Effects of two alpha2 agonists, rilmenidine and clonidine, on the morphine withdrawal syndrome and their potential addictive properties in rats

Tierney, Caroline; Nadaud, D.; Koenig-Berard, Elisabeth; Stinus, L.

doi:10.1016/0002-9149(88)90462-6

Cited by 27 publications

(29 citation statements)

References 7 publications

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“…Kosten (1994) has suggested that the intrinsic reinforcing properties of clonidine itself may be required to overcome the aversive consequences of opiate withdrawal as measured in the place aversion paradigm. The minimal doses of clonidine found to be effective in the current study, however, are below those reported to produce a conditioned place preference (Cervo et al 1993;Tierney et al 1988). Our findings are in agreement with those of Nader and van der Kooy (1996), who found that 50 g/kg of clonidine could attenuate conditioned place aversions produced by naloxone-precipitated opiate withdrawal without producing any conditioned preferences by itself in opiate-dependent, nonwithdrawn rats.…”

Section: Discussionsupporting

confidence: 91%

“…Our findings are in agreement with those of Nader and van der Kooy (1996), who found that 50 g/kg of clonidine could attenuate conditioned place aversions produced by naloxone-precipitated opiate withdrawal without producing any conditioned preferences by itself in opiate-dependent, nonwithdrawn rats. Nonetheless, it is possible that the complete reversal of place aversion seen with 100 to 400 g/kg doses of clonidine was dependent, at least in part, on the ability of these doses to produce a place preference (Cervo et al 1993;Nader and van der Kooy 1996;Tierney et al 1988).…”

Section: Discussionmentioning

confidence: 99%

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Clonidine Blocks Acquisition But not Expression of Conditioned Opiate Withdrawal in Rats

Schulteis

Stinus

Risbrough

et al. 1998

Neuropsychopharmacology

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Previous studies in rodents have reported that clonidine, anAddiction can be defined as a "behavioral pattern of drug use, characterized by overwhelming involvement with the use of a drug (compulsive use), the securing of its supply, and a high tendency to relapse after withdrawal" (Jaffe 1990). Among the factors that may contribute to loss of control over drug intake and relapse after periods of abstinence are conditioned associations that are formed over a course of repeated drug experience. Within the domain of opiate withdrawal symptomatology, it is now recognized that somatic/autonomic signs and affective or emotional signs (e.g., anxiety, depression, dysphoria), each with their own unique underlying neurophysiological substrates (reviewed by Maldonado et al. 1996;Schulteis and Koob 1996), may differentially motivate continued drug use, with the affective signs hypothesized to be of greater motivational significance than the somatic signs.A considerable body of both clinical and preclinical literature suggests that positive (drug reward) and negative (drug withdrawal) affective states can become associated with stimuli in the drug-taking environment and that these conditioned stimuli themselves acquire motivational significance in maintaining compulsive use and in precipitating relapse after periods of abstention (Baldwin and Koob 1993;Childress et al. 1994;

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Clonidine Blocks Acquisition But not Expression of Conditioned Opiate Withdrawal in Rats

Schulteis

Stinus

Risbrough

et al. 1998

Neuropsychopharmacology

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“…Considerable evidence indicates that a 2 -adrenergic agonists and antagonists can induce CPP or conditioned place aversion (CPA; see review Tzschentke, 1998). The a 2 -agonist clonidine is shown to produce CPP over a range of doses (Asin and Wirtshafter, 1985;Tierney et al, 1988), while the a 2 antagonist yohimbine has been found to produce CPA (File, 1986). Also increasing evidence indicates the effect of a 2 -adrenergics on opioid-induced CPP.…”

Section: Introductionmentioning

confidence: 99%

Agmatine Potentiates Morphine-Induced Conditioned Place Preference in Mice: Modulation by Alpha(2)-Adrenoceptors

