been reported that apomorphine in small doses, produces hypomotility and sedation in mice, rats (Str~mbom, 1976; Di Chiara, Porceddu, Vargiu, Argiolas and Gessa, 1976; Maj, Przewlocka and Kukulka, 1977; Wachtel, 1978) and in man (Corsini, Del Zompo, Manconi, Piccardi, Onali and Mangoni, 1977) whereas larger doses produce behavioural activation. The present experiments were intended to extend the previous data obtained in fowls by studying and comparing the behavioural and electrocortical effects of dopamine and apomorphine infused into areas rich in dopamine nerve endings, i.e. hypothalamus, pilleostriatum uu~mentutum (also known as n. basalis and homologous to the mammalian caudate nucleus) (Juorio and Vogt, 1967; Falck, Ljunggren and Nordgren, 1969; Gargiulo and Nisticb, 1975) or into the III cerebral ventricle or lateral ventricle from which these areas are readily accessible and in areas, i.e. mesencephalicus profirndus, homologous to the mammalian s. nigra, where dopamine cell-bodies are located (Karten and Dubbeldam, 1973; Gargiulo and Nisticb, 1975).
963 NP 19.10.<
G. NISTIC~, D. ROTIROTI and
964 MATERIALS
AND METHODS
Rhode Island Red fowls (2.0-2.5 kg) housed at 2&25”C were used. Methods for operative procedures, stereotaxic implantation of cannulae into different areas of the brain, electrocortical electrodes and thermistors have been described previously (Marley and Stephenson, 1970; Marley and Nisticb, 1972). The fowls were not tested until at least 1 week after the operative procedures and thereafter at intervals of at least one week. Cannulae positions were verified at time of implantation by outflow of clear cerebrospinal fluid from the ventricular cannulae and for these and those implanted into specific areas of the brain the position was verified histologically at post-mortem. Electrocortical activity was automatically integrated for consecutive 1 min periods, large amplitude potentials producing high integral counts and alert low voltage electrocortical pattern giving low integrals (Dewhurst and Marley, 1965). Drug infusions were made at the rate of 1 &min. Those into the III ventricle were of 5 ~1; all other infusions were of 1~1 volume or less. Control infusions of the same volume of the vehicle (pyrogen-free distilled H20) lacked effects on behaviour, electrocortical activity and body temperature. Drugs used were dopamine hydrochloride (Serva), apomorphine hydrochloride (Macfarlan-Smith Ltd), haloperidol and spiroperidol (Janssen), mebanazine oxalate (ICI). The number of experiments for each dose is reported in brackets. Values are expressed as means _t SEM.
J. D.
STEPHENKIN
Statistical analysis using the one-tailed was performed.
Student’s
RESULTS
Infusion of dopamine into the III cerebral ventricle, /atera ventricle, hypothalamus and paleostriatum augmentatum Dopamine infused into the III cerebral ventricle or lateral ventricle (0.1 and 0.5 pmol) or unilaterally into the hypothalamus (0.1 pmol) of fowls (number of experiments at least 5 for each dose and route), pretreated with the MAO-inhibitor mebanazine (100 pmol/kg, i.m., 18 and 1 hr before), produced behavioural and electrocortical sleep lasting about 3 hr and decreased body temperature (max mean fall 1.2 f 0.04”C with recovery after about 3 hr). Behavioural and electrocortical sleep elicited by intraventricular (0.25 and 0.5 pmol) (Fig. 1) or intrahypothalamic (0.1 and 0.2 pmol) infusion of dopamine (6 experiments for each dose and route) in fowls without mebanazine pretreatment was shorter-lasting. These effects were associated with contralateral head-neck deviation and superimposed stereotyped head-neck movements and preening, confirming previous results (Marley and Nisticb, 1972). Sleep was not evoked in the 6 fowls tested after infusing (0.2 pmol) dopamine into the right paleostriatum augmentatum but contralateral turning of head-neck and stereotyped behaviour was elicited.
INTRAVENTRICULAR Minute
DA 0.25
integral
,umol C
A
cJ s w
50OT 0
I
r 20
I
I 40
I
* 60
t-test
1
1 80
1
1 100
’
I 120
Fig. 1. Representative example of the effects of dopamine (0.25 pmol), given into the III cerebral ventricle of an adult fowl pretreated with an MAO inhibitor, on electrocortical activity. (A) Control electrocortical pattern. (B) Higher amplitude, lower frequency ECoG potentials after dopamine (DA). C. Electrocortical activity returning to pretreatment pattern 72 min after dopamine. At the bottom: histogram of integrated minute by minute electrocortical activity showing in comparison to control ECoG activity a marked increase of integral values after dopamine lasting about 50 min.
