Involvement of septal and striatal dopamine D-2 receptors in yawning behavior in rats

A behavioral study was performed in an attempt to understand the neuronal mechanisms involved in yawning behavior in rats. Subcutaneous injections of low doses of apomorphine (0.05–0.25 mg/kg) or piribedil (0.2–1.0 mg/kg), which preferentially activate presynaptic dopamine autoreceptors at those doses, evoked yawning. Marked yawning responses were also elicited by both 3-PPP (5–20 mg/kg, SC) and TL-99 (1–2 mg/kg, SC). SK & F 38393, a dopamine D-1 receptor agonist, at doses ranging from 0.1 to 8.0 mg/kg (SC) induced neither yawning nor stereotypy. However, bromocriptine (0.5–32.0 mg/kg, SC), a dopamine D-2 receptor agonist, induced yawning for which the dose-response curves showed a bell-shaped form. After a higher dose of 32 mg/kg (SC) bromocriptine, some rats occasionally showed sniffing and sawdust chewing. Yawning responses induced by systemic injection of apomorphine, piribedil, 3-PPP or bromocriptine were wholly suppressed after treatment with sulpiride (10 mg/kg SC), a dopamine D-2 receptor antagonist. Bilateral injections of apomorphine (20 g/side×2), piribedil (100 g/side×2) or 3-PPP (50, 100 g/side×2) into the striatum or septum also elicited marked yawning. The results indicate that low doses of apomorphine, piribedil, 3-PPP, TL-99 or bromocriptine elicit yawning by stimulating dopamine D-2 receptors and striatal and septal dopaminergic systems may be related to the occurrence of yawning behavior.     

Effects of apomorphine and haloperidol on “spontaneous” stereotyped licking behaviour in the Cebus monkey

Three recently arrived drug naive Cebus apella monkeys with spontaneous stereotyped oral movements were treated with apomorphine and haloperidol using a wide dose range. Low doses of apomorphine (0.05–0.1 mg/kg) suppressed the oral stereotypies without affecting normal behaviour such as grooming and scratching. Higher doses of apomorphine (0.25–1.0 mg/kg) and haloperidol (0.01–0.1 mg/kg) also decreased or abolished the oral stereotypies, but induced generalized stereotypies (apomorphine) or dystonia/parkinsonism (haloperidol), suppressing normal behaviour. The findings indicate that dopamine is involved in these presumably stress-induced (not drug-induced) stereotypies.     

Studies on interactions between conditioned and unconditioned behavioural responses to apomorphine in rats

Summary Interactions between the direct (unconditioned) behavioural effects apomorphine and its conditioned effects after pairing with previously neutral stimuli were studied. Rats were injected once daily for 3–12 times, with apomorphine (2.0 mg/kg or 0.5 mg/kg or 0.07 mg/kg s.c. the dose kept constant in each series), in the presence of defined environmental stimuli (a wire cage in association with an acoustic and an olfactory stimulus) as conditional stimuli. The two larger doses produced stereotyped sniffing, licking, and gnawing, the smallest dose akinesia, ptosis, yawning and penile erections. During the conditioning phase, the drug produced most of the effects with increasing intensity and in the case of the stereotypies, there also was a shift to higher scores of stereotypy, with a reduced latency in onset of the signs. On the test day, 1 day after the last administration of apomorphine, the conditioned rats as well as pseudoconditioned controls were treated with a test dose of apomorphine in the presence of the conditional stimuli. Pseudoconditioned rats had been treated with the same pharmacological schedule of apomorphine and had the same familiarity with the stimuli, but both were kept separate. A test dose of 0.5 mg/kg of apomorphine produced stereotypies with a significantly higher score and shorter latency in onset in conditioned than in pseudoconditioned rats. Rats conditioned with the lowest dose showed a significantly longer total duration and a shorter latency in onset of akinesia and ptosis. In rats conditioned with the largest dose (2.0 mg/kg), administration of the lowest dose on the test day produced no stereotypies; neither the akinesia nor the ptosis were different between conditioned and pseudoconditioned rats, but yawning occurred with a higher frequency and a shorter latency in pseudoconditioned rats. When rats were conditioned with the lowest dose and tested with 0.5 mg/kg, the level of stereotypies was identical in both groups of rats, whereas akinesia and ptosis were not observed. Yawning and penile erections occurred more frequently, but for short periods only, in conditioned rats.The results showed that apomorphine-induced stereotypies, akinesia and ptosis could be conditioned, and the conditioned effects mimicked the unconditioned responses, which depended on the dose. Conditioned and unconditioned signs of an increased dopaminergic neurotransmission, observed after large doses of apomorphine, thus acted in a synergistic way; the same applied to conditioned and unconditioned signs observed after a small dose and were perhaps due to a decreased dopaminergic transmission. In contrast, when conditioned and unconditioned signs acted in a mutually antagonistic way (increased vs. decreased dopaminergic transmission), the unconditioned signs predominated. Send offprint requests to K. Kuschinsky at the above address     

