In order to identify potential medications for the treatment of drug addiction, animal models have been created that allow the elucidation of the underlying mechanisms of drug-induced behaviors. By its definition, addiction is a unique and complicated human behavior and a single animal model simply cannot predict medication efficacy in humans. Thus most investigators use an arsenal of in vitro and in vivo tests to study neurochemical mechanisms underlying the pharmacological actions and abuse liability of various drugs of abuse, as well as for discovering potential medications. In vitro binding and functional assays are generally used to determine mechanisms of action of test compounds (new compound entities, NCEs) and then those with the desired in vitro profile are further investigated in animal models. Biochemical assessment using in vivo microdialysis is often employed to further delineate NCE effects on neurotransmitter levels in various brain regions. Ultimately, behavioral models, initially in rodents, but ultimately nonhuman primates, have been developed to study drug seeking, taking, reward, reinstatement, and the molecular mechanisms associated with these behaviors that lead to addiction.
There are numerous animal models of the pharmacological actions of drugs of abuse including locomotor activity for psychostimulants and tail flick or the hotplate test for assessing analgesic effects of opioids. In addition, drug discrimination has emerged as a very important paradigm for ascertaining like- or attenuation of discriminative stimulant effects of the training drug.33 However, in this chapter the discussion is limited to animal models that are most commonly used to assess the addictive liability of a drug or the ability of a potential medication to attenuate drug reward or relapse.
6.07.3.1 Self-Administration/Reinstatement Model
Self-administration in animals requires an operant behavior (e.g., lever press) for the intravenous injection of a drug. A drug or NCE is considered to be reinforcing when either the rate of responding on the drug-correct lever exceeds that of the control or vehicle-paired lever, or if the response rate of the drug-receiving animal is greater than that of a yoked-control animal. Once self-administration behavior is established, the experimenter can increase the number of lever presses required for a drug injection and thereby measure the reinforcing properties of the drug. When the number of lever presses required exceeds the 'work' that the animal is willing to do to receive an injection, extinction of lever-pressing/self-administration will ensue. Several schedules of reinforcement can be employed. The fixed ratio (FR) schedule requires the animal to press the lever a fixed number of times before receiving a drug injection. The fixed interval (FI) schedule is used to determine how many presses an animal will make in a fixed interval of time. The most commonly used schedule is the progressive ratio (PR) in which a progressively larger number of lever presses are required to receive the same drug injection. The highest response requirement a drug will sustain is called the 'break point' and this has been used to measure drug reinforcement properties. Furthermore, the attenuation of the break point has been used to evaluate potential medications or other conditions that might decrease the reinforcing effects of the drug.33 Most drugs abused by humans are generally self-administered by animals and laboratory-based self-administration in humans has also been used to study drug addiction.34
In addition, this model can be extended to a reinstatement model of relapse.35 In the reinstatement model, the animal is trained to self-administer the drug of abuse. Once this behavior is established, the drug injections are replaced with saline injections. In time, the animal will no longer press the lever for a drug injection and this is called 'extinction.' Several investigators have demonstrated that drug- or cue-induced reinstatement of drug taking behavior (e.g., lever pressing) can be induced by a single priming injection of the drug of abuse or a cue that had previously been paired with the drug injection, during training. In addition, aversive conditions used as a model of stress, such as foot shock, can also reinstate lever pressing behavior. This test has face validity as a model for relapse to drug use by humans and has been suggested to further model the effects of stress on drug taking behavior.35 Further, the attenuating effects by certain medication candidates in this model have prompted intense interest in particular mechanisms for drug development, such as DA D3 and mGluR5 receptors (see Section 6.07.7).36,37
6.07.3.2 Intracranial Self-Stimulation (ICSS)
This model has also been used to investigate rewarding and addictive properties of drugs.38 Rats will press a lever to self-stimulate due to a concomitant passage of a small electrical current into regions in the brain that involve the reward circuitry (e.g., VTA, prefrontal cortex, NAc). All addictive drugs, when acutely administered, will lower the threshold of stimulation required to maintain ICSS. This is interpreted as the ability of these drugs to enhance the stimulating effects of the ICSS. Conversely, acute withdrawal from drugs of abuse will elevate ICSS reward thresholds and is interpreted to reflect a precipitation of a deficit in brain reward function that can be alleviated by increasing ICSS. This observation suggests that ICSS may be a relevant behavioral model of the aversive emotional state associated with drug withdrawal39 further substantiating VTA DA cells as projections that play a key role in perpetuating the addiction cycle.22
6.07.3.3 Conditioned Place Preference (CPP)
This paradigm is a Pavlovian conditioning procedure in which an animal learns to prefer an environment that is paired with a drug of abuse, and has been promoted as modeling the environmental cues associated with drug addiction in humans.40 Indeed drugs of abuse are able to engender conditioned place preference, whereby the animal remains in the drug-paired side of the chamber for a longer period of time than in the other side (Figure 6).6 Thus, in CPP the degree of drug reinforcement and addictive liability is inferred from the degree of preference or
Pump dispensing drug or saline
Pump dispensing drug or saline
Drug-tested mouse prefers chamber in which drug was given
Figure 6 Conditioned place preference model in mice used to study the positive reinforcing effects of drugs. (Reprinted with permission from Cami, J.; Farre, M. N. Engl. J. Med. 2003, 349, 975-986, copyright © 2003 Massachusetts Medical Society. All rights reserved.)
