Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats

Lê, A. D.; Harding, Shannon M.; Juzytsch, Walter; Funk, Douglas; Shaham, Yavin

doi:10.1007/s00213-004-2036-y

Cited by 232 publications

(117 citation statements)

References 65 publications

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“…The fact that two different pharmacologic interventions that decrease noradrenergic signaling, but via different mechanisms, are both capable of suppressing alcohol drinking is consistent with evidence that activation of the noradrenergic system plays a key role in mediating voluntary alcohol drinking. These results are also consistent with reports that: a) the α 2 -adrenergic receptor agonist, lofexidine, reduces operant self-administration of alcohol by Wistar rats (Lé, Harding, Juzytsch, Funk, & Shaham, 2005), b) clonidine and another α 2 -adrenergic receptor agonist, guanfacine, decrease alcohol drinking by food-restricted rats selectively bred for alcohol drinking (descendants of the Finnish Alko Alcohol (AA) rats) (Opitz, 1990), c) depletion of brain norepinephrine decreases alcohol drinking (Amit, Brown, Levitan, & Ogren, 1977; Brown et al, 1977) and alcohol self-administration in unselected rats (Davis et al, 1978), and d) prazosin reduces acute withdrawal-induced operant self-administration of alcohol by alcohol-dependent Wistar rats (Walker, Rasmussen, Raskind, & Koob, 2008). …”

Section: Discussionsupporting

confidence: 93%

“…For example, clonidine decreases craving, anxiety, tension, irritability, and restlessness associated with nicotine withdrawal (Glassman et al, 1984). More recently, administration of clonidine or other α 2 -adrenergic receptor agonists (e.g., lofexidine, guanfacine, guanabenz) has been demonstrated to attenuate stress-induced reinstatement of opiate, cocaine, and alcohol seeking in rats (Erb et al, 2000; Highfield, Yap, Grimm, Shalev, & Shaham, 2001; Lé et al, 2005; Shaham et al, 2000). These results are consistent with evidence that blocking post-synaptic α 1 -adrenergic receptors with prazosin decreases consumption of cocaine, opiates, nicotine, and alcohol (Greenwell, Walker, Cottone, Zorrilla, & Koob, 2009; Rasmussen et al, 2009; Simpson et al, 2009; Villégier, Lotfipour, Belluzzi, & Leslie, 2007; Wee, Mandyam, Lekic, & Koob, 2008; Zhang & Kosten, 2005, 2007) and with the findings of the current study that inhibiting noradrenergic signaling with the α 2 -adrenergic receptor agonist, clonidine, decreases voluntary alcohol consumption.…”

Section: Discussionmentioning

confidence: 99%

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The α2-adrenergic receptor agonist, clonidine, reduces alcohol drinking in alcohol-preferring (P) rats

Rasmussen

Alexander

Malone

et al. 2014

Alcohol

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Evidence suggests that noradrenergic signaling may play a role in mediating alcohol-drinking behavior in both rodents and humans. We have investigated this possibility by administering clonidine to alcohol-drinking rats selectively bred for alcohol preference (P line). Clonidine is an α2-adrenergic receptor agonist which, at low doses, inhibits noradrenergic signaling by decreasing norepinephrine release from presynaptic noradrenergic neurons. Adult male P rats were given 24-h access to food and water and scheduled access to a 15% (v/v) alcohol solution for 2 h daily. Rats received intraperitoneal (IP) injections with clonidine (0, 10, 20, 40, or 80 µg/kg body weight [BW], 10–11 rats/treatment group) once/day at 30 min prior to onset of the daily 2-h alcohol access period for 2 consecutive days. Clonidine, in doses of 40 or 80 µg/kg BW, significantly reduced alcohol intake on both days of treatment (p < 0.001). Two weeks later, rats were treated with clonidine for 5 consecutive days and clonidine, in doses of 40 or 80 µg/kg BW, reduced alcohol intake on all 5 treatment days (p < 0.001). Clonidine did not alter water consumption during the daily 2-h free-choice between alcohol and water. In a separate group of male P rats, clonidine (40 µg/kg BW) suppressed intake of a saccharin solution (0.04 g/L). These results are consistent with and complement our previous findings that the α1-adrenergic receptor antagonist, prazosin, decreases voluntary alcohol drinking in alcohol-preferring rats, but suggests that effects of clonidine may not be specific for alcohol. The results suggest that although activation of the noradrenergic system plays an important role in mediating voluntary alcohol drinking, care is needed in selecting which drugs to use to suppress central noradrenergic signaling in order to maximize the selectivity of the drugs for treating alcohol-use disorders.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

The α2-adrenergic receptor agonist, clonidine, reduces alcohol drinking in alcohol-preferring (P) rats

Rasmussen

Alexander

Malone

et al. 2014

Alcohol

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“…Finally, duloxetine may decrease anxiety-related ethanol intake by attenuating LC output via activation of presynaptic α2-ARs, which act as autoreceptors in this region. In support of this, SNRIs have been shown to decrease LC output (Berrocoso and Mico, 2007), and α2-AR agonists are reported to reduce ethanol self-administration (Le et al, 2005). Further work is needed to determine how noradrenergic signaling is disrupted by chronic adolescent stress and subsequent ethanol intake, and where in the brain these pharmacotherapeutics are exerting their effects on stress-related voluntary ethanol consumption.…”

