Although animal behavioral models will never be able to fully recapitulate the human condition, especially for psychiatric disorders where several components, such as genetic, environment, social background, etc., are tangled. Nevertheless, they are key tools required to study, untangle, and understand core components of disorders, and it has been very successful with drug addiction.
Addiction is commonly defined by compulsive use of a substance, characterized by a loss of control over drug-taking despite negative consequences 104. Addiction can be seen as a cycle and broken down into several components that make up the different stages of the disease. Different behavioral models can then be used to study each of these different components. Animal models have been developed that have either face validity (i.e. appear mimic the human condition) or construct validity (i.e. have the same underlying etiology as the human condition)105 for the commonly defined three stages of addiction. For example, self-administration is used to study the initial stage of addiction, the binge and intoxication stage. Place conditioning, cue-induced seeking, and self-stimulation are models used to focus on the second stage of addiction, which is characterized by withdrawal and negative effects. Finally, the third stage is one of preoccupation and anticipation, where everything is done solely to get the drug regardless of any negative consequences. Animal models of resistance to punishment are used to study this phase of addiction 105,106. In an attempt to mimic the broad range of possible options that humans face, some models provide an alternative to drug intake, such as food or social interaction 107. We will briefly review the most commonly used rodent models in addiction research and detail the paradigms that are relevant for our project.
3.1 Modeling the binge/intoxication stage of addiction 3.1.1 Conditioned Place Preference (CPP)
CPP is probably the most used behavioral paradigm to investigate the motivational effects of drugs of abuse in animal research, even though this paradign is also used to study negative emotional states
associated with drug withdrawal 108. It is easy to set up, and it is also a relatively quick procedure. It can be used to study both the rewarding (conditioned place preference) and the aversive
(conditioned place aversion) effects of a drug 109. Although some variants can be found, the basic concept of CPP is to pair a specific environment with the drug and a different environment with no drug, or vehicle treatment. A pre-conditioning phase may occur where the animal will be habituated to the two different environments for 20 minutes but without any drug treatment. This phase usually lasts for only one day. Then, the pre-test occurs, wherein the animal has free access to all chambers without drug treatment for 20 minutes, so that initial preference for one side or the other can be determined. The following day, the conditioning begins. The experimenter injects the animal with a drug and confines it to one of the distinct environments for several minutes (usually around 20 min).
The following day, the animal receives vehicle treatment and is confined to the other environment.
This phase can take several days, alternating between drug and vehicle treatment. Finally, the test session occurs. Similar to the pre-test, the animal is placed in the center, between the two
environments, and has free access to the entire apparatus. No drug is administered during the test.
The time spent in each compartment is recorded, and the results are interpreted as a conditioned place preference if the animal spends significantly more time in the drug-paired compartment than in the vehicle-paired compartment. Conversely, the drug treatment induces a conditioned place aversion if the animal spends significantly more time in the vehicle-paired compartment than in the drug-paired compartment. Typically, drugs of abuse produce CPP 109, although the results can be equivocal and difficult to interpret. Indeed, the behavioral effects of a drug, and thus the behavioral readout, can dramatically vary depending on a lot of parameters such as species, route of
administration, time interval of the drug administration, concentration of the drug, and the
apparatus itself. Many drugs of abuse can even produce both CPP and CPA, depending on the dose administered 110. The introduction of new tools such as optogenetics has allowed “upgrades” that make this paradigm more specific (i.e. pathway selective) and unequivocal 84.
3.1.2 Self-administration (SA)
Figure 15. Schematic of an operant box for self-administration session, acquisition phase. The operant box contains a cue above the active lever, a press on which leads to either a drug or a vehicle infusion via a catheter implanted in the jugular vein and connected to a pump. The other lever is called the inactive lever, and a press on that one results in no outcome.
Self-administration paradigms are currently seen as the “gold standard” to study the first stage of addiction, i.e. the reinforcing effects of a drug 111.
In general, all substances with high addictive potential in humans are also voluntarily self-administered by animals with few exceptions 112. Even if the concept (a contingent intake of the substances) remains similar, variations exist in terms of how to set up and use self-administration as a model. In some paradigms, the animal has to “work” to receive the drug by pressing a lever or sometimes poking a hole with its snout multiple times before earning a reward. Generally, the substance is delivered intravenously, although less commonly it can be delivered orally. In some cases, the animal has free access to the substance, usually through a bottle that is available for oral consumption.