time spent in the drug-paired environment, as compared to the vehicle-paired environment. Conversely, aversion to a drug or condition can be also modeled in this paradigm, and, depending on dose, certain drugs can cause an animal to stay in the nondrug-paired side of the chamber. Motivational (affective) symptoms of drug withdrawal can be measured using this paradigm, even in the absence of overt symptoms of withdrawal. Indeed, studies using CPP for studying nicotine dependence have demonstrated that the reinforcing effects of nicotine can be controlled by environmental stimuli. This can be correlated to the high rates of relapse to cigarette smoking in humans, which in part may be due to the pairing of environments with the reinforcing effects of nicotine, such as home and workplace that are impossible to avoid.41
As described above, chronic drug use leads to neuroadaptations. Cessation of drug use can lead to biochemical, physiological, and behavioral changes that together constitute a withdrawal or abstinence syndrome. This is also described as a state of physical dependence. When an addict discontinues drug use, symptoms of withdrawal can range from dysphoria and anxiety, to paranoia, physical illness, seizures, and death. The withdrawal symptoms depend on the drug of abuse, its pharmacology, pharmacokinetics, and the nature of the adaptations that have occurred due to chronic drug intake. Physical dependence is especially prominent with opioids, barbiturates, and alcohol. For these drugs, withdrawal symptoms are highly aversive, dangerous, and at times, life-threatening, and are believed to play a major role in relapse.33 In animal studies, subjects are chronically dosed, often continuously via intragastric infusion for a prolonged period of time (e.g., 1 month). Behavioral and observational assessments during this phase of the testing provide documentation of physical and behavioral changes induced by chronic drug taking. Withdrawal can then be assessed either by abruptly stopping the drug administration or by precipitating withdrawal via administering a known antagonist (e.g., naltrexone for opioid-dependent animals). Comparisons of physical and behavioral assessments during this period to before and during drug treatment are then made.33 These tests provide the means to determine the potential of a drug to produce physical dependence, as well as the means to test the ability of NCEs to interrupt the development of physical dependence or to ameliorate the symptoms and signs of withdrawal.
