Pharmacological stimuli decreasing nucleus accumbens dopamine can act as positive reinforcers but have a low addictive potential.

Opioid peptides, through mu and delta receptors, play an important part in reward. In contrast, the role of kappa receptors is more controversial. We examined the possible positive reinforcing effects of a selective kappa agonist, RU 51599, by studying intravenous self-administration in the rat. The effect of RU 51599 on dopamine release in the nucleus accumbens was also studied, as opioids and dopamine seem to interact in the mediation of reward. The behavioural and dopaminergic effects of RU 51599 were compared with those of the mu agonist heroin. Rats self-administered both RU 51599 (6.5, 20 and 60 microg/inj) and heroin (30 microg/inj) at low ratio requirement. When the ratio requirement, i.e. the number of responses necessary to receive one drug infusion, was increased, self-administration of RU 51599 rapidly extinguished, whereas self-administration of heroin was maintained. Intravenous infusion of RU 51599 (100, 200 and 400 microg) dose-dependently decreased (25, 30 and 40%, respectively) extracellular concentrations of dopamine, as measured by means of microdialysis in freely moving rats. In contrast, heroin increased accumbens dopamine (130% over baseline). These results indicate that kappa receptors, similarly to mu ones, can mediate positive reinforcing effects of opioid peptides. However, the strength of the reinforcement is very low for kappa receptors. This suggests that changes in accumbens dopamine do not correlate with the capacity of a stimulus to induce reward or aversion. In contrast, a parallel seems to exist between an increase in accumbens dopamine and the drive to reach or obtain a positive reinforcer.

The kappa opioid agonist niravoline decreases brain edema in the mouse middle cerebral artery occlusion model of stroke.

The effect of niravoline (RU 51599), a kappa opioid receptor agonist with water diuretic properties, was assessed on the resorption of postischemic cerebral edema in the conscious mouse in comparison with U 50488, another kappa opioid receptor agonist, and mannitol. Ischemia was obtained by permanent occlusion of the right middle cerebral artery. Twenty-four hours after occlusion, at a time when brain water content is submaximal, blood samples were collected to measure serum osmolality, and brains were removed to measure the brain water content of two samples of frontoparietal cortical tissue corresponding to the core and the periphery of ischemia. When administered from 3 to 30 mg/kg as a single i.p. injection 20 h after occlusion, niravoline significantly reduced the brain cortical water increase by 27% up to 48% in the periphery of the ischemic tissue. At these same doses, it increased the serum osmolality to the same extent in ischemic as in nonischemic mice: 4 to 10 mOsm/kg. U 50488 generally showed a similar activity. In contrast, mannitol (1 or 2 g/kg i.p. 23 h after occlusion) increased serum osmolality but did not decrease brain water content. In conclusion, kappa opiate agonists could be an alternative to hyperosmotic agents in the treatment of cerebral edema of the focal ischemia type, the use of which is limited to the early phase of cerebral edema.

[Problems of laparoscopy using captoperitoneum: controlled ventilation, circulation, blood gas and body temperature]. / Probleme bei der Laparoskopie unter Kapnoperitoneum: kontrollierte Beatmung, Kreislauf, Blutgase und Körpertemperatur.

More and more veterinarians are going to perform laparoscopic diagnosis and surgery those days. But the technique using capnoperitoneum implicates several alterations of different physiological parameters, which, without proper monitoring, are often realized to late. Pathophysiology under CO2 insufflated abdomen as well as counter measures to keep or reestablish physiological situations are described. Within experimental studies, 27 pigs received partial colon resection using the laparoscopic technique, another six after laparotomy. They were compared concerning controlled ventilation, cardiovascular and blood gas parameters as well as the body temperature. Monitoring of the end-exspiratory CO2-gas tension as well as controlled ventilation seems to be essential. Blood gas analyses are proposed additionally. Under the described laparoscopic conditions blood circulation and body temperature seem to be influenced positively.

Effects of RU 52583, an alpha 2-antagonist, on memory in rats with excitotoxic damage to the septal area.

The anti-amnesic action of RU 52583, an alpha 2-adrenergic receptor antagonist, was evaluated through performance of spatial tasks in a radial maze by rats with N-methyl-D-aspartic acid (NMDA) lesion of the medial septal (MS) nuclei. Memory performance of lesioned or sham-operated rats was evaluated by measuring reference memory as long-term maintenance of an acquired performance and working memory or memory for recent events. The lesion: a produced significant impairments of the animals' memory performance, b) significantly reduced the sodium-dependent high-affinity choline uptake in the hippocampal formation, and c) deeply disrupted cholinergic hippocampal theta waves. Oral administration of RU 52583 at 1 and 2 mg/kg (tested doses: 1-5 mg/kg) prior to performance of the task markedly reduced memory impairments, whereas idazoxan, another alpha 2-adrenergic receptor antagonist, had no effect at tested doses (2-5 mg/kg). Cholinergic drugs--arecoline at 0.1 and 1 mg/kg (tested doses: 0.05-1 mg/kg) and physostigmine at 0.02 and 0.1 mg/kg (tested doses: 1, 2, and 5 mg/kg)-administered intraperitoneally showed a tendency to alleviate memory deficits. The present results show that the alpha 2-adrenergic antagonist RU 52583 possesses cognition-enhancing properties in rats with damage to the septohippocampal system.