Section: Discussionmentioning

confidence: 84%

Adolescent social isolation increases anxiety-like behavior and ethanol intake and impairs fear extinction in adulthood: Possible role of disrupted noradrenergic signaling

et al. 2015

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Alcohol use disorder, anxiety disorders, and post-traumatic stress disorder (PTSD) are highly comorbid, and exposure to chronic stress during adolescence may increase the incidence of these conditions in adulthood. Efforts to identify the common stress-related mechanisms driving these disorders have been hampered, in part, by a lack of reliable preclinical models that replicate their comorbid symptomatology. Prior work by us, and others, has shown that adolescent social isolation increases anxiety-like behaviors and voluntary ethanol consumption in adult male Long-Evans rats. Here we examined whether social isolation also produces deficiencies in extinction of conditioned fear, a hallmark symptom of PTSD. Additionally, as disrupted noradrenergic signaling may contribute to alcoholism, we examined the effect of anxiolytic medications that target noradrenergic signaling on ethanol intake following adolescent social isolation. Our results confirm and extend previous findings that adolescent social isolation increases anxiety-like behavior and enhances ethanol intake and preference in adulthood. Additionally, social isolation is associated with a significant deficit in the extinction of conditioned fear and a marked increase in the ability of noradrenergic therapeutics to decrease ethanol intake. These results suggest that adolescent social isolation not only leads to persistent increases in anxiety-like behaviors and ethanol consumption, but also disrupts fear extinction, and as such may be a useful preclinical model of stress-related psychopathology. Our data also suggest that disrupted noradrenergic signaling may contribute to escalated ethanol drinking following social isolation, thus further highlighting the potential utility of noradrenergic therapeutics in treating the deleterious behavioral sequelae associated with early life stress.

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“…In rats, administration of propranolol, a beta-adrenergic receptor antagonist, reduced operant responding for alcohol (Gilpin and Koob, 2010). Moreover, increasing NE transmission via inactivation of presynaptic alpha-2 adrenergic autoreceptors potentiates reinstatement of EtOH self-administration, while activating this receptor attenuates EtOH drinking (Le et al, 2005). Furthermore, prazosin, an alpha-1 adrenergic receptor antagonist, reduces EtOH drinking in alcohol-dependent (Walker et al, 2008) and -preferring rats (Verplaetse et al, 2012), and reduces stress-induced reinstatement of alcohol seeking in rats (Le et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Social Isolation Rearing Increases Nucleus Accumbens Dopamine and Norepinephrine Responses to Acute Ethanol in Adulthood

Karkhanis

Locke

McCool

et al. 2014

Alcoholism Clin & Exp Res

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BACKGROUND Early-life stress is associated with increased vulnerability to alcohol addiction. However, the neural substrates linking chronic childhood/adolescent stress and increased risk of alcohol addiction are not well understood. In the nucleus accumbens (NAc), dopamine (DA) and norepinephrine (NE) signaling can be profoundly influenced by stress, anxiety, and drugs of abuse, including ethanol. Here, we employed a rodent model of early-life stress that results in enduring increases in behavioral risk factors of alcoholism to gain a better understanding of how chronic adolescent stress may impact the ethanol sensitivity of DA and NE release in the NAc. METHODS Male Long Evans rats were either group housed (GH; 4 rats/cage) or socially isolated (SI; 1 rat/cage) for six weeks beginning on postnatal day 28. SI and GH rats were tested in adulthood for anxiety-like behaviors (elevated plus-maze), and the effects of ethanol (1 and 2 g/kg; i.p.) on NAc DA and NE were assessed by microdialysis. RESULTS SI animals showed increased anxiety-like behavior compared to GH animals. Although SI had no effect on baseline levels of DA or NE, baseline DA levels were positively correlated with anxiety measures. In addition, while no significant differences were observed with 1 g/kg ethanol, the 2 g/kg dose induced significantly greater DA release in SI animals. Moreover, EtOH (2 g/kg) only elevated NAc NE levels in SI rats. CONCLUSIONS These results suggest that chronic early-life stress sensitizes accumbal DA and NE release in response to an acute ethanol challenge. A greater EtOH sensitivity of DA and NE release dynamics in the NAc may contribute to increases in behavioral risk factors of alcoholism, like greater ethanol self-administration, that are observed in SI rats.

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Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats

Cited by 232 publications

References 65 publications

The α2-adrenergic receptor agonist, clonidine, reduces alcohol drinking in alcohol-preferring (P) rats

The α2-adrenergic receptor agonist, clonidine, reduces alcohol drinking in alcohol-preferring (P) rats

Adolescent social isolation increases anxiety-like behavior and ethanol intake and impairs fear extinction in adulthood: Possible role of disrupted noradrenergic signaling

Social Isolation Rearing Increases Nucleus Accumbens Dopamine and Norepinephrine Responses to Acute Ethanol in Adulthood

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