Individual and morphological differences in the behavioural response to apomorphine in rats

The topography of stereotyped behaviour produced by apomorphine in rats was studied by using either a scoring system, based on observation in a wire cage, or by quantification of horizontal and vertical activities, and of the total distances run in an open field, using an automatic recording system. The latter design was combined with a classification of the type of stereotyped behaviour observed during recording. In addition, the reproducibility of the nature of the stereotyped behaviour and its dose-dependence in individual animals was evaluated. In rats observed in a wire cage, apomorphine at lower doses (0.25 or 0.50 mg/kg SC) produced stereotyped sniffing. Increasing the doses led to stereotyped licking and the largest dose (5.00 mg/kg SC) produced predominantly stereotyped gnawing, as was demonstrated graphically. The type of behaviour produced by 2 mg/kg apomorphine in the open field was reproduced well in individuals after a second administration 4 days later. The shift from sniffing to gnawing was observed in most, but not all of the individually classified animals after administration of the largest dose (5 mg/kg). The locomotor part of motility was highest in sniffing animals and lower when gnawing occurred. The non-locomotor part of motility was low in sniffing rats and increased when licking and gnawing occurred. In some of the animals a characteristic climbing behaviour was observed in addition after the larger doses, which did not interfere with sniffing, licking or gnawing.A combination of classification by observation and automatic recording seems the most appropriate way to study the topography of stereotyped behaviour produced by apomorphine.     

Differences in the stereotypy response but not the hypomotility response to apomorphine in the roman high and low avoiding strains of rats

Two experiments were carried out to investigate differences in the behavioural responses to high and low doses of apomorphine in two strains of rats selectively bred for high and low avoidance on a two-way active avoidance task: the Roman High and Low Avoiders. Significant strain differences were found in the stereotypy resulting from a high dose of apomorphine (2 mg/kg s.c.). In a second experiment no strain differences were, however, apparent for the hypomotility produced by low doses of the drug (0.05 mg/ kg s.c.). Pretreatment with a low dose of apomorphine had no effect on the stereotypy response when the animals were subsequently retested with the high dose. These results may indicate differential sensitivities of dopamine receptors in these strains.     

Caffeine produces contralateral rotation in rats with unilateral dopamine denervation: comparisons with apomorphine-induced responses

