Comparative Evaluation of Partial α₂‐Adrenoceptor Agonist and Pure α₂‐Adrenoceptor Antagonist on the Behavioural Symptoms of Withdrawal after Chronic Alcohol Administration in Mice

Abstract

As an addictive drug, alcohol produces withdrawal symptoms if discontinued abruptly after chronic use. Clonidine (CLN), a partial a 2 -adrenergic agonist, and mirtazapine (MRT), an antagonist of a 2 -adrenoceptor, both clinically aid alcohol withdrawal. Considering different mechanisms of action of the two drugs, this study was designed to see how far these two mechanistically different drugs differ in their ability to decrease the severity of ethanol withdrawal syndrome. The effect of CLN and MRT on ethanol withdrawal-induced anxiety, depression and memory impairment was analysed using EPM, FST and PAR tests, respectively. Animals received distilled water, ethanol and/or either of the drugs (CLN and MRT) in different doses. Relapse to alcohol use was analysed by CPP test. Animals received ethanol as a conditioning drug and distilled water, CLN or MRT as test drug. CLN and MRT both alleviated anxiety in a dose-dependent manner. MRT (4 mg/kg) was more effective than CLN (0.1 mg/kg) in ameliorating the anxiogenic effect of alcohol withdrawal. However, CLN treatment increased depression. It significantly decreased swimming time and increased immobility time, whereas MRT treatment decreased immobility time and increased climbing and swimming time during abstinence. The effect was dose dependent for both drugs. The results of PAR test show that CLN treatment worsens working memory. Significant increase in SDE and TSZ and decrease in SDL were observed in CLN-treated animals. MRT treatment, on the other hand, improved working memory at both doses. Further, both CLN and MRT alleviated craving. A significant decrease in time spent in the ethanol-paired chamber was seen. MRT treatment at both doses showed better effect than CLN in preventing the development of preference in CPP test. These findings indicate a potential therapeutic use and better profile of mirtazapine over clonidine in improving memory, as well as in alleviating depression, anxiety and craving associated with alcohol withdrawal.Drug addiction is a pathological state which involves the progression of acute drug use to the development of drugseeking behaviour, vulnerability to relapse and decreased ability to respond to naturally rewarding stimuli [1,2]. The abused drugs produce an extensive and wide range of effects on the structure and networking of nerve cells throughout the brain's reward circuitry. These changes are believed to underlie the long-lasting behavioural changes which are characteristic of addiction [3]. Amongst all the drugs of abuse, alcohol is one of the most frequently abused. Chronic overuse of alcohol damages brain cells and its neuro-toxic potential has made it amongst the leading causes of dementia worldwide. Epidemiological studies report a significant association between alcohol and comorbid anxiety and depressive disorders [4]. Abstinence from long-term ethanol consumption induces an increase in negative emotional responses such as feelings of anxiety, restlessness, hyper-irritability, and depressed mood [5,6].Autonomic ...

Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development

“…In an early rat study in which alcohol dependence was induced by repeated intragastric alcohol administration, clonidine suppressed withdrawal signs, whereas yohimbine, which increases norepinephrine levels, exacerbated withdrawal (Trzaskowska and Kostowski, 1983). Subsequent studies have shown that a 2 -adrenergic agonists decrease somatic signs of alcohol withdrawal in animal models (Parale and Kulkarni, 1986;Riihioja et al, 1997), including responses that are associated with hyperkatifeia, such as the clonidine-induced blockade of anxiogenic-like effects of alcohol withdrawal in mice (Arora and Vohora, 2016). The a 2 -adrenergic agonists decreased alcohol intake in Finnish Alko alcohol rats that had free-choice access to 10% alcohol and drinking water (Opitz, 1990).…”

Affective Disruption During Forced Ethanol Abstinence in C57BL/6J and C57BL/6NJ Mice

“…Unlike with studies of anxiety‐like behavior, inconsistent findings regarding depressive‐like behavior during acute withdrawal have been reported, and results appear to be significantly dependent on the method of EtOH administration and to some extent, the behavioral assay utilized. In mice, forced methods of EtOH administration (Arora and Vohora, 2016; Karadayian et al, 2013; Metten et al, 2018), as opposed to long‐term voluntary consumption paradigms (Holleran et al, 2016; Lee et al, 2015; Lee et al, 2016; Lee et al, 2017; Stevenson et al, 2009), seem to more reliably produce depressive‐like behavior during acute withdrawal. Nonetheless, there is abundant evidence for the presentation of depressive‐like behavior in mice during early abstinence, across various methods of EtOH administration and behavioral assays (Gong et al, 2017; Holleran et al, 2016; Kim et al, 2017; Pang et al, 2013; Roni and Rahman, 2017; Stevenson et al, 2009).…”

Methadone, Buprenorphine, and Clonidine Attenuate Mitragynine Withdrawal in Rats

“…Clonidine is a non-opioid drug, that is a partial agonist of alpha 2 -adrenergic receptors ( Giovannitti et al, 2015 ; Arora and Vohora, 2016 ). It was used in opioid substitution treatment over the years ( Jamadarkhana and Gopal, 2010 ).…”