Dopaminergic mechanisms and stereotyped behaviour in fowls
965
N. MESENCEPHALICUS PROFUNDUS
Minute
integral
160
_ + ioopv~ ’ sec
290
+
280
A MEBANAZINE
+ DA
C
B
320
0 0
80
z: 0 I
0
I
I
I
40
I
80
I
I
120
I
1
160
200
Fig. 2. Representative example of the effects of dopamine (0.1 pmol), given into the n. mesencephu/icus with mebanazine (lOOfimol/kg, i.m., 18 and 1 hr before), on electrocortical activity. (A). Control electrocortical activity. (B) and (C) Higher amplitude, lower frequency ECoG potential, 60 and 120min respectively after dopamine. At the bottom: histogram of electrocortical activity integrated minute by minute showing a sustained and long-lasting (over 3 hr) increase of integral values after dopamine.
projiindus of an adult fowl pretreated
Infusion
of dopamine
into the n. mesencephalicus
pro-
fundus
In 8 fowls pretreated with mebanazine (lOO~mol/ kg 18 and 1 hr previously) the administration of dopamine (0.1 pmol) into the right n. mesencephalicus profundus pars ventralis produced behavioural and electrocortical sleep lasting over 4 hr (Fig. 2). In addition, the fowls showed an asymmetrical posture, lowering of the wings, especially on the side of the infusions, a sustained ipsilateral deviation of the headneck on which smaller head-neck movements were superimposed. The fowls squatted, occasionally standing and circling ipsilaterally. Infusion tricle,
of apomorphine
hypothalamus
into the lateral and III
ven-
and into the n. mesencephalicus
experiments for each site and dose) produced behavioural and electrocortical arousal (Fig. 4) lasting 30 to 60min according to the dose, increased locomotor activity and produced stereotyped head-neck movements, vocalization and a slight increase in body temperature (mean max increase 0.5”C * 0.12) except in one fowl in which 40 min after an initial fall (-0.6”C) there was a large (+ 2.2”C) increase in body temperature lasting 3.3 hr. Stereotyped head-neck movements and increased locomotor activity elicited by lateral ventricular or intrahypothalamic injection were mostly contralateral to the site of injection, whereas
>
2
APOMORPHlNE (005 prrd)
mr
XP< 001
profindus
Apomorphine produced behavioural and electrocortical sleep or arousal depending on the dose. Low doses (0.01 pmol) given into the lateral or third ventricle, into the n. mesencephalicus profundus or into the hypothalamus (n = 8 experiments for each site) produced behavioural and electrocortical sedation and sleep lasting about 4MO min, accompanied by stereotyped head-neck movements. No significant changes in body temperature were recorded and the fowls showed decreased locomotor activity. In contrast, apomorphine (0.05 and 0.1 pmol) given into the lateral ventricle, hypothalamus, III ventricle or into the n. mesencephalicus profundus (at least 6
&Y
LATERAL N.hdES. HYPOTHAL vENlRla_E FROF
Fig. 3. Stereotyped behaviour induced after microinjection of apomorphine (0.05 pmol) into the lateral ventricle (n = 6), n. mesencephalicus profundus (n = 6) or hypothalamus (n = 8). In comparison to the effects evoked by the lateral ventricle microinjection, a significant (P < 0.01) smaller number of head-neck movements was observed after infusions into the NMP or into the hypothalamus.
G. NISTIC~, D. ROTIROTIand
966
LATERAL
J. D.
STEPHENKIN
VENTRICLE Minute
integral
150 B fi
1oopvc I set
*
100
c
150
APO
0 lpmal
OL 1
I
I
0
IO
20
I
30
40
50
60
70
I
80
,
90
Fig. 4. Representative example of the effects of apomorphine (0.01 pmol) given into the lateral ventricle of an adult fowl on electrocortical activity. (A) Control electrocortical activity. (B) Lower amplitude, higher frequency ECoG potentials 12 min after apomorphine. (C) Electrocortical activity returning to baseline activity 46 min after apomorphine. At the bottom: histogram of integrated minute by minute electrocortical activity showing in comparison to pretreatment values a sustained decrease after apomor-
phine lasting about 30 min.
after infusion into n. mesencephalicus profindus no specific ipsi- or contralateral postural or locomotor changes were observed. The order of intensity of stereotyped behaviour was: lateral ventricle > n. mesencephalicus profundus > hypothalamus (Fig. 3). Antagonism to upomorphine and dopamine In previous studies (Marley and Nisticb, 1972; Nisticb, 1976) it was shown that stereotyped headmovements evoked by dopamine were prevented or greatly reduced by haloperidol or pimozide given either systemically or intraventricularly. A dose of haloperidol, which given systemically did not produce sedation or sleep (0.05 mg/kg, i.v.), prevented sleep produced by subsequent intraventricular infusion of 0.01 pmol of apomorphine (n = 6 experiments), larger doses of haloperidol alone (0.1 and 0.2 mg/kg) produced sedation and sleep lasting approximately 2 hr. Haloperidol given 15 min before apomorphine reduced, in a dose-related manner (Fig. 5), the intensity of apomorphine-induced stereotyped head-neck movements (n = 6 experiments for each dose of the antagonist). Haloperidol (0.1 mg/kg) given intravenously 15 min before, significantly reduced (P < 0.01) the stereotyped behaviour as well as behavioural and electrocortical arousal and the increased locomotor activity elicited by apomorphine (0.05 pmol) given into the n. mesencephalicus profundus (n = 5 experiments) or into the hypothalamus (n = 7 experiments). Pretreatment with a single dose (0.5 pg) of spiroperi-
dol given into the n. mesencephalicus profundus (n = 6 experiments) significantly reduced stereotypies and prevented sedation or sleep by subsequent (15 min later) infusion of apomorphine (0.01 pmol). Increased
sensitivity to upomorphine
In fowls pretreated with haloperidol (0.05 mgjkg, i.m., for 5 days) or with spiroperidol (1 pg for 5 consecutive days into the lateral ventricle) the subsequent infusion of apomorphine (0.01 pmol 24 hr later) produced a very intense and more marked (P < 0.001) increase in side to side head-neck movements (Fig. 6)
I
HALOPERIDOL DOSE(mg/kg
i.v
1
Fig. 5. Dose-dependent antagonism by haloperidol (i.v., 15 min before) of stereotyped head-neck movements induced by apomorphine (0.05pmol) given into the right lateral ventricle. Circles: mean values of 6 experiments: vertical bars = standard errors.
