Cannabis, THC, or SCs are known to produce four classic physiological effects known as the ‘tetrad’ via their prominent action on CB1—analgesia, hypothermia, hypoactivity, and catalepsy (Metna‐Laurent et al., 2017). Despite their frequent use in rodent cannabinoid behavioral research, when compared to the reported behavioral effects of acute cannabis/THC use in humans discussed above, they offer little translational validity beyond determining whether a pharmacological phenomenon is potentially mediated by CB1 activity. A caveat to this statement might be analgesia because of the potential for development of cannabinoid‐based pain medications. The tetrad behaviors and other behavioral effects of cannabinoid administration often have clear dose responses, with higher doses being mainly disruptive and inhibitory and low doses potentially stimulatory. For example, locomotor activity is suppressed at higher doses of THC or synthetics cannabinoids while lower doses can have a stimulatory effect that increases locomotion and behavioral activities (Chaperon & Thiebot, 1999; Stark & Dews, 1980).

As with many drugs of abuse, THC and THC‐like synthetic cannabinoids have a long history of reward, reinforcement, and motivation‐related research (Justinova, 2019). Naturally, researchers are interested in studying the neural circuits involved in the addicting characteristics of THC. However, historically this has been difficult to do, as it is difficult to obtain ‘rewarding’ effects from THC using standard behavioral procedures (Chaperon & Thiebot, 1999; Justinova, 2019). This is clearly different from the case in humans, as many humans obviously readily self‐administer cannabis, THC, and THC‐like compounds. Acute administration of high doses of THC appears to be aversive as indicated by conditioned place preference and taste aversion studies (Lepore et al., 1995). In these studies, THC is paired with a specific compartment within an arena, or with a novel food, and this will generally cause the animal to avoid that place or food in the future. This is likely because of the initial aversive and anxiogenic potential of THC administration in many animal models (Murray & Bevins, 2010). Indeed, pretreating mice with THC while they are in their home‐cage appears to ameliorate the aversive effects of the drug in place preference paradigms (Valjent & Maldonado, 2000) and self‐administration (Spencer et al., 2018), presumably by temporally distancing the association of the initial treatment from the conditioning procedure. Interactions between high doses of THC and the endogenous opioid system may mediate these dysphoric effects (Maldonado et al., 2011), as genetic knockdown/knockout of genes involved in endogenous opioid signaling can block dysphoric and facilitate reinforcing effects of cannabinoid administration (Cheng et al., 2004; Mendizabal et al., 2006; Zimmer et al., 2001).

The classic paradigm used in the pre‐clinical setting to study drug abuse is the operant self‐administration procedure. In this procedure, animals are typically tasked with pressing a lever or poking their nose into a hole to earn drug rewards. Usually, these rewards are brief intravenous (i.v.) infusions of the drug through a chronically implanted jugular catheter. Again, it has been historically quite difficult to obtain i.v. self‐administration of THC in animal models, particularly in rodents (Lupica & Hoffman, 2018). That is not to say it is impossible, as there are a few studies reporting i.v. THC self‐administration in rats (Spencer et al., 2018; Stringfield & Torregrossa, 2021; Takahashi & Singer, 1979; Wakeford et al., 2017). Most of these studies used smaller doses of THC than typically administered in other behavioral experiments, though Stringfield and Torregrossa found that an escalation procedure potentially allowed adolescent rats to self‐administer the drug at relatively higher doses (Stringfield & Torregrossa, 2021). There have been some recent advances in rodent THC/cannabis self‐administration procedures that move away from i.v. administration, and instead allow the rodents to earn cannabis‐infused dough pellets (Smoker et al., 2019) or brief exposure to cannabis vapor (Freels et al., 2020). These later paradigms are particularly interesting as they better model human administration of these drugs.

While difficult in rodents, THC is readily self‐administered by squirrel monkeys (Justinova et al., 2003; Tanda et al., 2000), providing a reliable non‐human primate model to study behavioral pharmacology related to specific aspects of cannabis use (Panlilio & Justinova, 2018). The studies using squirrel monkeys and other non‐human primates recapitulate most aspects of cannabinoid drug use, including acquisition (Justinova et al., 2003), maintenance (Justinova et al., 2013), relapse/reinstatement (Justinova et al., 2008, 2013), and withdrawal (Fredericks & Benowitz, 1980). These studies can provide valuable insight into pharmacological interventions with translational relevance related to these cannabinoid related drug abuse phenomena. However, it is harder to glean information about the cellular/molecular and systems level neural mechanisms underlying these phenomena because of the lack of transgenic and genetic techniques in non‐human primates, as well as the lower availability of subjects and high cost of non‐human primate research.

Lupica and Hoffman hypothesize that the difficulty in establishing rodent models of cannabinoid self‐administration may stem from their widespread action on CB1 receptors throughout the brain, and in particular in the hippocampus; an effect that can profoundly disrupt coherence of network activity that is critical for learning associations necessary to perform self‐administration procedures. They further suggest that differences in experimental conditions between rodent and non‐human primate studies might account for differences in the efficacy of self‐administration procedures between these types of model organism, though they admit the underlying cause is unclear (Lupica & Hoffman, 2018).