Tahsili-Fahadan

Yahyavi-Firouz-Abadi

Khoshnoodi

et al. 2005

Neuropsychopharmacol

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The effects of agmatine, an endogenous polyamine metabolite formed by decarboxylation of L-arginine, and its combination with morphine on conditioned place preference (CPP) has been investigated in male mice. Our data show that subcutaneous administration of morphine (1-7.5 mg/kg) significantly increases the time spent in the drug-paired compartment in a dose-dependent manner. Intraperitoneal administration of agmatine (1-40 mg/kg) alone does not induce either CPP or conditioned place aversion, while combination of agmatine and subeffective doses of morphine leads to potent rewarding effects. Lower doses of morphine (0.1, 0.05, and 0.01 mg/kg) are able to induce CPP in mice pretreated with agmatine 1, 5, and 10 mg/kg, respectively. Concomitant intraperitoneal administration of UK 14 304 (0.5 mg/kg), a highly selective a 2 -agonist, with per se noneffective dose of morphine (0.5 mg/kg) and also its combination with noneffective doses of agmatine (1 mg/kg) plus morphine (0.05 mg/kg) produces significant CPP. UK 14 304 (0.05, 0.5 mg/kg) alone, or in combination with agmatine (1, 5 mg/kg) have had no effect. We have further investigated the possible involvement of the a 2 -adrenoceptors in the potentiating effect of agmatine on morphine-induced place preference. Selective a 2 -antagonists, yohimbine (0.005 mg/kg) and RX821002 (0.1, 0.5 mg/kg), block the CPP induced by concomitant administration of agmatine (5 mg/kg) and morphine (0.05 mg/kg). Yohimbine (0.001-0.05 mg/kg) or RX821002 (0.05-0.5 mg/kg) alone or in combination with morphine (0.05 mg/kg) or agmatine (5 mg/kg) fail to show any significant place preference or aversion. Our results indicate that pretreatment of animals with agmatine enhances the rewarding properties of morphine via a mechanism which may involve a 2 -adrenergic receptors.

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“…Several animal studies have demonstrated clonidine's ability to lessen somatic signs of opiate withdrawal and attenuate the aversive aspects of this state when administered prior to each withdrawal-conditioning episode (Caillé et al, 1999;Kosten, 1994;Schulteis et al, 1998;Tierney et al, 1988). Clonidine administration also prevents the DA decrease in the nucleus accumbens that normally accompanies opiate withdrawal (Pothos et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, I1Rs are not expressed in the locus coeruleus (LC) (King et al, 1995;Ruggiero et al, 1998). In the central nervous system the functions associated with imidazoline receptors are largely unknown but evidence exists for their involvement in the withdrawal syndrome resulting from chronic opiate abuse (Tierney et al, 1988) as well as in major depression and neurodegenerative diseases (for a review see GarciaSevilla et al, 1999). Therefore, the second aim of the present study was to assess the role of I1Rs in VTA DA neuronal activity during morphine withdrawal.…”

Section: Introductionmentioning

confidence: 99%

Prolonged Activation of Mesolimbic Dopaminergic Neurons by Morphine Withdrawal Following Clonidine: Participation of Imidazoline and Norepinephrine Receptors

Georges

Aston‐Jones

2003

Neuropsychopharmacol

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The a2 adrenoceptor (a2R) agonist clonidine is used as a treatment for heroin addiction. Substantial evidence indicates that dopaminergic and noradrenergic systems have key roles in opiate dependence and withdrawal but the possible interactions between these two pathways remain unclear. The objective of this study was to establish the effects of clonidine pretreatment on ventral tegmental area dopaminergic (VTA DA) neuronal activity during morphine withdrawal. Responses of VTA DA neurons to withdrawal precipitated by naltrexone were characterized in anesthetized rats using extracellular recordings. As expected, withdrawal produced a marked inhibition of VTA DA neuronal activity. However, pretreatment with clonidine prevented this inhibition induced by withdrawal, and instead produced a long-lasting activation of firing rate (+50%) and burst firing (+19%). In contrast, pretreatment with a more selective a2R agonist, UK14304, did not prevent the inhibition of VTA DA neuron activity during withdrawal. We tested whether the high affinity of clonidine for imidazoline-1 receptors (I1Rs) was responsible for the difference between these two a2R agonists. In morphine-dependent rats pretreated with rilmenidine (mixed a2R/I1R agonist), precipitation of withdrawal elicited a 22% increase of VTA DA impulse activity. The action of clonidine on I1Rs was studied by coadministering clonidine with RX821002, a specific a2R antagonist. Pretreatment with RX821002 plus clonidine prevented the inhibition of VTA DA activity during withdrawal but failed to produce excitation. These results indicate that the pharmacological effects of clonidine on VTA DA neurons during morphine withdrawal is related to actions on I1Rs as well as a2Rs.

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Effects of two alpha2 agonists, rilmenidine and clonidine, on the morphine withdrawal syndrome and their potential addictive properties in rats

Cited by 27 publications

References 7 publications

Clonidine Blocks Acquisition But not Expression of Conditioned Opiate Withdrawal in Rats

Clonidine Blocks Acquisition But not Expression of Conditioned Opiate Withdrawal in Rats

Agmatine Potentiates Morphine-Induced Conditioned Place Preference in Mice: Modulation by Alpha(2)-Adrenoceptors

Prolonged Activation of Mesolimbic Dopaminergic Neurons by Morphine Withdrawal Following Clonidine: Participation of Imidazoline and Norepinephrine Receptors

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