Dopaminergic mechanisms and stereotyped behaviour in fowls LATERAL MNTRICLE,
APCNlORPtiM
SRRQplDOL
5
days
AFhlCRPHINE
Fig. 6. Significant (P < 0.001) increase, in comparison to fowls (n = 12) receiving only apomorphine, of head-neck movements produced by apomorphine (0.01 pmol) given into the lateral ventricle after pretreatment with spiroperidol (1 pg into the lateral ventricle for 5 days).
than seen in non-pretreated controls (n = 12 experiments for each drug); sometimes these were superimposed on a sustained contralateral head-neck deviation. The fowls were not sedated after the neuroleptic drugs but became so after apomorphine, this effect lasting about 2 hr. Similarly, the daily infusion of spiroperidol (0.5 pg x 5 days) into the n. mesencephalicus profundus produced a marked increase in the stereotyped behaviour elicited by subsequent (24 hr later) infusion of apomorphine (0.01 pmol) into the same site (n = 12 experiments). DISCUSSION Sites sensitive to dopamine have been found within the paleostriatum, hypothalamus and mesencephalon. The interpretation of these results in terms of dopaminergic pathways is more difficult than in mammals because our knowledge of these pathways is less complete. The suggestion that the n. mesencephulicus profundus is homologous to the mammalian s. nigra and that the strio-tegmentalis tract, hereafter referred to as the meso-paleostriatal pathway, corresponds to the nigro-striatal pathway, is supported by histochemical fluorescent studies in pigeons, chicks, adult fowls (Bertler, Falck, Guttfries, Ljunggren and Rosengren, 1964; Fuxe and Ljunggren, 1965; Juorio and Vogt, 1967; Gargiulo and Nisticb, 1975; Muhibullah & Stephenson, personal communication). More recently, H.P.-liquid chromatographic analysis has shown that the concentration of dopamine in punched n. mesencephalicus profundus is considerably greater than that of noradrenaline and serotonin (Nisticb and De Luca, unpublished results). In fowls pretreated with mebanazine, dopamine injected unilaterally into the nucleus mesencephalicus profundus, produced ipsilateral head rotation on which smaller movements of the head and neck were superimposed. Microiontophoretic studies have demonstrated the existence of dopamine sensitive autoreceptors on dopamine neurones in the pars com-
967
pacta of the rat s. nigra which inhibit neuronal firing (Aghajanian and Bunney, 1977). In the present experiments, stimulation of similar dopamine autoreceptors by injection of dopamine into the nucleus mesencephalicus profundus would inhibit the meso-paleostriatal pathway and so produce ipsilateral head-neck movements whereas its injection into more anterior sites such as the lateral ventricle, hypothalamus and paleostriatum augmentutum would stimulate post-synaptic receptors to produce contralateral head-neck movements, as described for rats (Ungerstedt, 1971). The most intense stereotyped behaviour was evoked from infusions of dopamine and apomorphine into the lateral ventricle probably because of the large population of dopamine-sensitive receptors reached by such injections. Stereotyped behaviour evoked by dopamine and apomorphine was prevented by a previous systemic or intracerebral injection of haloperidol or spiroperidol, suggesting that these effects are due to activation of specific dopamine receptors. Stereotyped behaviour could be evoked independently of behavioural and electrocortical sleep; sleeplike behaviour was only seen after intrahypothalamic and intramesencephalic injections of dopamine and apomorphine. The opposite effects of large equimolar doses of apomorphine, which produced arousal, and of dopamine which produced sleep, might be explained by the multiple receptors described for dopamine (Kebabian and Calne, 1979) but the possibility that formation of noradrenaline contributed to the long duration of dopamine-induced sleep cannot be excluded since noradrenaline is a potent hypnogenie agent in both young and adult fowls (Marley and Stephenson, 1970; Marley and Nisticb, 1972). Small doses of apomorphine produced behavioural and electrocortical sleep and stereotyped movements similar to those evoked by dopamine suggesting an action on dopamine receptors. Larger doses produced behavioural and electrocortical arousal, vocalization and slight hyperthermia in addition to the stereotyped movements. The co-existence, after intracerebral injection of small doses of apomorphine, of sleep-like and stereotyped behaviour contrasts with results from mammals in which sedation and stereotypies were evoked separately by small and large intraperitoneal doses of apomorphine respectively (Stromborn, 1976; Di Chiara et al., 1976; Maj et al., 1977; Watchel, 1978). This co-existence of stereotyped behaviqur and sleep after small doses of apomorphine excludes the possibility that arousal seen after large doses was secondary to stereotypy and is probably a direct consequence of the unilateral injection; an imbalance in the dopaminergic mechanisms of the two hemispheres would arise irrespective of whether pre- or postsynaptic receptors were stimulated. The supersensitivity to apomorphine induced stereotyped behaviour seen after 5 days treatment with systemic haloperidol, intraventricular or intranigral injection of spiroperidol is in agreement with the results of other investigators (Klawans and Rubo-
