Dexmedetomidine, Diazepam, and Propranolol in the Treatment of Ethanol Withdrawal Symptoms in the Rat

Abstract

In this study, the effects of dexmedetomidine, a selective alpha 2-adrenoceptor agonist, on ethanol withdrawal symptoms, were compared with those of diazepam and propranolol. The rats were given highly intoxicating doses of ethanol for 4 days. After the intoxication period, rats were divided into four equal groups: a dexmedetomidine-treated group (30 micrograms/kg, sc), a diazepam-treated group (2 mg/kg, sc), a propranolol-treated group (5 mg/kg, sc), and a control group with no medication. Medication was given in the withdrawal phase-2, 8, 14, and 20 hr after the onset of the withdrawal symptoms. The severity of the ethanol withdrawal symptoms (rigidity, tremor, irritability, and hypoactivity) was observed up to 33 hr after the onset of the ethanol withdrawal symptoms. Both dexmedetomidine and diazepam significantly relieved tremor compared with the control group. Diazepam reduced irritability significantly, compared with the control group. When measured as the sum score of the three most specific withdrawal signs (rigidity, tremor, and irritability), dexmedetomidine and diazepam significantly relieved the ethanol withdrawal reaction. Propranolol attenuated tremor, but was inefficient against other withdrawal symptoms. Dexmedetomidine may thus represent a new effective drug in the treatment of the ethanol withdrawal syndrome.

α1-noradrenergic receptor antagonism blocks dependence-induced increases in responding for ethanol

“…Both pre-and postsynaptic noradrenergic ligands that have the generalized effect of attenuating noradrenergic transmission (with antagonists at postsynaptic receptors or agonists at presynaptic inhibitory autoreceptors) are effective at reducing both the somatic and behavioral symptoms associated with acute withdrawal (Aston-Jones and Harris, 2004; Delfs et al, 2000;Ozdogan et al, 2003;Riihioja et al, 1997a;Riihioja et al, 1997b;Trzaskowska et al, 1986;Van der Laan, 1987). Although prazosin was administered peripherally in the present study, previous evidence has implicated central noradrenergic transmission as participating in withdrawal-induced behavioral changes (Aston-Jones et al, 1999;Aston-Jones and Harris, 2004;Maldonado, 1997).…”

“…Postsynaptic β-adrenergic antagonists have been shown to reduce withdrawal-induced convulsions (Trzaskowska et al, 1986) and tremors (Riihioja et al, 1997b). Likewise, presynaptic α 2 -noradrenergic receptor agonists have been shown to reduce rigidity, tremor and irritability associated with ethanol withdrawal (Riihioja et al, 1997a;Riihioja et al, 1997b). Additionally, α 1 -adrenergic receptor antagonists have been shown to reduce the locomotor hyperactivity produced by ethanol withdrawal (Trzaskowska et al, 1986).…”

“…Although it has been shown previously that norepinephrine depletion produced by blockade of the synthetic pathway attenuates ethanol self-administration in rats Brown et al, 1977;Davis et al, 1978), noradrenergic systems have received much less attention in ethanol-dependence. However, there is evidence suggesting that modulation of noradrenergic systems shows efficacy in alleviating certain aspects of ethanol withdrawal and dependence that could be related to enhanced ethanol consumption (Patkar et al, 2003;Rasmussen et al, 2006;Riihioja et al, 1997a;Riihioja et al, 1997b;Trzaskowska et al, 1986) from a negative reinforcement perspective (i.e., removal of negative stimuli translates into a positive event that is considered reinforcing).…”

“…Pharmacologically, ligands targeting different receptor subtypes of the norepinephrine system have shown efficacy for reducing certain aspects of ethanol withdrawal symptomology. Postsynaptic β-adrenergic antagonists have been shown to reduce withdrawal-induced convulsions (Trzaskowska et al, 1986) and tremors (Riihioja et al, 1997b). Likewise, presynaptic α 2 -noradrenergic receptor agonists have been shown to reduce rigidity, tremor and irritability associated with ethanol withdrawal (Riihioja et al, 1997a;Riihioja et al, 1997b).…”

Temporally Specific Burst in Cell Proliferation Increases Hippocampal Neurogenesis in Protracted Abstinence from Alcohol

“…In a two ϫ two design, control and ethanol-exposed rats received diazepam (10 mg/kg) or vehicle (two drops of Tween 20 quantum sufficit to 10 ml with physiological saline) every 8 hr for 24 hr. The 10 mg/kg dose of diazepam has been shown to significantly reduce epileptiform activity (Mhatre et al, 2001), alcohol withdrawal symptoms (Aaronson et al, 1982;Riihioja et al, 1997), and in the alcohol model used here, it specifically reduced withdrawal behaviors (Bone et al, 1989). At T ϭ 10 hr, rats were injected with diazepam or vehicle and then observed for withdrawal behaviors until T ϭ 24 hr.…”