Like the dopamine agonist apomorphine, the methylxanthines caffeine, theophylline and theobromine produced dose-dependent contralateral rotation in rats with unilateral 6-hydroxydopamine denervation, a response considered to be dependent upon dopamine receptors rendered supersensitive. This response was also observed after the injection of the substances into the denervated striatum. Indeed, intrastriatal administration of caffeine into the dopamine denervated striatum produced, dose-dependently (1.0–50.0 g/l), contralateral rotation. However, while apomorphine produced ipsilateral rotation in rats with unilateral striatal kainic acid lesions, a response considered to be dependent upon normosensitive dopamine receptors, neither caffeine nor theophylline produced rotational responses. As for apomorphine, the rotational behaviour elicited by caffeine (15.0 mg/kg SC) and theophylline (25.0 mg/kg SC) was inhibited by the dopamine antagonistscis-(Z)flupentixol, haloperidol and sulpiride. Nevertheless, despite the fact thatcis-(Z)flupentixol was the most potent inhibitor of the caffeine response, no more than 50% inhibition was produced with doses as high as 1.0–10.0 mg/kg SC ofcis-(Z)flupentixol. Pretreatment with alpha methyl-p-tyrosine inhibited the rotational response produced by caffeine in 6-OHDA-lesioned animals, but did not significantly modify the apomorphine response. Furthermore, the benzodiazepine diazepam produced a dose-dependent inhibition of the caffeine rotation, but again, the apomorphine response, although qualitatively modified, was not significantly inhibited.     

Inhibitory dopamine receptors on sympathetic neurons innervating the cardiovascular system of the pithed rat

Summary Additional experimental evidence was obtained for an inhibitory function of prejunctional ₂-adrenoceptors and/or dopamine receptors located on noradrenergic neurons innervating the heart and resistance vessels of the pithed normotensive rat. Mixed ₂-adrenoceptor receptor agonists, differing in selectivity towards either receptor type, i.e. N,N-di-n-propyldopamine (DPDA), 2-N, N-di-n-propylamino-6, 7-dihydroxy-1,2,3,4-tetrahydronaphthalene (DP-6,7-ADTN), B-HT 920 and B-HT 933 (azepexole) were used.In pithed normotensive rats, DPDA (30 and 100 g/kg/min) dose-dependently inhibited the electrical stimulation-induced increase in diastolic pressure, but did not significantly affect the stimulation-evoked increase in heart rate. The inhibition exerted by DPDA was blocked by haloperidol and sulpiride (0.3 mg/kg of each), but not by yohimbine (1 mg/kg), indicating the involvement of dopamine receptors. In this respect, sulpiride and haloperidol were found approximately equipotent.DP-6,7-ADTN (10 and 30 g/kg/min) impaired both tachycardic and vasoconstrictor responses in a dose-dependent manner. Sulpiride (0.3 mg/kg) only partially restored the DP-6,7-ADTN-depressed stimulation-evoked increase in diastolic pressure, whereas yohimbine (1 mg/kg) alone was without effect. The combination of both antagonists completely prevented the inhibition caused by DP-6,7-ADTN. On the other hand, yohimbine (1 mg/kg), but not sulpiride (0.3 mg/kg), selectively antagonized the DP-6,7-ADTN-induced inhibition of stimulation-evoked tachycardia.B-HT 920 (1, 3 and 10 g/kg/min) very effectively reduced the increase in diastolic pressure and heart rate caused by electrical stimulation. Inhibitory dopamine as well as ₂-adrenoceptors participated in the vascular effects of B-HT 920, whereas ₂-adrenoceptors were only involved in the cardioinhibitory response to this agonist.B-HT 933 (0.6 and 1 mg/kg/min) dose-dependently reduced the stimulation-evoked increase in arterial pressure through selective stimulation of inhibitory ₂-adrenoceptors, dopamine receptors not taking a part.The results confirm and extend the observations that in addition to ₂-adrenoceptors inhibitory dopamine receptors are located on the sympathetic neurons connected with the arterial vasculature of the pithed normotensive rat. The sympathetic nerves innervating the rat heart do not contain inhibitory dopamine receptors; their activity only can be modulated by ₂-adrenoceptor stimulation. In the pithed normotensive rat, activation of prejunctionally located ₂-adrenoceptors more effectively inhibits the sympathetic activity directed to the heart than that to the resistance vessels.     