G. NISTIC~. D. ROTIROTI and J. D. STEPHENSIN
968
vitz, 1972; Rotrosen, Angrist, Wallach and Gershon, 1972; Von Voigtlander, Losey and Triezenberg, 1975; Symes, Lal, Young, Tsang and Sourkes, 1977). Hypothermic effects evoked by dopamine infused into the III ventricle and the hypothalamus of fowls (Marley and Nisticb, 1972) have been also obtained in several other species with dopamine or dopamine agonists (see Ary, Lomax and Cox, 1977). In rabbits, apomorphine increases body temperature (Hill and Horita,
1972;
Quack,
Carino
and
Horita,
1975)
but
seen in the present study after larger doses of apomorphine given intraventricularly or intrahypothalamically could well be a consequence of the increased locomotor activity, as for instance is seen after injection of TRH into the same sites (Nistich, Rotiroti, De Sarro and Stephenson, 1978). In conclusion, the present experiments provide evidence of dopamine sensitive receptor sites at both mesencephalic and paleostriatal levels, areas of origin and ending respectively of a meso-paleostriatal dopaminergic system. In addition, they show that in fowls dopamine produces stereotyped behaviour and support the idea that, as in mammalian species, dopamine autoreceptors may exists on dopamine cell bodies within the mesencephalon. the slight
hyperthermia
Acl;nou,ledgements~ -Partial support from the Italian Ministry of Public Education and CNR (contract n. 79.01940.04) (Roma) is gratefully acknowledged. Our thanks to Mrs Adriana Mastroeni for the excellent typing of the manuscript.
Aghajanian,
G. K. and Bunney, B. S. (1977). Dopamine “Autoreceptors”: Pharmacological characterization by recording studies. microiontophoretic single cell Arch.
cup.
Path.
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Ary, M., Lomax, P. and Cox, B. (1977). Apomorphine hypothermia in the rat: central sites and mechanisms. Neurophormacoloy~
16: 731-735.
Bertler, A., Falck, B., Guttfries, C. G., Ljunggren, L. and Rosengren, E. (1964). Some observations on adrenergic connections between mesencephalon and cerebral hemispheres. Actu pharmuc. taxi&. 21; 283-289. Cheng, H. C. and Long, J. P. (1974). Dopaminergic nature of apomorphine induced pecking in pigeons. Eur. J. Pharmac.
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Corsini, G. U., Del Zompo, M., Manconi, S., Piccardi, M. P., Onali, P. L. and Mangoni, A. (1977). Evidence for dopamine receptors in the human brain mediating sedation and sleep. L@ Sci. 20: 1613-1618. Costa, E. and Cessa, G. L. (1977). Nonstriatal dopaminergic neurons. In: Adacmces in Biochemical Psychophurmucology, Vol. 16. Raven Press, New York. De Lanerolle, N. C. and Youngren, 0. M. (1978). Chick vocalization and emotional behavior influenced by apomorphine. J. camp. physic)/. Psycho/. 92: 416430. Dewhurst, W. G. and Marley, E. (1965). Methods for quantifying behaviour and cerebral electrical activity and the effects of drugs under controlled conditions. Br. J. Pharmw.
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969
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OF
G. NISTI~, D. ROTIROTI’ and J. D. STEPHENSON~ ‘Institute of Pharmacology. Faculty of Medicine, University of Messina, Italy and “Institute of Psychiatry, University of London. England (ArreptPd 1 Mnp 1980) Summary-The effects of dopamine and apomorphine, infused into the third cerebral ventricle, lateral ventricle or into several discrete areas of the CNS, on stereotyped behaviour, electrocortical activity and body temperature of adult fowls (Gallus domesticus) were studied. Dopamine infused into the lateral ventricle or hypothalamus of fowls, pretreated with an MAO inhibitor, evoked behavioural and electrocortical sleep with contralateral head-neck deviation and side to side stereotyped head-neck movements, repetitive preening and pecking associated with a fall in body temperature. Infusion of dopamine into the pnleostriatum augmentutum produced an intense pattern of stereotyped movements and contralateral head-neck deviation; sleep was not elicited. Dopamine, given into the right n. mesencephulicus prcfundus pars centralis in fowls pretreated with a MAO-inhibitor. produced behavioural and electrocortical sleep associated with ipsilateral sustained head-neck deviation on which repetitive head-neck movements were superimposed. Apomorphine given into the same sites produced an intense pattern of stereotyped movements. Behavioural and electrocortical sleep associated with stereotyped movements, similar to those elicited by dopamine, was obtained after infusing smaller doses (0.01 pmol) into the ventricles, hypothalamus or n. mese~~epha~ieus pro~uf~dus, whereas larger doses (0.05 and 0.1 pmol) produced behavioural and electrocortical arousal, vocalization and increase in locomotor activity. Haloperidol or spiroperidot prevented behavioural, electrocortical effects and stereotypies evoked by subsequent infusion of apomorphine into the cerebral ventricles or into the n. mesencephalicus profundus. Pretreatment of fowls for 5 consecutive days with haloperidol or spiroperidol significantly increased the number of head-neck stereotypies evoked by subsequent infusion of apomorphine into the paleostriurum uuymenratum or into the lateral ventricle.