Ameliorating effects of RU 47213, a novel oral and long-lasting cholinomimetic agent, on working memory impairments in rats.

The anti-amnesic effects of RU 47213 [1-(4-chlorophenoxycarbonyl)-1,2,5, 6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime], a prodrug with oral and long-lasting cholinergic activity, were evaluated on working memory impairments, using tasks of unequal levels of difficulty involving the same reinforcement and motivation in rats: a spatial-based task in a radial maze and a delayed reinforced alternation task in a T-maze. Tetrahydroaminoacridine (THA; tacrine), a cholinesterase inhibitor was used as a reference. Groups of rats were trained in an automated radial maze or T-maze until they had attained an asymptotic level of performance. On test days, memory impairment was produced by administration of scopolamine (0.1 mg/kg s.c.) 15 min prior to testing. Both THA (1.3, and 5 mg/kg) and RU 47213 (0.2, 0.5, 1, and 2 mg/kg) given prior to testing markedly reduced or suppressed the scopolamine induced working memory deficits in both tasks. This activity was evidenced by either a significant decrease in the number of errors or an increase in the number of correct responses. These results show that RU 47213 possesses the capacity to reduce memory deficits induced by an impairment of cholinergic transmission in the rat.

Antagonism of scopolamine-induced memory impairments in rats by the muscarinic agonist RU 35,926 (CI-979).

The promnesic effects of RU 35,926 (CI-979), a muscarinic receptor agonist, were evaluated on memory impairments induced by the muscarinic antagonist scopolamine, using a radial arm maze task, in comparison with tetrahydroaminoacridine (THA), a cholinesterase inhibitor. Groups of rats were trained in a standard version of the radial maze until they had attained an asymptotic level of performance. The animals were then retested with one trial a day. Twenty minutes before each retest, the rats were given subcutaneous administration of 0.1 mg/kg scopolamine. Oral administration of RU 35,926 (0.02, 0.05, 0.1, 0.2, and 0.5 mg/kg) 30 min before memory retest markedly reduced or suppressed the scopolamine-induced deficit. This reduction was evidenced by a significant decrease in the different types of errors and an increase in the number of correct responses. THA (3 mg/kg, intraperitoneally or orally) given 20 min to testing also significantly reduced or suppressed the scopolamine-induced deficits. These results show that RU 35,926 possesses the capacity to reduce memory impairments induced by a deficit of cholinergic transmission in the rat.

Tolerance to the serotonin 5-HT1 agonist RU 24969 and effects on dopaminergic behaviour.

The pharmacological responses to intraperitoneal injection of the serotonin (5-HT) 5-HT1 agonist RU 24969 (0.25-5 mg/kg) were studied in rats either after single administrations or after repeated treatment (5 mg/kg per day for 3 days). The following effects were recorded after a single dose: (A) a strong increase in locomotor activity in intact rats and its potentiation after 5,7-dihydroxytryptamine lesion of 5-HT neurons; (B) at a low dose, a potent enhancement of the circling behaviour induced by the dopamine (DA) D2 agonist LY 171555 in 6-hydroxydopamine-lesioned rats; (C) an early reduction (2 h) of 5-hydroxyindole acetic acid levels in the striatum and the nucleus accumbens followed by a late increase (24 h) in the latter structure. The following modifications were observed 24 h after the repeated treatment with RU 24969: (A) the locomotor effect of the drug was strikingly reduced both in intact and 5,7-dihydroxytryptamine-lesioned animals. On the contrary, the locomotion elicited by the DA releaser d-amphetamine, or the 5-HT1A agonist 8-OH-DPAT, was unchanged; (B) the rotation scores of 6-hydroxydopamine-lesioned rats injected with LY 171555 after a low dose of RU 24969, were greatly reduced. Moreover, the circling response was almost abolished in rats treated with the DA agonist alone; (C) the early reduction of 5-hydroxyindole acetic acid levels was antagonized while the late increase was enhanced. It is concluded that both the state of tolerance and the reversal of the action of RU 24969 that followed repeated treatment might be related to down-regulation of a subtype of the 5-HT1 receptor, possibly the 5-HT1B subtype, that would play a critical role in the expression of DA-mediated behaviour, locomotor activity and 5-HT metabolism.

