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V Daugé

Publications and source records attributed to V Daugé.

At least 37 records · Page 2Linked to original sources
PubMed1994

The selective CCK-B agonist, BC 264, impairs socially reinforced memory in the three-panel runway test in rats.

The role of CCK-B receptor activation in memory processes has been reassessed using the three-panel runway task, under conditions which avoid the effects of CCK on satiety and reduce emotional responses. For this purpose the food reinforcement usually used was replaced by a social reinforcement. The results show that learning and memory can be assessed using this procedure. Moreover, under these experimental conditions, drugs such as scopolamine, amphetamine or kinurenic acid injected into the nucleus accumbens produced behavioral deficits. BC 264, a highly selective CCK-B agonist, peripherally administered or infused into the anterolateral part of the nucleus accumbens also impaired memory. These effects were suppressed by L-365,260 supporting the involvement of CCK-B receptors and of the nucleus accumbens in memory processes.

Amino Acid Sequence↗
PubMed1994

Different modifications of the dopamine metabolism in the core and shell parts of the nucleus accumbens following CCK-A receptor stimulation in the shell region.

After the injection of CCK8 into the posterior N. Acc. of rats DA, DOPAC HVA contents were determined from punches of the anterior and posterior N. Acc. and VTA. CCK8 (20 pmol/side) modified these levels only in the posterior N. Acc. and these responses were inhibited by the CCK-A antagonist devazepide. Five min after treatment, DA, DOPAC and HVA were increased in the N. Acc.shell and 10 min later they were decreased in the N. Acc.core. These data suggest that in these regions CCK8 could both abolish the influence of DA from the core on the transmission of motor information and favor that of DA from the shell on emotional-like responses.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Effects of CCK8 and of the CCKB-selective agonist BC264 on extracellular dopamine content in the anterior and posterior nucleus accumbens: a microdialysis study in freely moving rats.

The effects of the local administration of cholecystokinin octapeptide (CCK8) in the posterior nucleus accumbens (N. Acc.) and of BC264 (a selective CCKB agonist) in the anterior N. Acc. on dopamine (DA) neurotransmission were studied in awake rats. Microdialysis was used to quantify the extracellular contents of DA and its two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). In the posterior N. Acc., a perfusion of 10(-5) M CCK8 for 40 min (i.e. 25 pmol) increased the extracellular levels of DA, DOPAC and HVA. In contrast, 10(-4) M BC264 perfused for 40 min (i.e. 350 pmol) into the anterior N. Acc. reduced extracellular DA but did not modify DOPAC and HVA levels. These findings suggest that the CCK-DA interactions are different in various regions of the N. Acc. and emphasize the functional heterogeneity of the N. Acc., issuing in part from its particular DA innervation (mixed CCK-DA terminals only in the posterior region) but also from the distribution of the CCK fibers and binding sites in this nucleus. This microdialysis study, using perfusions of CCK compounds in the N. Acc. of freely moving rats, shows that the CCK system might play an important regulatory role in limbic DA function.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Involvement of D2 dopaminergic receptors in the emotional and motivational responses induced by injection of CCK-8 in the posterior part of the rat nucleus accumbens.

When CCK-8 was injected in the rat posterior nucleus accumbens, where it is in part co-localized with dopamine, a decrease in exploration of the four hole box and the elevated plus maze was observed. In this study, a selective destruction of the dopaminergic mesoaccumbens pathway induced by local injection of 6-hydroxydopamine (6-OHDA) in the nucleus accumbens was found to suppress the CCK-8-evoked behavioral effects. Moreover, an ex vivo measurement of the dopaminergic metabolism has been performed after injection of CCK-8 in the posterior nucleus accumbens by electrochemical detection of dopamine and its metabolites extracted from punches of brain tissue. The results showed that CCK-8 decreased the turnover of dopamine in the posterior part but not in the anterior part of the nucleus accumbens or in the ventral tegmental area. Furthermore, sulpiride, a selective antagonist for D2 dopamine receptors, but not SCH 23390, a selective antagonist for D1 dopamine receptors, prevented CCK-8-induced behavioral responses. Taken together, these results suggest that CCK-8 could be involved in behavioral adaptation to situations producing change in emotional and/or motivational states through modulation of presynaptic D2 receptor functioning.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Effect of inhibiting enkephalin catabolism in the VTA on motor activity and extracellular dopamine.