Although much progress has been made in the last decade in understanding the functions of dopamine in the mammalian CNS (see Costa and Gessa, 1977), the literature concerning the role of dopaminergic mechanisms in avian species is still scanty (Nisticb and Stephenson, 1979). In young chicks dopamine, given systemically produces ~havioural and electrocortical sleep (Key and Marley, 1962; Dewhurst and Marley, 1965) whereas larger doses produce a biphasic response, i.e. an initial period of behavioural arousal followed after some 30 min by sleep (Spooner and Winters, 1966). In adult fowls dopamine, infused into the III cerebral ventricle or into the hypothalamus, produces behavioural and electrocortical sleep, lowers body temperature and evokes stereotyped head-neck movements (Marley and Nisticb, 1972). Stereotyped pecking occurs in pigeons (Koster, 1957; Cheng and Long, 1974; Saxena, Naresh Chawala and Johri Shama Iqbal, 1977) after systemic or intracerebroventricular administration of apomorphine, a dopamine receptor agonist. In addition, it has been reported that apomorphine, given systemically in young chicks, increases locomotor activity, produces pecking, vocalization (de Lanerolle and Youngren, 1978) and aggressive behaviour (Osuide and Adejoh, 1973). In adult fowls apomorphine, given
into the III cerebral ventricle or into the hypothalamus, produces stereotyped head-neck movements, behavioural and electrocortical arousal, vocalization and increases body temperature (Nisticb, 1976; Koc and Marley, 1977). Recently, it has been reported that apomorphine in small doses, produces hypomotility and sedation in mice, rats (Str~mbom, 1976; Di Chiara, Porceddu, Vargiu, Argiolas and Gessa, 1976; Maj, Przewlocka and Kukulka, 1977; Wachtel, 1978) and in man (Corsini, Del Zompo, Manconi, Piccardi, Onali and Mangoni, 1977) whereas larger doses produce behavioural activation. The present experiments were intended to extend the previous data obtained in fowls by studying and comparing the behavioural and electrocortical effects of dopamine and apomorphine infused into areas rich in dopamine nerve endings, i.e. hypothalamus, pilleostriatum uu~mentutum (also known as n. basalis and homologous to the mammalian caudate nucleus) (Juorio and Vogt, 1967; Falck, Ljunggren and Nordgren, 1969; Gargiulo and Nisticb, 1975) or into the III cerebral ventricle or lateral ventricle from which these areas are readily accessible and in areas, i.e. mesencephalicus profirndus, homologous to the mammalian s. nigra, where dopamine cell-bodies are located (Karten and Dubbeldam, 1973; Gargiulo and Nisticb, 1975).
963 NP 19.10.<
G. NISTIC~, D. ROTIROTI and
964 MATERIALS
AND METHODS
Rhode Island Red fowls (2.0-2.5 kg) housed at 2&25”C were used. Methods for operative procedures, stereotaxic implantation of cannulae into different areas of the brain, electrocortical electrodes and thermistors have been described previously (Marley and Stephenson, 1970; Marley and Nisticb, 1972). The fowls were not tested until at least 1 week after the operative procedures and thereafter at intervals of at least one week. Cannulae positions were verified at time of implantation by outflow of clear cerebrospinal fluid from the ventricular cannulae and for these and those implanted into specific areas of the brain the position was verified histologically at post-mortem. Electrocortical activity was automatically integrated for consecutive 1 min periods, large amplitude potentials producing high integral counts and alert low voltage electrocortical pattern giving low integrals (Dewhurst and Marley, 1965). Drug infusions were made at the rate of 1 &min. Those into the III ventricle were of 5 ~1; all other infusions were of 1~1 volume or less. Control infusions of the same volume of the vehicle (pyrogen-free distilled H20) lacked effects on behaviour, electrocortical activity and body temperature. Drugs used were dopamine hydrochloride (Serva), apomorphine hydrochloride (Macfarlan-Smith Ltd), haloperidol and spiroperidol (Janssen), mebanazine oxalate (ICI). The number of experiments for each dose is reported in brackets. Values are expressed as means _t SEM.
J. D.
STEPHENKIN
Statistical analysis using the one-tailed was performed.
Student’s
RESULTS
Infusion of dopamine into the III cerebral ventricle, /atera ventricle, hypothalamus and paleostriatum augmentatum Dopamine infused into the III cerebral ventricle or lateral ventricle (0.1 and 0.5 pmol) or unilaterally into the hypothalamus (0.1 pmol) of fowls (number of experiments at least 5 for each dose and route), pretreated with the MAO-inhibitor mebanazine (100 pmol/kg, i.m., 18 and 1 hr before), produced behavioural and electrocortical sleep lasting about 3 hr and decreased body temperature (max mean fall 1.2 f 0.04”C with recovery after about 3 hr). Behavioural and electrocortical sleep elicited by intraventricular (0.25 and 0.5 pmol) (Fig. 1) or intrahypothalamic (0.1 and 0.2 pmol) infusion of dopamine (6 experiments for each dose and route) in fowls without mebanazine pretreatment was shorter-lasting. These effects were associated with contralateral head-neck deviation and superimposed stereotyped head-neck movements and preening, confirming previous results (Marley and Nisticb, 1972). Sleep was not evoked in the 6 fowls tested after infusing (0.2 pmol) dopamine into the right paleostriatum augmentatum but contralateral turning of head-neck and stereotyped behaviour was elicited.