Different strains of rats behave differently to various drugs of abuse, and this has been demonstrated, for example, using CPP.40 More recently the use of genetically mutated strains or transgenic mice that have specific receptors or transporters deleted has provided another approach to determining mechanistic correlates to drug abuse and addiction. Successful manipulation of gene expression by homologous recombination has enabled researchers to knockout specific receptors or transporters (e.g., DAT knockout) to ultimately compare these genetically mutated mice to wild-type littermates in various behavioral models of drug abuse and addiction.42 These knockout (ko) mice can provide valuable information, especially when selective drugs are not available to pharmacologically 'knockout' the receptor or transporter. One of the seminal studies using DAT knockout mice in cocaine abuse research demonstrated that these animals were extremely hyperactive and did not demonstrate further increases in locomotor activity when cocaine or amphetamine was administered.43 Subsequently work showed that DAT knockout mice indeed self-administer cocaine, and that only the dual DAT/SERT (serotonin transporter) knockout mice no longer self-administer cocaine, suggesting that additional mechanisms may be involved in the reinforcing effects of cocaine.44 Nevertheless, strain, as well as compensatory and developmental differences, in these ko mice requires caution in interpretation of these results in the absence of substantive pharmacological data. Other transgenic mouse strains have also been created for drug dependence research, including, but not limited to, DA D1, D2, D3, D4, and D5 receptors, as well as 5HT1B, and nicotine-acetylcholine receptor kos. The production of subtype-specific DA, 5HT, and acetylcholine receptor ko mice as well as dual kos (e.g., DAT/SERT) have provided genetic tools with which to further delineate molecular mechanisms underlying the addictive properties of drugs. When conditional mutation of these genes is achieved concerns about compensatory and development modification that occur upon gene deletion procedures will be reduced.42
Drug dependence is a chronic relapsing medical illness similar in many respects to other chronic medical diseases such as diabetes and hypertension.45 Clinical trials in the drug dependence arena face special challenges. These include high cost, difficulties recruiting patients, the high rate of comorbidities, high dropout rates, poor patient compliance, ambiguous and difficult-to-measure clinical trial endpoints, and a lack of validated biomarkers.46
The high level of comorbidity between psychiatric illness, e.g., depression and bipolar disorder, and drug dependence not only complicates the task of recruiting homogeneous patient populations for clinical trials, but also suggests that any medication that might be found to have some efficacy in treating an 'uncomplicated' group of patients would not work in a more typical community sample of addiction patients with a higher level of psychiatric comorbidity. These considerations indicate the importance of analyzing data from clinical trials to determine the efficacy of the medication on subgroups of patients defined on the basis of their psychiatric history.47 A significant factor that can complicate the design of clinical trials for pharmacotherapeutic agents for cocaine addiction is the fact that chronic cocaine use alters many aspects of brain neurochemistry and circuitry. Thus, testing a medication that works via a single well-defined mechanism of action might be doomed to failure, since a single mechanism agent would 'normalize' just one of many brain mechanisms dysregulated by chronic cocaine. Viewed from this perspective, perhaps it is not surprising that most controlled trials of medications for cocaine addiction have failed to demonstrate efficacy.48 One way of addressing this problem is to conduct clinical trials with two (or more) medications that act via different mechanisms, or alternatively, as suggested for developing medications for schizophrenia and mood disorders, the ideal medications for substance dependence disorder may well be ''selectively nonselective drugs.''49 Finally, given the intrinsic difficulties for developing pharmacotherapeutics for substance abuse disorders, some argue that, rather than defining a successful medication as one that 'cures' drug addiction, which seems unlikely due to its chronic and relapsing nature, a medication that reduces drug use or mitigates the harm produced by a drug of abuse,50 would also be a useful pharmacotherapeutic.
A significant factor that complicates medication development efforts in the drug abuse field is that the most successful therapeutics to date apply the principle of agonist substitution therapy: e.g., nicotine, delivered by various routes, and methadone, a m opioid receptor agonist, for heroin addiction. Despite being clinical practice since the 1960s,7 the use of a potential drug of abuse to treat an addiction to a similar substance remains troubling to many. Not surprisingly, the possible use of stimulants, such as D-amphetamine, to treat stimulant dependence, although promising, is controversial.51 Recent research shows, however, that it is possible to design medications that act in a manner similar to amphetamine or cocaine but which lack their stimulant and reinforcing properties.52,53
Decades of research led to the development of US Food and Drug Administration (FDA) approved medications for nicotine, alcohol, and heroin dependence (Figure 7). For a variety of reasons, although progress is being made, the effort to develop medications for cocaine and methamphetamine dependence has been slow.
Another significant factor that impacts the development of medications for cocaine dependence, and to a lesser extent for alcohol dependence, is that large pharmaceutical companies do not invest resources into this area. As described by Gorelick et al.,54 market factors that disinterest the large pharmaceutical companies in this endeavor include: the small and uncertain market for cocaine dependence medication, a substance abuse treatment system with limited physician involvement and antimedication attitudes among nonphysician clinicians, poor insurance coverage, and the expectation of low prices by the government entities that fund most substance-abuse treatment programs. Thus, the development of medications for substance dependence indications, and addiction research in general, falls to the public sector.
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