Selective breeding for high alcohol preference is associated with increased sensitivity to cannabinoid reward within the nucleus accumbens shell
Introduction
Marijuana is the most commonly used illicit drug in America. Approximately 43.5% of all Americans have used marijuana in the past year (SAMHSA, 2019). Marijuana use is common in young Americans with 34.8% of those aged 18–25 years old using marijuana in the past year. Additionally, its use is at a historic high among college-age Americans with approximately 42.6% using marijuana in the last year (Schulenberg et al., 2019). Marijuana use is usually paired with other drug use/abuse (polydrug abuse), in particular alcohol.
Epidemiological data indicate that 58% of subjects who use alcohol or have alcohol use disorders (AUD) also abuse marijuana (Martin et al., 1996). The high prevalence of alcohol and cannabis co-abuse may be predicated upon both a common predisposing genetic factor and the interaction of the drugs within the organism (Uhl, 2004; Uhl et al., 2006, Uhl et al., 2008). The common predisposing genetic factor could be based upon innate differences in the endogenous cannabinoid (eCB) system. A single nucleotide polymorphism (SNP) in the human gene encoding an eCB inactivating enzyme, fatty acid amide hydrolase (FAAH), has been strongly associated with drug and alcohol abuse (Sipe et al., 2002) and reduced central nervous system (CNS) FAAH protein levels have been found in individuals with AUD (Vinod et al., 2010). The interrelationship between eCB and alcohol use is also indicated by findings that cannabinoid agents can alter alcohol consumption (Caille and Parsons, 2006; Getachew et al., 2011). Therefore, it is possible that genetic variation in the eCB system may predispose individuals to abuse alcohol and/or be diagnosed with AUD.
Many of the rewarding effects of eCB and Δ9-tetrahydrocannabinol (Δ9-THC), the principal psychoactive component of marijuana, are mediated primarily through the CB1 receptors (CB1Rs) (Monory et al., 2007). CB1Rs are predominantly localized in the brain and are expressed in the mesocorticolimbic (MCL) dopaminergic (DAergic) reward system [i.e., ventral tegmental area (VTA), nucleus accumbens (Acb), and medial prefrontal cortex (mPFC)]. The CB1Rs in the Acb mediate food and drug reward (Oleson and Cheer, 2012). It has been reported that intra-accumbal administration of CB1R agonist can induce a conditioned place preference (CPP; Karimi et al., 2013). Numerous studies have also indicated that the eCB system regulates alcohol consumption. For example, CB1R knockout (KO) mice do not develop ethanol (EtOH) conditioned place preference (Houchi et al., 2005; Thanos et al., 2005) and exhibit significantly reduced voluntary alcohol consumption (Hungund et al., 2003; Poncelet et al., 2003; Naassila et al., 2004; Thanos et al., 2005). Furthermore, the ability of systemic administration of EtOH to increase dopamine (DA) levels in the Acb is not apparent in CB1R knockout mice (Hungund et al., 2003).
Neurochemical systems that are modified by alcohol and cannabinoids converge within the mesolimbic DA system. Like all drugs of abuse, alcohol and cannabinoids elevate extracellular levels of DA in the Acb shell (AcbSh; Koob, 2000; Di Chiara et al., 2004). The CB1R system appears to be one pathway in which alcohol produces reinforcement within the mesolimbic DA system (Mechoulam and Parker, 2003). There is a positive correlation between CB1R expression levels within the MCL DA pathway and alcohol preference (Wang et al., 2003). CB1R antagonism prevents EtOH-induced elevations in DA levels of the Acb, as well as DA cell-firing in the Acb and VTA (Perra et al., 2005; Cheer et al., 2007). The ability of CB1R agents to mediate EtOH consumption appears to be limited to CNS areas that support EtOH and cannabinoid self-administration. A series of studies have confirmed that infusions of a CB1R antagonist in the Acb and posterior, but not anterior, VTA decreases EtOH self-administration in rats (Caille and Parsons, 2006; Caille et al., 2007; Alvarez-Jaimes et al., 2009b). In addition, EtOH consumption can also increase CNS extracellular levels of the eCB 2-arachidonoylglycerol (2-AG; Caille et al., 2007). In general, multiple sources indicate that the CB1R system may be one of the platforms in which alcohol acts within the brain.