A selective 5-HT(1) agonist, RU 24969, increases locus coeruleus catechol metabolic and neuronal activity.

Locus coeruleus activity was monitored by either in vivo electrochemistry, post-mortem HPLC, or single unit activity, after systemic administration of RU 24969, a potent serotonin-1 agonist. Whatever the methodology, activation of the locus coeruleus appeared after RU 24969 injection. Catechol oxidation current, assessed by in vivo differential pulse voltammetry and single unit activity in the locus coeruleus showed simultaneous increases after RU 24969. The increase in catechol oxidation current after RU 24969 was dose dependent (ED(50) = 1.4 mg kg(?1) of i.p. RU 24969). This increased activity was also observed on microdissected locus coeruleus as shown by the increased levels of dopamine and 3,4-dihydroxyphenylacetic acid measured with high performance liquid chromatography. Furthermore, RU 24969 treatment decreased 5-hydroxyindolacetic acid/serotonin ratio in the same microdissected locus coeruleus. This increased locus coeruleus catechol metabolic activity was suppressed by making lesions in the serotonergic systems with 5,7-dihydroxytryptamine. By contrast, neither 8-OHDPAT nor methysergide produced significant changes in the catechol oxidation current recorded in the locus coeruleus.

Distinct functions for dopamine and serotonin in locomotor behaviour: evidence using the 5-HT1 agonist RU 24969 in globus pallidus-lesioned rats.

The locomotor effect of RU 24969, a potent 5-HT1 agonist, was tested in two experimental conditions. Firstly, 5-HT neurons were degenerated by i.c.v. infusion of 5,7-dihydroxytryptamine (5,7-DHT). Secondly, outputs of the nigrostriatal and mesolimbic dopaminergic (DAergic) systems were bilaterally disrupted by electrolytic lesion of the globus pallidus (GP). After both types of lesion, RU 24969 (1.25-5 mg/kg, i.p.) induced an intense and long-lasting hyperlocomotion which was more pronounced than in intact rats. The hyperlocomotion induced in 5,7-DHT lesioned rats as well as that in intact rats was abolished by the DA blocker haloperidol (0.5 mg/kg, i.p.). On the contrary the hyperlocomotion induced in GP-lesioned rats was either unmodified or increased both by haloperidol even at a very high dose (2 mg/kg, i.p.) and by methysergide (5 mg/kg, i.p.). It is concluded that (i) there is no DAergic link in the locomotor response to RU 24969, (ii) 5-HT1 receptors are involved in the motor execution of locomotion, (iii) DA initiates and controls the 5-HT-mediated locomotion in normal rats.

Evidence for hyperdensity of 5HT1B binding sites in the substantia nigra of the rat after 5,7-dihydroxytryptamine intraventricular injection.

High affinity serotonin (5HT) binding sites have been found highly concentrated in the substantia nigra (SN) of the rat brain in each classical anatomical subdivisions of this structure, SN reticulata (SNR), SN lateralis (SNL), SN compacta (SNC). In all of the anatomical samples examined along the posteroanterior brain axis (at 200 um intervals), they corresponded to 5HT1B binding sites. The analysis of their distribution performed in rats 15 days after 5,7-DHT intraventricular injection has revealed : (1) the post-synaptic localization of these 5HT1B sites ; (2) the selective increase in their density at the level of SNR. This increase was found heterogeneously distributed inside the SNR and clearly differentiated in external and internal portions of this structure. This hyperdensity in 5HT1B sites in the SNR likely explains the functional hypersensitivity previously demonstrated by local injection of exogenous 5HT into the SN and systemic administration of RU 24969, a preferential 5HT1B agonist.

Postsynaptic striatal dopamine agonist or antagonist actions of (+) or (-) 3-PPP and modification after receptor deafferentation.

The effects of the (+) and (-) enantiomers of 3-PPP on striatal postsynaptic dopaminergic (DAergic) receptors were studied using two rotation behaviour models in the rat. After unilateral deafferentation of the striatum by injection of 6-hydroxydopamine into the nigrostriatal DAergic tract and the development of hypersensitivity, apomorphine (0.025 mg/kg s.c.) and each of the enantiomers of 3-PPP (0.5-10 mg/kg s.c.) caused marked postural asymmetry and contralateral rotations by preferential stimulation of the DAergic receptors of the lesioned side. These rotations were antagonised by haloperidol (0.5 mg/kg i.p.). After unilateral inactivation of the nigrostriatal loop by extensive electrolytic lesion of the substantia nigra, apomorphine (0.5 mg/kg s.c.) and (+)3-PPP (25 and 50 mg/kg s.c.) caused ipsilateral rotations by stimulation of the striatal DAergic receptors on the intact side. By contrast (-)3-PPP (2-50 mg/kg i.p.) did not cause rotations and furthermore partially or completely opposed the action of apomorphine. These studies showed that (-)3-PPP has either an antagonistic or an agonistic action on the postsynaptic DAergic receptors or the striatum, respectively afferentiated or deafferentiated. Like apomorphine (+)3-PPP has a DAergic agonistic action under both circumstances.

