Nicotinic aspects of the discriminative stimulus effects of arecoline

Abstract

Despite the evidence that the muscarinic agonist arecoline is a drug of abuse throughout Southeast Asia, its stimulus characteristics have not been well studied. The goal of this work was to understand more about the mediation of discriminative stimulus effects of arecoline. Arecoline (1.0 mg/kg s.c.) was trained as a discriminative stimulus in a group of eight rats. The ability of various cholinergic agonists and antagonists to mimic or antagonize the discriminative stimulus effects of arecoline and to modify its rate-suppressing effects was evaluated. A muscarinic antagonist, but neither of two nicotinic antagonists, was able to modify the discriminative stimulus effects of arecoline, suggesting a predominant muscarinic basis of arecoline's discriminative stimulus effects in this assay. However, both nicotine itself and two nicotine agonists with selective affinity for the α4β2* receptor (ispronicline and metanicotine) produced full arecolinelike discriminative stimulus effects in these rats. The discriminative stimulus effects of the selective nicotine agonists were blocked by both the general nicotine antagonist mecamylamine and by the selective α4β2* antagonist, dihydro-beta-erythroidine (DHβE). Surprisingly, only DHβE antagonized the rate-suppressing effects of the selective nicotine agonists. These data indicate a selective α4β2* nicotine receptor component to the behavioral effects of arecoline. Although the nicotinic aspects of arecoline's behavior effects could suggest that abuse of arecoline-containing material (e.g. betel nut chewing) is mediated through nicotinic rather than muscarinic actions, further research, specifically on the reinforcing effects of arecoline, is necessary before this conclusion can be supported.

Arecoline Induces an Excitatory Response in Ventral Tegmental Area Dopaminergic Neurons in Anesthetized Rats

“…The arecoline dosage used in the present study was 0.2 mg/kg (administered via intravenous injection), which was far below the lethal dose ( Sahoo et al, 2018 ). However, our reports, as well as those of others, have demonstrated that a low dose of arecoline was sufficient to induce cardiovascular effects ( Deng et al, 2020 ) or behavioral manifestations ( Winger, 2021 ). Low doses of arecoline induced a significant increase in neuronal activity, suggesting that dopaminergic neurons were sensitive to arecoline stimulus.…”

“…Arecoline is a natural cholinomimetic drug that evokes a wide spectrum of pharmacological effects on the nervous, cardiovascular, digestive, and endocrine systems, and also has anti-parasitic effects ( Peng W et al, 2015 ; Peng W et al, 2015 ; Liu et al, 2016 ). Arecoline exhibits multiple adverse effects, including growth retardation, developmental defects, locomotive impairment, cardiovascular disorders, and hyporeflexia, as shown in studies of zebrafishes, mice, rats, and humans ( Pichini et al, 2005 ; Peng W. H et al, 2015 ; Peng et al, 2016 ; Dasgupta et al, 2017 ; Dasgupta et al, 2018 ; Winger, 2021 ). Arecoline induces severe toxicity on cellular and molecular levels, such as oral submucosal fibrosis, oral squamous cell carcinoma, and genotoxicity ( Liu et al, 2016 ; Drake and Pjh, 2018 ).…”

Overlap in oncogenic and pro-inflammatory pathways associated with areca nut and nicotine exposure

“…Arecoline is a known muscarinic receptor agonist; however, its nicotinic activity has recently been reported, which might be a common reason for addiction and other similar effects caused by both arecoline and nicotine. 6 , 13 , 14 Similarly, nicotine can cause non-areca nut OSF. 15 Thus, there is a possible overlap between the mechanisms of action of areca nuts and tobacco in the human body, which needs to be investigated in detail.…”