INTRAVENTRICULAR Minute
DA 0.25
integral
,umol C
A
cJ s w
50OT 0
I
r 20
I
I 40
I
* 60
t-test
1
1 80
1
1 100
’
I 120
Fig. 1. Representative example of the effects of dopamine (0.25 pmol), given into the III cerebral ventricle of an adult fowl pretreated with an MAO inhibitor, on electrocortical activity. (A) Control electrocortical pattern. (B) Higher amplitude, lower frequency ECoG potentials after dopamine (DA). C. Electrocortical activity returning to pretreatment pattern 72 min after dopamine. At the bottom: histogram of integrated minute by minute electrocortical activity showing in comparison to control ECoG activity a marked increase of integral values after dopamine lasting about 50 min.
Dopaminergic mechanisms and stereotyped behaviour in fowls
965
N. MESENCEPHALICUS PROFUNDUS
Minute
integral
160
_ + ioopv~ ’ sec
290
+
280
A MEBANAZINE
+ DA
C
B
320
0 0
80
z: 0 I
0
I
I
I
40
I
80
I
I
120
I
1
160
200
Fig. 2. Representative example of the effects of dopamine (0.1 pmol), given into the n. mesencephu/icus with mebanazine (lOOfimol/kg, i.m., 18 and 1 hr before), on electrocortical activity. (A). Control electrocortical activity. (B) and (C) Higher amplitude, lower frequency ECoG potential, 60 and 120min respectively after dopamine. At the bottom: histogram of electrocortical activity integrated minute by minute showing a sustained and long-lasting (over 3 hr) increase of integral values after dopamine.
projiindus of an adult fowl pretreated
Infusion
of dopamine
into the n. mesencephalicus
pro-
fundus
In 8 fowls pretreated with mebanazine (lOO~mol/ kg 18 and 1 hr previously) the administration of dopamine (0.1 pmol) into the right n. mesencephalicus profundus pars ventralis produced behavioural and electrocortical sleep lasting over 4 hr (Fig. 2). In addition, the fowls showed an asymmetrical posture, lowering of the wings, especially on the side of the infusions, a sustained ipsilateral deviation of the headneck on which smaller head-neck movements were superimposed. The fowls squatted, occasionally standing and circling ipsilaterally. Infusion tricle,
of apomorphine
hypothalamus
into the lateral and III
ven-
and into the n. mesencephalicus
experiments for each site and dose) produced behavioural and electrocortical arousal (Fig. 4) lasting 30 to 60min according to the dose, increased locomotor activity and produced stereotyped head-neck movements, vocalization and a slight increase in body temperature (mean max increase 0.5”C * 0.12) except in one fowl in which 40 min after an initial fall (-0.6”C) there was a large (+ 2.2”C) increase in body temperature lasting 3.3 hr. Stereotyped head-neck movements and increased locomotor activity elicited by lateral ventricular or intrahypothalamic injection were mostly contralateral to the site of injection, whereas
>
2
APOMORPHlNE (005 prrd)
mr
XP< 001
profindus
Apomorphine produced behavioural and electrocortical sleep or arousal depending on the dose. Low doses (0.01 pmol) given into the lateral or third ventricle, into the n. mesencephalicus profundus or into the hypothalamus (n = 8 experiments for each site) produced behavioural and electrocortical sedation and sleep lasting about 4MO min, accompanied by stereotyped head-neck movements. No significant changes in body temperature were recorded and the fowls showed decreased locomotor activity. In contrast, apomorphine (0.05 and 0.1 pmol) given into the lateral ventricle, hypothalamus, III ventricle or into the n. mesencephalicus profundus (at least 6
&Y
LATERAL N.hdES. HYPOTHAL vENlRla_E FROF
Fig. 3. Stereotyped behaviour induced after microinjection of apomorphine (0.05 pmol) into the lateral ventricle (n = 6), n. mesencephalicus profundus (n = 6) or hypothalamus (n = 8). In comparison to the effects evoked by the lateral ventricle microinjection, a significant (P < 0.01) smaller number of head-neck movements was observed after infusions into the NMP or into the hypothalamus.