The mixed inhibitor of enkephalin catabolism, kelatorphan, was microinjected into the ventral tegmental area (VTA) of rats to determine if endogenous enkephalins can modulate dopamine transmission in the mesoaccumbens projection. The concentration of extracellular dopamine content in the nucleus accumbens was monitored using in vivo microdialysis simultaneously with measuring motor behavior. Kelatorphan microinjection into the VTA produced a dose-related increase in motor activity and extracellular dopamine in the nucleus accumbens. While the change in extracellular dopamine was modest as compared to exogenous stimulation by a mu agonist such as DAMGO, there was a marked increase in the extracellular content of dopamine and serotonin metabolites. This suggests that mesoaccumbens dopamine transmission is under tonic control of endogenous enkephalins at the ventral tegmental area level.

Amino Acid Sequence↗
PubMed1992

Antidepressant-type effects of endogenous enkephalins protected by systemic RB 101 are mediated by opioid delta and dopamine D1 receptor stimulation.

The role of endogenous enkephalins in behavioural control in mice was investigated by i.v. injection of RB 101 (N-[(R,S)-2-benzyl-3[(S)(2-amino-4- methylthio)butyl dithio]-1-oxopropyl]-L-phenylalanine benzyl ester). RB 101 is a recently reported systemically active mixed inhibitor prodrug of the two enzymes which metabolize the enkephalins neutral endopeptidase 24.11 and aminopeptidase N. RB 101 (2.5-10 mg/kg) induced a dose-dependent long-lasting hyperlocomotion and attenuated the conditioned suppression of motility in mice placed in an environment where they had received footshocks 24 h before. In addition, RB 101 decreased the duration of immobility in the forced swim test. All these actions of RB 101 were antagonized by the selective delta antagonist, naltrindole, supporting the preferential involvement of delta opioid receptors in these enkephalin-controlled behavioural responses. The effects induced by RB 101 were also suppressed by prior administration of the selective dopamine D1 antagonist, SCH 23390, but not by the D2 antagonist, sulpiride. Attenuation of the conditioned suppression of motility was associated with increased striatal dihydroxyphenylacetic acid (DOPAC)/dopamine (DA) and homovanillic acid (HVA)/DA ratios, both effects being antagonized by naltrindole. This latter compound is also efficient to inhibit the effect of imipramine in the mouse forced swim test. Taken together, these results support the occurrence of tonic and phasic controls of mood-related behaviour by endogenous enkephalins through delta and D1 receptor stimulation and suggest a possible future use of these mixed inhibitors as new antidepressants.

Animals↗
PubMed1992

The selective CCK-B agonist, BC 264 injected in the antero-lateral part of the nucleus accumbens, reduces the spontaneous alternation behaviour of rats.

The aim of this study was to examine the behavioural effects induced by stimulation of CCK receptors in the nucleus accumbens of the rat, which contains a high density of heterogenously distributed CCK-B receptors. The drug BC264 (Boc-Tyr(SO3H)-gNle-mGly-Trp-(NMe)Nle-Asp-Phe-NH2), a highly potent and selective CCK-B agonist, injected into the postero-median or antero-median n. accumbens did not modify the spontaneous alternation and exploratory behaviour observed in a Y-maze. In contrast, when administered into the antero-lateral part of the n. accumbens, BC264 (0.3-1.0 nmol) reduced alternation to chance level, without changing the number of arm visits. This effect was suppressed by the selective CCK-B antagonist: L365,260, but not by the selective CCK-A antagonist: MK329. The physiological relevance of this effect was supported by the similar responses induced, in the same concentration range, by the CCK8-like agonist, BDNL (Boc diNle28,31CCK7). These results emphasize the functional heterogeneity of the CCK network in the n. accumbens of the rat and the participation of the peptide in the expression of alternation behaviour, through stimulation of CCK-B receptors. They also show that the recently described anxiolytic effects, induced by CCK-B antagonists, do not seem to occur at this level.

