Chronic nicotine exposure attenuates the effects of Δ⁹‐tetrahydrocannabinol on anxiety‐related behavior and social interaction in adult male and female rats

Abstract

IntroductionAnxiogenic and anxiolytic effects of cannabinoids are mediated by different mechanisms, including neural signaling via cannabinoid receptors (CBRs) and nicotinic cholinergic receptors (nAChRs). This study examined the effects of prior nicotine (the psychoactive component in tobacco) exposure on behavioral sensitivity to delta‐9‐tetrahydrocannabinol (THC; the psychoactive component of cannabis) challenge in animals.MethodsMale and female adult Sprague‐Dawley rats (N = 96) were injected daily with nicotine (1 mg/kg, i.p.) or vehicle for 14 days, followed by a 14‐day drug‐free period. On test day, rats were injected with THC (0.5, 2.0, or 5.0 mg/kg, i.p.) or vehicle and anxiety‐related behavior was assessed in the emergence (EM), elevated plus maze (EPM), and social interaction (SI) tests.ResultsChronic nicotine pretreatment attenuated some of the anxiogenic effects induced by THC challenge which can be summarized as follows: (a) THC dose‐dependently affected locomotor activity, exploratory behavior, and social interaction in the EM, EPM, and SI tests of unconditioned anxiety; (b) these effects of acute THC challenge were greater in females compared with males except for grooming a conspecific; (c) prior nicotine exposure attenuated the effects of acute THC challenge for locomotor activity in the EPM test; and (d) prior nicotine exposure attenuated the effects of THC challenge for direct but not indirect physical interaction in the SI tests.ConclusionsThe ability of nicotine prior exposure to produce long‐lasting changes that alter the effects of acute THC administration suggests that chronic nicotine may induce neuroplastic changes that influence the subsequent response to novel THC exposure.

One Is Not Enough: Understanding and Modeling Polysubstance Use

“…Although many studies have focused on simultaneous drug combinations, sequential patterns of polydrug consumption are more frequently reported (Leri et al, 2004;Roy et al, 2013) and produce unique circuit adaptations following acute and repeated drug exposure (Cunha-Oliveira et al, 2008). Understanding sex differences in frequency and pattern of polydrug use (McClure et al, 2017), drug discrimination (Spence et al, 2016), and circuit alterations (Canterberry et al, 2016;Manwell et al, 2019) is also necessary to fully understand the interactions and impacts of polydrug use in clinical populations. Furthermore, although powerful behavioral economic models allow comparisons across drug classes, these experiments must be designed with consideration of different scales of intake and indifference points for drug valuation in order to accurately model parameters and interpret data (Newman and Ferrario, 2019).…”

“…In addition, THC and nicotine coadministration exacerbates the somatic symptoms of THC withdrawal (Valjent et al, 2002). However, after repeated nicotine treatment and 2 weeks of drug abstinence, nicotine readministration attenuates THC-induced decreases in locomotor activity, increases in anxiety measures (when assessed in the elevated-plus maze), and changes in social interaction (Manwell et al, 2019). These findings suggest that nicotine enhances the negative symptoms of THC when administered concurrently or in close temporal proximity.…”

Nicotinic Acetylcholine Receptor Dysfunction in Addiction and in Some Neurodegenerative and Neuropsychiatric Diseases

“…Several studies have indicated that consumption of Δ-9-tetrahydrocannabinol (THC), the main addictive component in Cannabis sativa , is associated with anxiogenic-like effects, working memory impairments, and ataxia [ 88 , 89 ]. These adverse THC effects appear to be reduced upon nicotine administration [ 90 , 91 , 92 , 93 , 94 ].…”

Translational models of cannabinoid vapor exposure in laboratory animals

“…In mice, THC (0.3 mg/kg, intraperitoneal) increased time spent in the light compartment of a light-dark box, a measure of anxiolytic behavior (Berrendero and Maldonado, 2002; Harte-Hargrove and Dow-Edwards, 2012). Acute THC (1–5 mg/kg, intraperitoneal) increased anxiety-like behavior in a social interaction test in rats (Malone et al , 2009; Klein et al , 2011; Manwell et al , 2019). Acute THC (2–5 mg/kg, intraperitoneal) also shows anxiogenic effects in the elevated plus-maze and open field ‘emergence’ test (Manwell et al , 2019).…”

“…Acute THC (1–5 mg/kg, intraperitoneal) increased anxiety-like behavior in a social interaction test in rats (Malone et al , 2009; Klein et al , 2011; Manwell et al , 2019). Acute THC (2–5 mg/kg, intraperitoneal) also shows anxiogenic effects in the elevated plus-maze and open field ‘emergence’ test (Manwell et al , 2019). In adolescent rats, chronic administration (7 days) of a low-dose of THC (2 mg/kg, intraperitoneal) increased, while a high dose (15 mg/kg, intraperitoneal) decreased, time spent in the center of an open field arena, representing an anxiolytic and anxiogenic response respectively (Harte-Hargrove and Dow-Edwards, 2012).…”