α-Methyl-p-tyrosine inhibition of a conditioned avoidance response: Reversal by dopamine applied to the nucleus accumbens

These experiments sought to determine whether dopamine (DA) could reverse the depressive effects of -methyl-p-tyrosine (AMPT) on a conditioned avoidance response (CAR). Rats were randomly allocated to shocked groups (CAR-trained) and non-shocked (CAR-naive) groups. The CAR-trained rats, conditioned to avoid an electric shock, were administered AMPT (150 mg/kg at-24 h and 50 mg/kg at-1 h, both IP), nialamide (80 mg/kg IP at-1 h) and saline (1 l) or DA (5 or 10 g/l, dissolved in 1 l saline, at time 0) directly into the nucleus accumbens. The rats were then tested for CAR at 0.5, 1, 2, 3, 4, 8, 12, 24 and 48 h. The CAR-naive rats, conditioned to the behavioural environment without electric shock being presented, were administered AMPT, nialamide and DA or saline as above. Both doses of DA antagonised the AMPT-induced suppression of the CAR in the CAR-trained rats, reaching a maximum 2–4 h after its local application. In the CAR-naive rats, DA produced a pseudo-CAR that lasted about 4 h, but which completely disappeared at 8 h when the DA effect had worn off. These CAR-naive rats did not learn a CAR under the influence of DA. In a third group of rats, DA produced locomotor activation which, in its time course, resembled the effect of DA on CAR. It is concluded that the ability of DA to antagonise AMPT-induced depression of CAR is, in all likelihood, dependent upon DA-induced locomotor excitation, rather than upon an effect of DA on associative learning.     

Involvement of cholecystokinin receptors in the control of striatal dopamine autoreceptors

Summary The interaction of locally perfused cholecystokinin-8 (sulphated) with systemically administered apomorphine was studied on the release of dopamine and its metabolites using microdialysis in the neostriatum of the halothane-anaesthetized male rat. Dialysate levels of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid were assayed by high performance liquid chromatography in combination with electrochemical detection. Perfusion with cholecystokinin-8 (100 M but not 1 M or 10 nM) increased the dialysate levels of dopamine without affecting those of DOPAC or HVA. At low concentrations (1 M and 10 nM but not 1 nM), cholecystokinin-8 counteracted the inhibitory effect of apomorphine (0.05 mg/kg, s. c.) on dopamine release. This counteraction was antagonized by perfusion with the cholecystokinin-8 antagonist proglumide (3 M). At this concentration, proglumide perfused alone was without effect on basal or apomorphine-reduced levels of dopamine. The results indicate a facilitatory effect of cholecystokinin-8 on dopamine release in rat neostriatum only at high concentrations. At lower concentrations, cholecystokinin-8 appears to modulate dopamine release by an inhibitory effect on dopamine autoreceptors possibly involving an intramembrane interaction between presynaptic cholecystokinin-8 receptors and dopamine autoreceptors. Send offprint requests to K. Fuxe at the above address     

Conditioned tolerance to haloperidol- and droperidol-induced catalepsy

Summary The possible mechanisms of conditioned tolerance to the cataleptogenic effects of haloperidol and droperidol were studied in order to discriminate between classical and conditioned tolerance. Rats were conditioned by repeated administration (19–27 times) of haloperidol (1.5 mg/kg i. p.) or droperidol (1.5 mg/kg i. p.), respectively, in the presence of a sum of defined environmental (auditory, olfactory and tactile) stimuli. The animals were compared with pseudoconditioned rats, which underwent the same number of drug injections and exposures to the environmental stimuli, but neither were associated. In part of the experiments, one further group of rats was repeatedly treated with only solvent in the presence of the environmental stimuli. Rats conditioned with haloperidol or droperidol showed tolerance to the cataleptogenic effect of a test dose of haloperidol (1.5 mg/kg i. p.) or droperidol (1.5 mg/kg i.p.), respectively, when they were tested in presence of the defined conditioning stimuli. The rats conditioned with droperidol showed significantly less catalepsy than the pseudoconditioned animals 30 min after droperidol administration, whereas in rats conditioned with haloperidol, the catalepsy was less pronounced no sooner than 120 min after haloperidol administration. This was a manifestation of conditioned tolerance. In rats pseudoconditioned with droperidol, the catalepsy was similar to that produced by the drug in drug-naive rats, suggesting no classical tolerance due to repeated administration of the neuroleptic drug. The dopamine turnover in striatum or nucleus accumbens after administration of 1.5 mg/kg of haloperidol i.p. was not altered in rats conditioned with haloperidol when compared with pseudoconditioned animals. The stereotypies produced by apomorphine (0.16 mg/kg s. c.) were most pronounced in conditioned, less pronounced in pseudoconditioned and very small in drug-naive rats. These result suggest that the conditioned tolerance to the neuroleptic drugs is connected with an increased sensitivity of the basal ganglia to dopaminergic drugs. In another series of experiments, rats were conditioned with apomorphine 8 times and tested with 0.66 mg/kg of droperidol i.p. Rather unexpectedly, the catalepsy was significantly more pronounced in conditioned than in pseudoconditioned animals. This observation suggests that the type of conditioned effect, which becomes manifest, depends in part on the drug used in the presence of the conditioned stimuli.Send offprint requests to K. Kuschinsky     