Amino Acid Sequence↗
PubMed1991

Lesion of dopamine mesolimbic neurons blocks behavioral effects induced by the endogenous enkephalins but not by a mu-opioid receptor agonist.

Lesioning of dopamine neurons by injection of 6-hydroxydopamine into the nucleus accumbens blocked the increased rearing activity measured in the open-field and induced by injection into the ventral tegmental area of: [R)-3-(N-hydroxylcarboxamido-2-benzyl-propanoyl)-L-alanine), kelatorphan (complete inhibitor of enkephalin catabolism) or by (Tyr-D-Ser(OtBu)-Gly-Phe-Leu-Thr(OtBu)): BUBU (selective delta agonist) but not the hypolocomotion evoked by the mu agonist (Tyr-D-Ala-Gly-N(Me)-Phe-Glyol): DAMGO. This suggests the involvement of different neuronal pathways in mu and delta effects.

Amino Acid Sequence↗
PubMed1991

Opioid delta agonists and endogenous enkephalins induce different emotional reactivity than mu agonists after injection in the rat ventral tegmental area.

The possible role of opioid receptor heterogeneity in the biphasic changes in locomotion (activation and inhibition) induced by non-selective opiates such as morphine, has been investigated by measuring the behaviour of rats exposed to different environments after injection into the ventral tegmental area, of selective mu (DAGO) or delta (DTLET, DSTBULET, BUBU) opioid agonists and of kelatorphan, a complete inhibitor of enkephalin metabolism. delta agonists or kelatorphan-induced hyperactivity in a familiar (actimeter), unfamiliar (four-hole box) and a fear inducing (open-field) environment. These effects were suppressed by naloxone and delta selective antagonists (ICI 174, 864 2 mg/kg SC, naltrindole 7 nmol in the ventral tegmental area). Moreover, the delta agonists and endogenous enkephalins protected by kelatorphan did not affect the emotional state of rats measured in an elevated plus maze. Infused into the ventral tegmental area, DAGO also enhanced locomotion in the actimeter but in contrast to delta agonists and kelatorphan, the mu agonist decreased activity in the open-field and the four-hole box. The hypoactivity observed in these tests could be related to an enhanced emotionality produced by mu receptor stimulation, as shown by the significant decrease in the number of visits and time spent in open arms of the elevated plus maze. Naloxone (0.3 mg/kg SC) but not delta selective antagonists, blocked the various responses induced by DAGO.

Animals↗
PubMed1991

Systemic administration of (Tyr-D-Ser(O-tert-butyl)-Gly-Phe-Leu-Thr(O-tert-butyl), a highly selective delta opioid agonist, induces mu receptor-mediated analgesia in mice.

The mu opioid receptors are unquestionably implicated both in supraspinal and spinal analgesia, but there is some controversy about the role of delta receptors in the control of pain at the supraspinal level. This could be due, at least in part, to the local or i.c.v. administration of the opioid agonists. It was therefore interesting to reassess the overall contribution of mu and delta opioid receptors in modulating nociceptive thermal stimuli in the hot plate-test in mice after i.v. injections of DAMGO (Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol) and BUBU (Tyr-D-Ser(O-tert-butyl)-Gly-Phe-Leu-Thr(O-tert-butyl), two highly selective mu and delta receptor agonists, respectively, whose passage into the brain has been demonstrated recently. Both agonists induced dose-dependent, short-lasting (less than 30 min), antinociceptive responses that peaked 5 min after the administration of DAMGO and 10 min after the administration of BUBU. At these times, DAMGO [ED50: 1.26 mumols (0.65 mg)/kg] was 34 times more potent than BUBU [ED50: 42.5 mumols (34 mg)/kg] in the jump response and 13 times more potent in the paw lick. Apparent pA2 values of naloxone (0.004-0.1 mg/kg s.c.) antagonism for DAMGO and BUBU did not differ significantly, 6.95 +/- 0.054 and 7.28 +/- 0.030 for paw lick tests and 7.11 +/- 0.045 and 7.25 +/- 0.027 for jump tests, respectively. The slopes of the pA2 plots were close to the theoretical -1 value for competitive antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗
PubMed1990

Chronic blockade of D2 but not D1 dopamine receptors facilitates behavioural responses to endogenous enkephalins, protected by kelatorphan, administered in the accumbens in rats.