In rodents, the intravenous SA paradigm is the most commonly used. This model is used to
investigate the primary reinforcing effect of drugs 113. The animal will be trained in consecutive daily sessions that usually last from 2 to 6h, depending on the focus of the study. They obtain rewards, which in this is case a drug infusion, by performing an operant response. The drug infusion can be paired with a light and/or sound cue to enhance the association between the operant behavior and the reinforcer. Most SA protocols use a fixed ratio (FR) schedule, where the animal has to perform a fixed number of responses in order to obtain the drug 113. Another type of schedule that can be used in SA protocols is the progressive ratio schedule, where the number of responses needed to obtain
the drug infusion increases for each subsequent reward until the animal gives up. The highest number of responses corresponds to the “break point” and reflects the motivational properties of the drug 114.
This model is considered the gold standard for several reasons. First of all, it has excellent predictive validity. Indeed, there is great similarity between rodent self-administration and human drug-taking behaviors 115,116. Secondly, the SA model is closely linked to human practices (face validity) in terms of administration, especially for heroin which is usually administered intravenously by human addicts 19, and in terms of the behavioral responses needed to obtain the drug infusions 117. Finally, although this paradigm is mainly used to study the reinforcing properties of a drug, it can also be used to investigate the mechanisms underlying drug-seeking behaviors (i.e. motivation to get the drug). The only disadvantage of this model is the complexity of the technique. The drug is delivered via jugular catheter, and the surgery and maintenance for the catheter is quite challenging in small rodents like mice.
Other models we will not detail are also used to study thie first phase of the addiction cycle. Those include intracranial self-stimulation, drug discrimination, and genetic models (for a full description of these models, see Koob, Arends, and Le Moal 2014).
3.2 Modeling relapse, animal models of the withdrawal/negative stage of the addiction cycle
The withdrawal stage is a period where the drug is no longer available. The physical signs of withdrawal are often drug-specific, and in the case of opioids they are particularly painful. Classic opioid withdrawal symptoms in humans include muscle aches and pains, loose stools, piloerection, irritability, sleep disturbances, sympathetic activation, rhinorrhea, and lacrimation. The peak of these symptoms usually occurs approximatively 72h after cessation of drug consumption and lasts at least a week 118. Opioid withdrawal symptoms can also be observed in rodents and are quite similar to those of humans. Indeed, rodents experience diarrhea, rhinorrhea, teeth chattering, ‘wet dog shakes,’ and decreased food consumption (anorexia) that leads to weight loss 119. These signs can easily be observed and quantified, and they can therefore be used as specific markers to investigate the neurobiological mechanisms of physical dependence 115. There are even standardized rating scales for opioid, nicotine, and ethanol withdrawal to quantify the severity of withdrawal 120–122. Moreover, the drug withdrawal state is a powerful tool to explore the motivational aspects of drug dependence and the counter-adaptive mechanisms that drive addiction. The drug withdrawal phase can be studied using operant schedules, conditioned place aversion, or intracranial self-stimulation.
3.3 Modeling relapse, animal models of the preoccupation/anticipation stage of addiction
Relapse is a defining characteristic of addiction and one of the biggest obstacles to recovery. Animal models of relapse can be divided into three categories: drug-induced reinstatement, cue-induced reinstatement (or cue-induced seeking), and stress-induced reinstatement. The general concept behind relapse models is that through classical conditioning, associations between cues, both internal and external (physical effect of the drugs, light or sound, respectively), and the reinforcing effects of the drugs, positive or negative, will trigger drug use or drug seeking during abstinence.
3.3.1 Cue-induced reinstatement
Figure 16. Schematic of an operant box for cue-induced reinstatement session. In this paradigm, the animal is placed in the same operant box as for the acquisition phase (fig. 14). The settings are the same (two levers presented, visual cue above the active lever, and sound cue at the activation of the pump), but a press on the active lever does not provide a drug infusion.
Environmental cues, such as specific objects or places that are associated with drug consumption, can be paired with drug intake and robustly trigger responding after forced withdrawal or extinction.
During the training/acquisition phase, animals learn to self-administer drugs by performing an
operant response such as lever pressing or nose poking. A cue, usually a tone and/or a light, precedes and accompanies drug delivery. After the acquisition phase, the animal should have acquired stable and robust self-administration. It is then subjected to either forced withdrawal, where the animal has no access to drug for an extended period, or extinction sessions, where a lever press no longer results in the delivery of the drug or cues. After detoxification, or when responding is extinguished,
reinstatement sessions can be conducted. The animal is placed in the same setting as the acquisition phase, but this time only the cues are presented. The cue by itself should induce strong lever-pressing responses. This protocol is a classic model used to study the neurobiological substrates of relapse 123.
3.4 Summary of animal models of addiction
Animal models of drug addiction are very useful tools in untangling the different components of addiction because they allow researchers to focus on specific characteristics or phases of the disease (binge, withdrawal or relapse). Thus, they greatly contribute to the identification of new therapeutic targets. However, each model has its limits and its caveats, and even if the core components of addiction can be modeled, the results obtained can still not be directly applied to humans.