Role of dopamine D-1 and D-2 receptor subtypes in mediating dopamine agonist effects on food consumption in rats

The effects of selective D-2 and D-1 dopamine (DA) receptor agonists on food consumption were investigated in free-feeding rats. A selective D-2 receptor agonist, (+)-4-propyl-9-hydroxynaphthoxazine (PHNO), increased the consumption of standard food pellets in the dose range of 7.5–120 g/kg, while SKF 38393 (5.0 mg/kg), a selective D-1 receptor agonist, decreased food pellet intake. The increase in food pellet intake produced by PHNO was blocked by haloperidol (an antagonist relatively selective for the D-2 receptor at the dose used, 0.05 mg/kg) and SCH 23390 (20 g/kg, a D-1 receptor selective antagonist). Increasing arousal by disturbance associated with repeated food weighting also increased food pellet consumption, but did not diminish PHNO-elecited feeding. However, the same range of doses of PHNO (7.5–120 g/kg) which increased food pellet intake decreased consumption of a liquid diet, and had no overall effect on a highly palatable liquid diet. The increase in consumption of solid food induced by PHNO appears to be secondary to enhancement of chewing behaviors. In contrast, the decrease in food intake induced by SKF 39393 may be due to a direct action of the drug on neural feeding mechanisms.     

The mode of action of bromocriptine following pretreatment with reserpine and α-methyl-p-tyrosine in rats

The ability of bromocriptine (BRC), a selective dopamine D-2 receptor agonist, to induce yawning responses was studied in rats pretreated with reserpine and -methyl-p-tyrosine (-MPT). BRC (1–20 mg/kg IP) evoked yawning responses, which were pronounced at 2.5 mg/kg and characterized by the head moving downward. Higher doses of BRC (5–20 mg/kg) dose-dependently delayed the onset and peak time of yawning. A low dose of the selective D-1 dopamine receptor agonist SK&F38393 did not induce yawning but enhanced the BRC-induced response. Pretreatment with reserpine (1 and 5 mg/kg SC), -MPT (100 and 300 mg/kg IP) and reserpine (1 mg/kg) plus -MPT (100 mg/kg) was able to significantly reduce BRC-induced yawning. The inhibitory effects were prevented by a low dose of SK&F38393 (0.5 mg/kg IP). In particular, combined treatment with reserpine (5 mg/kg) and BRC (10 and 20 mg/kg) elicited upright fighting and jumping behaviors which were inhibited by haloperidol (1 mg/kg IP), a non-selective D-1 and D-2 receptor antagonist, SCH23390 (0.05 mg/kg SC), a selective D-1 receptor antagonist, or sulpiride (20 mg/kg IP), a potent D-2 receptor antagonist, and were potentiated by SK&F38393 (0.5 mg/kg). SCH23390 (0.05 mg/kg) decreased BRC-induced yawning and the apomorphine (low doses)-induced potentiation of BRC yawning, and prevented the apomorphine (high doses)-induced reduction of BRC yawning. SCH23390 also inhibited apomorphine-induced stereotypy and BRC-induced potentiation of apomorphine stereotypy. Furthermore, haloperidol (0.02 and 1.0 mg/kg IP), sulpiride (20 mg/kg IP) or scopolamine (0.5 mg/kg IP) inhibited BRC-induced yawning, but prazosin (1.0 and 3.0 mg/kg IP), an -1 receptor antagonist, did not affect this behavior. These results suggest that BRC-induced yawning may be mediated via presynaptic dopaminergic neuron activity and that BRC, in addition to the stimulation of dopamine D-2 receptors, appears to require endogenous dopamine or receptor activation by another dopamine agonist (D-1 agonist) for the induction of yawning, stereotypy and upright fighting responses. The ability of dopamine agonists to induce these behaviors seems to depend apon the potency and ratio of D-2 versus D-1 receptor activity.     