Comparative study of central dopaminergic properties of RU 29717 (N-propyl-9-oxaergoline) and pergolide.

RU 29717, a 9-oxaergoline derivative, has been compared with pergolide in a variety of biochemical and behavioural tests indicative of dopaminergic (DAergic) activity. RU 29717 and pergolide have a similar affinity for DA receptors labelled by [3H]spiroperidol or [3H]dihydroergocryptine ( [3H]DHEC) by using striatal or anterior pituitary membranes respectively. Both compounds stimulate the striatal DA-sensitive adenylate cyclase and inhibit the activity of this enzyme in dispersed cells from the neurointermediate lobe of the pituitary gland. In anterior pituitary cells in primary culture, they decrease prolactin release with the same efficacy. In vivo, they exert a long-lasting inhibition of the reserpine-induced hyperprolactinemia. They equally retard the alpha-MPT-induced disappearance of striatal DA and increase striatal acetylcholine levels. In behavioural models, the similarity between RU 29717 and pergolide is also evident: they induce contralateral circling in animals lesioned unilaterally with 6-OHDA, produce stereotyped behaviour and have emetic activity within the same dose range. Therefore, RU 29717, like pergolide, is a potent direct acting DAergic agonist. In experimental models used to investigate this activity at the striatal or the anterior pituitary levels the compounds present a similar profile of action.

Antidopaminergic effect of estrogens at the striatal level.

The present study investigates the possibility that a potent synthetic estrogen (moxestrol) possesses an antidopaminergic effect at the striatal level. Moxestrol and other estrogens, but not progestagens, androgens or corticosteroids, blocked the apomorphine-induced increase in striatal acetylcholine (ACh) levels. This effect required the repeated administration of moxestrol to develop and lasted for at least 24 hr after the final moxestrol injection. Moxestrol-treatment alone did not alter striatal ACh levels nor did it affect striatal choline acetyltransferase or acetylcholinesterase activities. This estrogen did not modify either the basal or the apomorphine-induced decrease in striatal dopamine turnover. In rats with a unilateral 6-OHDA lesion of the nigro-striatal dopamine pathway, moxestrol antagonized the contralateral circling elicited by apomorphine. The effect of moxestrol on the apomorphine-induced increase in striatal ACh levels was abolished by hypophysectomy and mimicked by pituitary transplants under the renal capsule. These findings, together with previous clinical and pharmacological observations, strongly support the hypothesis that moxestrol exerts an antidopaminergic effect at the striatal level by decreasing dopaminergic postsynaptic transmission via mediation of the pituitary gland.

Time course of apomorphine-induced circling behaviour after striatal dopamine receptor denervation.

The curve describing the time course of apomophine-induced circling behaviour in rats with a 6-hydroxydopamine-induced lesion of the nigrostriatal dopamine (DA) pathway was studied with a microcomputerized rotometer. Up to a 2-week interval after lesioning, the contralateral circling response was a single bell-shaped curve but this gradually became a double-peaked curve after 4-5 months. At this time the bell-shaped curve was, however, restored by haloperidol pretreatment. It is concluded that the response of striatal DA receptors was modified either by the lesion of another neuronal system and/or that the absence of DA nerve endings induced changes in the striatal DA receptor itself.

[Psychopharmacological profile of a new dopaminergic agonist, RU 24213 (author's transl)]. / Profil psychopharmacologique d'un nouvel agoniste dopaminergique, le RU 24213.

The psychopharmacological properties of RU 24213 were compared to those of other dopaminergic agonists (apomorphine, dexamphetamine, bromocriptine and L-dopa) in various behavioural tests. In naive mice the drug reduced the locomotor hyperactivity in the primary exploratory phase and produced stimulation in the subsequent stabilized activity period. In rats it provoked dose-related stereotypies, specially gnawing and sniffing. It delayed the cataleptic state induced by prochlorperazine without affecting its intensity. In animals unilaterally lesioned with 6-OHDA in the nigro-striatal pathway, RU 24213 caused contralateral turning. It exhibited relatively weak emetic and anorexic effects in dogs. Core temperature recordings in rats revealed a biphasic hypo- and hyperthermic activity. In drug interaction studies it was obsers in rats with unilateral electrolytical striatal lesion. The results obtained suggest that RU 24213 stimulates dopamine receptors both directly and indirectly. In this respect it could be compared to bromocriptine but unlike this latter compound it has an immediate effect which is of shorter duration.