It has previously been shown that kelatorphan, (R)-3-(N-hydroxycarboxamido-2-benzyl-propanoyl)-L-alanine, a mixed inhibitor of the catabolism of enkephalins, injected into the nucleus accumbens, induced a dose-dependent hyperlocomotion in rats. In this study, the consequence of chronic treatment with sulpiride, a selective D2 dopamine receptor antagonist, SCH 23390, a selective D1 dopamine receptor antagonist, or haloperidol, a nonspecific but preferential D2 receptor antagonist, on the behavioural response induced by acute administration of kelatorphan into the accumbens, has been investigated in rats. The drug SCH 23390 did not modify the behavioural response to kelatorphan, whereas sulpiride and haloperidol induced an increase which was maximal in the third week after the beginning of treatment, a period corresponding to the appearance of the antipsychotic effect of the neuroleptics. This facilitation was reversed by prior administration of the delta-selective antagonist, ICI 174864. These results suggest that the phasic activity of enkephalinergic neurones of the nucleus accumbens and the associated behavioural hyperactivity are facilitated after chronic blockade of the D2 but not the D1 subtypes of dopamine receptor.

Animals↗
PubMed1990

Novel approaches in the development of new analgesics.

A recently developed series of highly selective and systemically active delta-agonists such as Tyr-X-Gly-Phe-Leu-Thr(OtBu), with X = D.Ser (OtBu) in BUBU and X = D.Cys(StBu) in BUBUC, and complete inhibitors of enkephalin metabolism (Kelatorphan, RB 38 A, PC 12) have enabled the major role played by mu-opioid receptors in supraspinal analgesia to be demonstrated. This is in agreement with the results of in vivo mu-receptor occupancy measured by taking into account the cross-reactivity of the delta-ligands for mu-sites. In contrast, mu and delta binding sites seem to act independently to control pain at the spinal level. Strong analgesic effects, especially in arthritic rats, can also be obtained by complete protection of tonically or phasically released endogenous enkephalins with mixed inhibitors such as RB38A. Chronic icv administration of the mu agonist DAGO, led to a severe naloxone precipitated withdrawal syndrome whilst a weak dependence was seen with the delta agonist, DSTBULET or with RB 38 A. Moreover, mixed inhibitors did not induce any significant respiratory depression. All these data emphasize the interest in developing delta-agonists and mixed inhibitors with appropriate bioavailability for clinical evaluation.

Amino Acid Sequence↗
PubMed1990

Effects induced by chronic treatment with selective D1 or D2 antagonists on open-field behavior and colonic temperature.

We have studied the behavioral responses in open-field and the changes in body temperature induced after chronic treatment with a selective D1 antagonist, SCH 23390, a selective D2+ antagonist, sulpiride, or a non specific but preferential D2 antagonist, haloperidol. After chronic treatment with SCH 23390 or sulpiride, rats were challenged with SKF 38393, selective D1 agonist, or LY 171555, selective D2 agonist, in order to study the responses of D1 and D2 stimulation. After chronic SCH 23390, an increase of the locomotion and of the number of rears were observed whereas, no changes were induced by chronic sulpiride or haloperidol. Acute treatment with sulpiride blocked the hyperlocomotion induced by chronic SCH 23390. In naive rats acute administration of SKF 38393 or LY 171555 did not produce any change in locomotion or rearing. In rats treated chronically with SCH 23390 this acute administration of LY 171555 induced an increase of the number of squares and of the number of rears. In these animals, acute administration of SKF 38393 also augmented the number of squares crossed. In contrast, chronic sulpiride did not modify behavioral responses obtained after acute SKF 38393 or LY 171555. Colonic temperature was not changed after acute SKF 38393 while acute LY 171555 induced a hypothermia. Chronic sulpiride did not modify the responses of SKF 38393 or LY 171555, but an increase in body temperature was observed after acute SKF 38393 in animals chronically treated with SCH 23390. The present results support a different behavioral expression of D1 and D2 supersensitivity in rats. Furthermore, chronic treatment with a D1 antagonist induced facilitatory effects on D2 behavioral responses; however, these D1-D2 interactions were not observed in body temperature responses.