G. NISTIC~, D. ROTIROTIand
966
LATERAL
J. D.
STEPHENKIN
VENTRICLE Minute
integral
150 B fi
1oopvc I set
*
100
c
150
APO
0 lpmal
OL 1
I
I
0
IO
20
I
30
40
50
60
70
I
80
,
90
Fig. 4. Representative example of the effects of apomorphine (0.01 pmol) given into the lateral ventricle of an adult fowl on electrocortical activity. (A) Control electrocortical activity. (B) Lower amplitude, higher frequency ECoG potentials 12 min after apomorphine. (C) Electrocortical activity returning to baseline activity 46 min after apomorphine. At the bottom: histogram of integrated minute by minute electrocortical activity showing in comparison to pretreatment values a sustained decrease after apomor-
phine lasting about 30 min.
after infusion into n. mesencephalicus profindus no specific ipsi- or contralateral postural or locomotor changes were observed. The order of intensity of stereotyped behaviour was: lateral ventricle > n. mesencephalicus profundus > hypothalamus (Fig. 3). Antagonism to upomorphine and dopamine In previous studies (Marley and Nisticb, 1972; Nisticb, 1976) it was shown that stereotyped headmovements evoked by dopamine were prevented or greatly reduced by haloperidol or pimozide given either systemically or intraventricularly. A dose of haloperidol, which given systemically did not produce sedation or sleep (0.05 mg/kg, i.v.), prevented sleep produced by subsequent intraventricular infusion of 0.01 pmol of apomorphine (n = 6 experiments), larger doses of haloperidol alone (0.1 and 0.2 mg/kg) produced sedation and sleep lasting approximately 2 hr. Haloperidol given 15 min before apomorphine reduced, in a dose-related manner (Fig. 5), the intensity of apomorphine-induced stereotyped head-neck movements (n = 6 experiments for each dose of the antagonist). Haloperidol (0.1 mg/kg) given intravenously 15 min before, significantly reduced (P < 0.01) the stereotyped behaviour as well as behavioural and electrocortical arousal and the increased locomotor activity elicited by apomorphine (0.05 pmol) given into the n. mesencephalicus profundus (n = 5 experiments) or into the hypothalamus (n = 7 experiments). Pretreatment with a single dose (0.5 pg) of spiroperi-
dol given into the n. mesencephalicus profundus (n = 6 experiments) significantly reduced stereotypies and prevented sedation or sleep by subsequent (15 min later) infusion of apomorphine (0.01 pmol). Increased
sensitivity to upomorphine
In fowls pretreated with haloperidol (0.05 mgjkg, i.m., for 5 days) or with spiroperidol (1 pg for 5 consecutive days into the lateral ventricle) the subsequent infusion of apomorphine (0.01 pmol 24 hr later) produced a very intense and more marked (P < 0.001) increase in side to side head-neck movements (Fig. 6)
I
HALOPERIDOL DOSE(mg/kg
i.v
1
Fig. 5. Dose-dependent antagonism by haloperidol (i.v., 15 min before) of stereotyped head-neck movements induced by apomorphine (0.05pmol) given into the right lateral ventricle. Circles: mean values of 6 experiments: vertical bars = standard errors.
Dopaminergic mechanisms and stereotyped behaviour in fowls LATERAL MNTRICLE,
APCNlORPtiM
SRRQplDOL
5
days
AFhlCRPHINE
Fig. 6. Significant (P < 0.001) increase, in comparison to fowls (n = 12) receiving only apomorphine, of head-neck movements produced by apomorphine (0.01 pmol) given into the lateral ventricle after pretreatment with spiroperidol (1 pg into the lateral ventricle for 5 days).
than seen in non-pretreated controls (n = 12 experiments for each drug); sometimes these were superimposed on a sustained contralateral head-neck deviation. The fowls were not sedated after the neuroleptic drugs but became so after apomorphine, this effect lasting about 2 hr. Similarly, the daily infusion of spiroperidol (0.5 pg x 5 days) into the n. mesencephalicus profundus produced a marked increase in the stereotyped behaviour elicited by subsequent (24 hr later) infusion of apomorphine (0.01 pmol) into the same site (n = 12 experiments). DISCUSSION Sites sensitive to dopamine have been found within the paleostriatum, hypothalamus and mesencephalon. The interpretation of these results in terms of dopaminergic pathways is more difficult than in mammals because our knowledge of these pathways is less complete. The suggestion that the n. mesencephulicus profundus is homologous to the mammalian s. nigra and that the strio-tegmentalis tract, hereafter referred to as the meso-paleostriatal pathway, corresponds to the nigro-striatal pathway, is supported by histochemical fluorescent studies in pigeons, chicks, adult fowls (Bertler, Falck, Guttfries, Ljunggren and Rosengren, 1964; Fuxe and Ljunggren, 1965; Juorio and Vogt, 1967; Gargiulo and Nisticb, 1975; Muhibullah & Stephenson, personal communication). More recently, H.P.-liquid chromatographic analysis has shown that the concentration of dopamine in punched n. mesencephalicus profundus is considerably greater than that of noradrenaline and serotonin (Nisticb and De Luca, unpublished results). In fowls pretreated with mebanazine, dopamine injected unilaterally into the nucleus mesencephalicus profundus, produced ipsilateral head rotation on which smaller movements of the head and neck were superimposed. Microiontophoretic studies have demonstrated the existence of dopamine sensitive autoreceptors on dopamine neurones in the pars com-
967
