A comparison of the inhibitory effects of clonidine and guanfacine on the behavioral and autonomic components of morphine withdrawal in rats

Buccafusco, Jerry J.; Marshall, Dennis C.; Turner, Robert

doi:10.1016/0024-3205(84)90398-9

Cited by 53 publications

(11 citation statements)

References 15 publications

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“…Such data are in agreement with several behavioral studies showing a high correlation between the affinity of a2-adrenergic agonists at I1Rs and their relative potency for decreasing the physiologic manifestation of the withdrawal syndrome (Buccafusco et al, 1984;Coupar, 1992;Maldonado, 1997;Tierney et al, 1988). In particular, the nonimidazoline agent and full a2-adrenergic agonist UK14304 (Andorn et al, 1988;Jansson et al, 1999) did not affect the expression of major opiate withdrawal signs (body shakes, teeth chattering, or diarrhea), whereas rilmenidine (mixed a2/I1 agonist) blocked the physiologic manifestations of the withdrawal syndrome (Tierney et al, 1988).…”

Section: Critical Role Of I1rs In the Protective Effect Of Clonidinesupporting

confidence: 92%

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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Section: Critical Role Of I1rs In the Protective Effect Of Clonidinesupporting

confidence: 92%

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 doses of naloxone that significantly increased MAP in the present study are of the same magnitude as those used by Wei (1973) to elicit an optimal withdrawal behaviour. Furthermore, MAP increased approximately to the same extent after similar doses of naloxone when compared to previous studies on cardiovascular and behavioural changes during morphine withdrawal in rats (Buccafusco 1983, Buccafusco et al 1984. This implies that the pellet implantation procedure used in our model induced a high degree of tolerancephysical dependence.…”

Section: Resultssupporting

confidence: 80%

Central haemodynamics during morphine abstinence in anaesthetized rats

Delle

Thorén

Ricksten

1988

Acta Physiologica Scandinavica

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Central haemodynamics were studied in one group of morphine-dependent rats, and in a non-dependent control group, before and after administration of repeated bolus doses of naloxone. Dependence was induced by s.c. morphine pellet implantations. Mean arterial pressure (MAP), heart rate (HR), cardiac output (CO) and mean transit time (MTT) were measured in the conscious state, after induction of chloralose anaesthesia and after the administration of naloxone (0.005, 0.05, 0.5 and 5 mg kg-1 i.v.). Total peripheral resistance (TPR), stroke volume (SV) and central blood volume (CBV) were subsequently calculated. The haemodynamic variables did not differ significantly in the conscious state, except for a lower SV, when compared with the non-dependent control group. However, in response to anaesthesia the dependent rats exhibited a greater fall in MAP, mainly due to a TPR decrease. Naloxone elicited a marked increase in MAP in the morphine-dependent group, which was mainly caused by an increase in TPR. Naloxone induced no significant change compared with the control group in CO and CBV, while SV increased concomitantly with a lowered HR after naloxone in the morphine-dependent group. These results suggest that the withdrawal hypertension during morphine abstinence was mainly explained by an increase in TPR, reflecting an augmented tone of the resistance vessels. The minor changes in CBV indicate that the tone of the venous capacitance vessels was largely unaffected by naloxone-induced morphine abstinence.

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“…After twelve hours the rats were evaluated for signs associated with morphine withdrawal, using methods previously described (Buccafusco et al, 1984; Marshall and Buccafusco, 1985). Signs associated with spontaneous morphine withdrawal included “wet dog” shakes, writhing, diarrhea, teeth chattering, escape attempts, and chromodacryorrhea around the eyes and nose.…”

Section: Methodsmentioning

confidence: 99%

The use-dependent, nicotinic antagonist BTMPS reduces the adverse consequences of morphine self-administration in rats in an abstinence model of drug seeking

et al. 2011

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In this study, the use-dependent, nicotinic receptor antagonist bis (2, 2, 6, 6-tetramethyl-4-piperidinyl) sebacate (BTMPS) was evaluated for its ability to attenuate the adverse consequences associated with morphine in rats in all three phases of an abstinence model of drug seeking: self-administration, acute withdrawal, and delayed test of drug seeking. Rats were allowed to self-administer morphine (FR1 schedule) with an active response lever, on a 24hr basis inside operant chambers, for 14 days. Each rat was subsequently evaluated for stereotypical behaviors associated with spontaneous morphine withdrawal. Rats were then placed in standard housing cages for a six week period of protracted abstinence from morphine. After this period, each rat was placed back into its respective operant chamber for a 14 day assessment of unrewarded drug seeking responses. BTMPS was administered to the animals in all three clinically relevant phases in three separate sets of experiments. BTMPS treatment during the self-administration phase resulted in up to a 34% reduction of lever responses to morphine when compared to vehicle treated control animals, as well as a 32% reduction in the dose of morphine self-administered. When given during self-administration and acute withdrawal, BTMPS treatment decreased acute withdrawal symptoms (up to 64%) of morphine use and reduced (up to 45%) drug seeking responses after six weeks of protracted withdrawal compared to control animals. BTMPS treatment after six weeks of abstinence from morphine had no effect. These results offer insight into the role of central cholinergic receptors in the onset and maintenance of drug addiction.

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A comparison of the inhibitory effects of clonidine and guanfacine on the behavioral and autonomic components of morphine withdrawal in rats

Cited by 53 publications

References 15 publications

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

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

Central haemodynamics during morphine abstinence in anaesthetized rats

The use-dependent, nicotinic antagonist BTMPS reduces the adverse consequences of morphine self-administration in rats in an abstinence model of drug seeking

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