Assessment of the muscarinic receptor subtype involved in the mediation of pilocarpine-induced purposeless chewing behaviour

Purposeless chewing behaviour in rats was enhanced by intraperitoneal administration of the muscarinic agonists pilocarpine (1.0–8.0 mg/kg). RS 86 (0.5–0.8 mg/kg), oxotremorine (1–2 mg/kg) and arecoline (2–32 mg/kg), but not by nicotine (0.1–3.2 mg/kg). Chewing behaviour was also induced by the ICV administration of the muscarinic agonists carbachol (12.5–100 g) and pilocarpine (50–200 g), but not by the putative M-1 receptor agonist McN-A-343 (50–200 g) or AH 6405 (100–200 g). The muscarinic receptor antagonists scopolamine (0.01–0.1 mg/kg SC), benzhexol (0.075–2.5 mg/kg SC), secoverine (1–10 mg/kg SC), and dicyclomine (1.25–10 mg/kg SC) antagonised purposeless chewing behaviour induced by pilocarpine (4 mg/kg IP). AF-DX 116 (2.5–100 mg/kg SC), an M-2 antagonist, partially inhibited the actions of pilocarpine (4 mg/kg IP). Based on ED₄₀ values the rank order of potency following IP administration was scopolamine > benzhexol > secoverine > dicyclomine > AF-DX 116. The ICV administration of the muscarinic antagonists N-methylscopolamine (2.5–10 g) and oxyphenonium (10–40 g) antagonised chewing behaviour induced by pilocarpine (4 mg/kg IP) in a dose-related manner. The M-2 antagonist 4-DAMP (40–160 g ICV), as well as AF-DX 116 (40–160 g ICV), also inhibited the effects of pilocarpine (40–160 g ICV). The putative M-1 receptor antagonist pirenzepine (80–320 g ICV) did not antagonise chewing behaviour induced by pilocarpine (4 mg/kg IP). Based on ED₄₀ values, the rank order of potency of muscarinic antagonists administered ICV was N-methylscopolamine > oxyphenonium > 4-DAMP > AF-DX 116 > pirenzepine. Comparisons of the actions of muscarinic antagonists in vivo, with their published actions in vitro suggest that pilocarpine-induced chewing behaviour is mediated through central M-2 receptors rather than via central M-1 sites.     

Dopaminergic factors in human prolactin regulation: A pituitary model for the study of a neuroendocrine system in man

This study in normal male subjects further investigates the effects of dopaminergic-antidopaminergic interactions as manifested by the prolactin response to dopamine and neuroleptic drugs. Incremental doses of dopamine hydrochloride (4 g/min, 15 g/min, 60 g/min, 300 g/min) were infused fused at a constant rate over 90–120 min after a fixed dose of a neuroleptic drug (sufficient for about half of the maximal prolactin response) had been given IV. A dose of dopamine in the order of 15–60 g/min appeared to match the los of endogenous dopaminergic inhibition due to the antidopaminergic effect of the neuroleptic drug. The lactotrophic cells of the pituitary gland are suggested to serve as a model in man for the study of some basic neurohormonal mechanisms.     