Systemic administration of CB1R agonists increases (Gallate et al., 1999; Colombo et al., 2002), while CB1R antagonists reduce alcohol consumption (Arnone et al., 1997; Colombo et al., 1998; Gallate and McGregor, 1999). Increasing eCB levels by systemic administration of an FAAH inhibitor enhances EtOH preference and intake in mice (Blednov et al., 2007) and heightened the 2-AG response to EtOH in the Acb of EtOH naïve rats (Alvarez-Jaimes et al., 2009a). In alcohol-preferring (P) rats (c.f., Bell et al., 2006, Bell et al., 2016; McBride et al., 2014), a CB1R antagonist reduced EtOH-seeking and EtOH self-administration, whereas a CB1R agonist increased EtOH-seeking and EtOH self-administration during relapse (Getachew et al., 2011). An additional observation indicated that the P rat may be more susceptible to the sedative properties of CB1 agonists at higher concentrations, suggesting a heightened CB1R system (Getachew et al., 2011). Thus, activation of CB1 receptors is involved in regulating EtOH-seeking as well as the reinforcing effects of EtOH.
O-1057 is a potent water-soluble CB1R agonist (Pertwee, 1999; Pertwee et al., 2000; Lichtman et al., 2000; Martin et al., 2006) and its effects can be blocked by SR141716A, a CB1R antagonist (Pertwee et al., 2000; Lichtman et al., 2000). O-1057 is significantly more potent at CB1Rs (Martin et al., 2006) and a more potent inhibitor of forskolin-stimulated cyclic AMP production than Δ9-THC (Pertwee et al., 2000). Thus, the objectives of the present study were to test the hypotheses that the activation of the CB1R receptor within the AcbSh is reinforcing and the AcbSh of the P rats is more sensitive to the reinforcing effects of a CB1R agonist, O-1057, than the AcbSh of outbred Wistar rats.
Section snippets
Animals
Experimentally naïve, female Wistar (Envigo, Indianapolis, IN, USA) and P rats (bred in-house, Indianapolis, IN, USA) weighing 250–320 g at the time of surgery were used. They were double-housed upon arrival and maintained on a 12 h reverse light-dark cycle (lights off at 0900). The P rats were bred at the school of dentistry building across campus and shipped in Envigo transport boxes and provided with the same transport items as Envigo deliveries. In order to avoid oversampling, the P rats
Results
The initial analysis examined the average number of reinforcers self-administered during the first 4 test sessions of acquisition with between group factors of ‘concentration’ and ‘line’ (Fig. 2). There was a significant ‘concentration’ X ‘line’ interaction (F4,64 = 3.31; p = 0.016). Reducing the interaction term by examining the effect of ‘concentration’ within each line revealed significant dose-response effects in Wistar (F4,34 = 36.3; p < 0.0001) and P (F4,30 = 17.5; p < 0.0001) rats.
Discussion
The major findings of this study are that a CB1R agonist within the AcbSh is reinforcing and that genetic selection for high alcohol consumption includes an AcbSh that is more sensitive to the reinforcing properties of CB1R agonists than its progenitor stock (Fig. 2, Fig. 3, Fig. 4). This was indicated by the findings that P rats will self-infuse lower concentrations of O-1057 (Fig. 2, Fig. 3) by readily discriminating the active from the inactive lever at 3.125 and 6.25 pmol doses (Fig. 3,
Sources of support
This research was supported in part by the National Institute of Alcohol Abuse and Alcoholism (NIAAA) grants AA07611, AA022287, AA13522 [INIA]. None of the authors has a conflict of interest associated with this research. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIAAA or National Institute of Health (NIH).
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