pacta of the rat s. nigra which inhibit neuronal firing (Aghajanian and Bunney, 1977). In the present experiments, stimulation of similar dopamine autoreceptors by injection of dopamine into the nucleus mesencephalicus profundus would inhibit the meso-paleostriatal pathway and so produce ipsilateral head-neck movements whereas its injection into more anterior sites such as the lateral ventricle, hypothalamus and paleostriatum augmentutum would stimulate post-synaptic receptors to produce contralateral head-neck movements, as described for rats (Ungerstedt, 1971). The most intense stereotyped behaviour was evoked from infusions of dopamine and apomorphine into the lateral ventricle probably because of the large population of dopamine-sensitive receptors reached by such injections. Stereotyped behaviour evoked by dopamine and apomorphine was prevented by a previous systemic or intracerebral injection of haloperidol or spiroperidol, suggesting that these effects are due to activation of specific dopamine receptors. Stereotyped behaviour could be evoked independently of behavioural and electrocortical sleep; sleeplike behaviour was only seen after intrahypothalamic and intramesencephalic injections of dopamine and apomorphine. The opposite effects of large equimolar doses of apomorphine, which produced arousal, and of dopamine which produced sleep, might be explained by the multiple receptors described for dopamine (Kebabian and Calne, 1979) but the possibility that formation of noradrenaline contributed to the long duration of dopamine-induced sleep cannot be excluded since noradrenaline is a potent hypnogenie agent in both young and adult fowls (Marley and Stephenson, 1970; Marley and Nisticb, 1972). Small doses of apomorphine produced behavioural and electrocortical sleep and stereotyped movements similar to those evoked by dopamine suggesting an action on dopamine receptors. Larger doses produced behavioural and electrocortical arousal, vocalization and slight hyperthermia in addition to the stereotyped movements. The co-existence, after intracerebral injection of small doses of apomorphine, of sleep-like and stereotyped behaviour contrasts with results from mammals in which sedation and stereotypies were evoked separately by small and large intraperitoneal doses of apomorphine respectively (Stromborn, 1976; Di Chiara et al., 1976; Maj et al., 1977; Watchel, 1978). This co-existence of stereotyped behaviqur and sleep after small doses of apomorphine excludes the possibility that arousal seen after large doses was secondary to stereotypy and is probably a direct consequence of the unilateral injection; an imbalance in the dopaminergic mechanisms of the two hemispheres would arise irrespective of whether pre- or postsynaptic receptors were stimulated. The supersensitivity to apomorphine induced stereotyped behaviour seen after 5 days treatment with systemic haloperidol, intraventricular or intranigral injection of spiroperidol is in agreement with the results of other investigators (Klawans and Rubo-
G. NISTIC~. D. ROTIROTI and J. D. STEPHENSIN
968
vitz, 1972; Rotrosen, Angrist, Wallach and Gershon, 1972; Von Voigtlander, Losey and Triezenberg, 1975; Symes, Lal, Young, Tsang and Sourkes, 1977). Hypothermic effects evoked by dopamine infused into the III ventricle and the hypothalamus of fowls (Marley and Nisticb, 1972) have been also obtained in several other species with dopamine or dopamine agonists (see Ary, Lomax and Cox, 1977). In rabbits, apomorphine increases body temperature (Hill and Horita,
1972;
Quack,
Carino
and
Horita,
1975)
but
seen in the present study after larger doses of apomorphine given intraventricularly or intrahypothalamically could well be a consequence of the increased locomotor activity, as for instance is seen after injection of TRH into the same sites (Nistich, Rotiroti, De Sarro and Stephenson, 1978). In conclusion, the present experiments provide evidence of dopamine sensitive receptor sites at both mesencephalic and paleostriatal levels, areas of origin and ending respectively of a meso-paleostriatal dopaminergic system. In addition, they show that in fowls dopamine produces stereotyped behaviour and support the idea that, as in mammalian species, dopamine autoreceptors may exists on dopamine cell bodies within the mesencephalon. the slight
hyperthermia
Acl;nou,ledgements~ -Partial support from the Italian Ministry of Public Education and CNR (contract n. 79.01940.04) (Roma) is gratefully acknowledged. Our thanks to Mrs Adriana Mastroeni for the excellent typing of the manuscript.
Aghajanian,
G. K. and Bunney, B. S. (1977). Dopamine “Autoreceptors”: Pharmacological characterization by recording studies. microiontophoretic single cell Arch.
cup.
Path.
Pharmuc.
297:
Ary, M., Lomax, P. and Cox, B. (1977). Apomorphine hypothermia in the rat: central sites and mechanisms. Neurophormacoloy~
16: 731-735.
Bertler, A., Falck, B., Guttfries, C. G., Ljunggren, L. and Rosengren, E. (1964). Some observations on adrenergic connections between mesencephalon and cerebral hemispheres. Actu pharmuc. taxi&. 21; 283-289. Cheng, H. C. and Long, J. P. (1974). Dopaminergic nature of apomorphine induced pecking in pigeons. Eur. J. Pharmac.
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Corsini, G. U., Del Zompo, M., Manconi, S., Piccardi, M. P., Onali, P. L. and Mangoni, A. (1977). Evidence for dopamine receptors in the human brain mediating sedation and sleep. L@ Sci. 20: 1613-1618. Costa, E. and Cessa, G. L. (1977). Nonstriatal dopaminergic neurons. In: Adacmces in Biochemical Psychophurmucology, Vol. 16. Raven Press, New York. De Lanerolle, N. C. and Youngren, 0. M. (1978). Chick vocalization and emotional behavior influenced by apomorphine. J. camp. physic)/. Psycho/. 92: 416430. Dewhurst, W. G. and Marley, E. (1965). Methods for quantifying behaviour and cerebral electrical activity and the effects of drugs under controlled conditions. Br. J. Pharmw.
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