Unilateral striatal dopamine denervation: Reduced motor inhibitory effects of dopamine antagonists revealed in models of asymmetric and circling behaviour

Summary Circling and asymmetric behaviours to apomorphine (dopamine agonist/antagonist) challenge were studied in rats with unilateral striatal electrolesions or 6-hydroxydopamine (6-OHDA) lesions, each induced by combined lesions at 3 striatal locations, to allow an assessment of drug action on normal receptors in the intact striatum or supersensitive receptors in the lesioned striatum respectively. The minimally effective dose of 6-OHDA (given in the presence of DMI and tranylcypromine) to cause functional change was 3×8 g, with 3×32 g providing maximal change. Electrolesions were shown histologically to be confined to striatal tissue, and dopamine depletions caused by 6-OHDA were selective for the striatum.Temporal differences were recorded for onset of asymmetry and circling behaviour, both between behaviours and between lesions. Thus, asymmetry developed during the 2nd–4th days after 6-OHDA lesion but circling developed more abruptly on postoperative days 10–12. In contrast, both asymmetry and circling behaviours were apparent from the first day following electrolesion. The dose-dependent effects of apomorphine were apparent at much lower doses in 6-OHDA lesioned than electrolesioned rats. This potency difference was also demonstrated for two further dopamine agonists, 2-di-n-propylamino-5,6-dihydroxytetralin and SK & F 38393. In contrast, the agonist-induced asymmetric and circling behaviours of electrolesioned rats were some 9–44 times more sensitive than those of 6-OHDA lesioned rats to antagonism by the neuroleptic agents haloperidol, -flupenthixol and oxiperomide, although tiapride antagonism was very similar in both the electrolesioned and 6-OHDA-lesioned rats. Thus, selective striatal denervation techniques are used to show that asymmetric and circling behaviours can be differentially induced and manipulated, and that the increased sensitivity (over electrolesions) of 6-OHDA lesioned rats to dopamine agonist action to induce these behavioural effects is associated with a reduced sensitivity to neuroleptic activity to reduce the asymmetric and circling responses.     

Evidence for increased apomorphine-sensitive dopaminergic effects after acute treatment with morphine

Apomorphine in a very small non-stimulant dose 0.05 mg/kg s.c. antagonized the locomotor stimulant effect of morphine (50 mg/kg) in mice. Apomorphine (0.05 mg/kg) antagonized also the locomotor stimulant effect of a single low dose of morphine (2 mg/kg) in the rat as well as the late stimulatory effect seen after a higher dose of morphine (10 or 20 mg/kg). The pretreatment with morphine in increasing doses induced an increasing degree of potentiation of stereotyped behavior induced by high doses of apomorphine (0.5 and 2 mg/kg s.c.) in the rat. The apomorphine stereotyped biting/gnawing activity was found strongly increased by morphine (10–50 mg/kg) during the time interval where morphine given alone induced catalepsy. Our results indicate that the acute treatment with morphine may induce an increase of apomorphine sensitive dopaminergic mechanisms. The inhibitory effect by a very small dose of apomorphine (0.05 mg/kg) of morphine stimulation may be due to a presynaptic dopamine receptor stimulant effect of apomorphine. The antagonism by the serotonin antagonist methergoline of morphine catalepsy and the increase by this drug of the late morphine excitation indicate in addition a role of a serotonergic mechanism.     

Intrastriatal injection of dl-2-amino-5-phosphonovaleric acid (AP-5) induces sniffing stereotypy that is antagonized by haloperidol and clozapine

dl-2-amino-5-phosphonovaleric acid (AP-5), which blocks glutamatergic transmission at the NMDA-preferring receptor, was injected into the antero-dorsal striatum of rats. AP-5-induced behavioural changes were assessed i) using a stereotypy rating scale and ii) using an experimental chamber designed to quantify sniffing. In both behavioural situations it was shown that AP-5 (10 g/0.5 l) induced continuous intensive sniffing similar to that induced by small doses of systemically administered amphetamine or apomorphine. However, oral stereotypies were not induced by AP-5. Systemically injected clozapine (5 and 10 mg/kg SC) as well as haloperidol (0.1 mg/kg IP) antagonized AP-5-induced sniffing. These results show that besides dopamine receptors, NMDA receptors are involved in the control of sniffing. In behavioural terms, the effect of glutamate mediated by the NMDA receptor in the striatum is opposite to that of dopamine.     