Animals↗
PubMed1989

Comparison of selective and complete inhibitors of enkephalin-degrading enzymes on morphine withdrawal syndrome.

We investigated the effects of thiorphan, a selective inhibitor of endopeptidase 24.11 'enkephalinase', kelatorphan ((R)-3-(N-hydroxy-carboxamido-2-benzylpropanoyl)-L-alanine), and RB 38 A ((R)-3-(N-hydroxycarboxamido-2-benzylpropanoyl)-L-phenylalanine) two almost complete inhibitors of enkephalin metabolism, on the naloxone-precipitated morphine withdrawal syndrome in rats. Inhibitors administered intracerebroventricularly reduced several symptoms of the withdrawal syndrome. Jumping, chewing and tooth chattering were decreased by all drugs. The rise in plasma corticosterone and the hypothermia were reduced by kelatorphan and RB 38 A whereas rhinorrhea was blocked by thiorphan, tremor by kelatorphan and diarrhoea by RB 38 A. Other signs remained unchanged. These data suggest that an increase in opioid receptor occupancy by endogenous opioid peptides, protected from biotransformation specially by mixed inhibitors reduced the severity of the morphine abstinence symptoms in rats.

Animals↗
PubMed1989

The behavioral effects of CCK8 injected into the medial nucleus accumbens are dependent on the motivational state of the rat.

The effects of CCK8 injected into the rat median nucleus accumbens on exploration and locomotion were measured in the four hole box and open-field tests. CCK8 (1 fmol to 100 pmol) induced hypoexploration in the four hole box (duration, frequency), with the pattern of the responses remaining unchanged compared to those of the control group. These effects were reversed by injection of the CCK antagonist proglumide (20 micrograms) into the nucleus accumbens. In the open-field test, CCK8 (100 pmol) only decreased locomotion and rearing when the rats were not habituated to the environment. These results show that the behavior of rats exposed to a novel external stimuli is highly sensitive to CCK8.

Animals↗
PubMed1989

Blockade of dopamine receptors reverses the behavioral effects of endogenous enkephalins in the Nucleus caudatus but not in the Nucleus accumbens: differential involvement of delta and mu opioid receptors.

We have previously (Daugé et al. 1988) demonstrated that injection of the mu agonist [D-Ala2, MePhe4, Gly-ol5]-enkephalin (DAGO) or the delta agonist [D-Thr2, Leu5]-enkephalyl-Thr6 (DTLET) into the rat Nucleus accumbens (N.Acc.), or Nucleus caudatus (N.Caud.) induced a hypoactivity followed by hyperactivity 150 min later in the case of the mu agonist and a hyperactivity in the case of the delta agonist. Moreover, naloxone reversible delta-type responses were obtained by local infusion of kelatorphan, ([(R)-3(N-hydroxylcarboxamido-2-benzylpropanoyl)-L-alanine]), a complete inhibitor of enkephalin catabolism, suggesting a tonic control of the behavioral activity of rat by the endogenous opioid peptides. In this work, the putative involvement of the dopaminergic system in these behavioral responses was investigated by using the DA antagonist thioproperazine. In the N.Acc., the behavioral effects of kelatorphan or of mu or delta agonists were not altered by thioproperazine-induced blockade of dopamine receptors. In contrast, the hyperactivity produced by DTLET or by kelatorphan in the N.Caud. was reversed by thioproperazine while the time-dependent biphasic effect resulting from DAGO injection remained unaffected by the DA antagonist. This blocking effect of thioproperazine is in agreement with the previously described delta-selective enhancement of the release of newly synthesized DA in the striatum but not in the N.Acc.

Animals↗