Acute dyskinesias in monkeys elicited by halopemide,mezilamine and the “antidyskinetic” drugs,oxiperomide and tiapride

Oxiperomide and tiapride are dopamine receptor antagonists claimed to have antidyskinetic properties in animal models and in the clinic. Halopemide and mezilamine are other dopamine antagonists predicted to lack extrapyramidal side effects in man on the basis of animal studies. Acute dyskinesias, a neuroleptic-induced acute extrapyramidal syndrome, were elicited in squirrel monkeys by oxiperomide (1 mg/kg), tiapride (30 mg/kg), and halopemide (10 mg/kg). The dyskinesias were virtually indistinguishable from those caused by a standard behaviorally equivalent dose of haloperidol (1.25 mg/kg PO) in the same individual monkeys. Mezilamine (0.3 mg/kg) also induced dyskinesias, which appeared to be less pronounced than those following haloperidol. The antidyskinetic properties of oxiperomide and tiapride evidently do not confer protection against dyskinetic movements induced by dopamine antagonism.     

Yawning elicited by systemic and intrastriatal injection of piribedil and apomorphine in the rat

The behavioural effects of systemic and intrastriatal injections of the dopamine agonists piribedil and apomorphine in male rats were examined. Bilateral application of piribedil (50 and 100 g) or apomorphine (5, 10 and 20 g) to the striatum produced yawning and chewing mouth movements accompanied by intermittent stretching and sexual arousal. Low doses of piribedil (1.25 and 2.5 mg/kg) and apomorphine (0.1 and 0.2 mg/kg) injected SC produced an identical yawning syndrome. Previous work has suggested that yawning elicited by systemic dopamine agonist treatment is a consequence of dopamine autoreceptor stimulation. Similarly, the most likely explanation of the present data is that yawning elicited by systemic and central dopamine agonist treatment was due to activation of dopamine autoreceptors. Systemic injection of haloperidol and scopolamine abolished yawning induced by intrastriatal piribedil and these data provide tentative support for the proposal that a dopamine-acetylcholine link may be involved in the expression of yawning.     

Conditioning of apomorphine effects: simultaneous analysis of the alterations in cortical electroencephalogram and behaviour

Summary The possible conditioning of pharmacological effects of apomorphine on the electroencephalogram was studied using telemetric recordings in rats. Previous studies have shown that apomorphine-induced stereotyped behaviour can be conditioned: after repeated pairings of defined stimuli with the drug effect, the presentation of the external stimuli alone elicited stereotype sniffing, licking, and gnawing. Since apomorphine, an agonist at dopamine receptors, also produces a characteristic EEG pattern with an increase of power in the alpha-1 band, the possibility that this effect could also be conditioned was studied.In fact, conditioning with a dose of 0.5 mg/kg apomorphine (s. c.) led to a significant increase in the number of short-lasting episodes with enhancement of the power in the alpha-1 range in the presence of the conditioned stimuli, according to a comparison of the results obtained in the conditioned group and those of the controls (pseudoconditioned).Moreover, behavioural studies were performed simultaneously in order to find possible correlations between conditioned effects on EEG and conditioned alterations in behaviour. In general, a fair correlation between the increase of power in the alpha-1 band and stereotyped behaviour was found. This was also the case during extinction, when the conditioned stimuli were repeatedly uncoupled from apomorphine administration: both behavioural parameters and EEG alterations showed similar time-courses and had almost disappeared during the fourth extinction session. Send offprint requests to: K. Kuschinsky at the above address