Self-administration

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Self-administration
MeSH D012646

Self-administration is, in its medical sense, the process of a subject administering a pharmacological substance to themself. A clinical example of this is the subcutaneous "self-injection" of insulin by a diabetic patient.

Contents

In animal experimentation, self-administration is a form of operant conditioning where the reward is a drug. This drug can be administered remotely through an implanted intravenous line or an intracerebroventricular injection. Self-administration of putatively addictive drugs is considered one of the most valid experimental models to investigate drug-seeking and drug-taking behavior. The higher the frequency with which a test animal emits the operant behavior, the more rewarding (and addictive), the test substance is considered. Self-administration of addictive drugs has been studied using humans, [1] non-human primates, [2] mice, [3] invertebrates such as ants, and, most commonly, rats.

Self-administration of heroin and cocaine is used to screen drugs for possible effects in reducing drug-taking behavior, especially reinstatement of drug-seeking after extinction. Drugs with this effect may be useful for treating people with drug addiction by helping them establish abstinence or reducing their probability of relapsing to substance use after a period of abstinence.

In a prominent model of self-administration developed by George Koob, rats are allowed to self-administer cocaine for either 1 hour each day (short access) or 6 hours each day (long access). Those animals who are allowed to self-administer for 6 hours a day show behavior that is thought to resemble cocaine dependence, such as an escalation of the total dose taken during each session and an increase in the dose taken when cocaine is first made available. [4]

Background

The "self-administration" behavioral paradigm serves as an animal behavioral model of the human pathology of addiction. During the task, animal subjects are operant conditioned to perform one action, typically a lever press, in order to receive a drug. Reinforcement (through the use of the drug) occurs contingent upon the subject performing the desired behavior. Drug dosing in self-administration studies is response-dependent. This is an important element of creating a disease model of drug addiction in humans because response-independent drug administration is associated with increased toxicity and different neurobiological, neurochemical, and behavioral effects. [5] In summary, the effects of response-dependent drug dosing greatly differ from response-independent drug dosing and self-administration studies appropriately capture this distinction.

History

As far back as the mid-20th century, researchers have investigated animals’ drive to consume addictive substances in order to better understand human addictive processes. Spragg was one of the first researchers to create a model of chronic morphinism in a chimpanzee to explore the role of operant conditioning in relation to a drug dependency. When deprived of both food and morphine, chimpanzees would repeatedly attempt to seek out the drug of choice, even doing so much as to physically pull the experimenter into the room housing morphine and syringes. [6] Weeks (1962) published an account of the first true use of the intravenous self-administration paradigm in a study aiming to model morphine addiction in unrestrained rats. For the first time, an addictive substance served as an operant reinforcer and rats self-administered morphine to satiety in stereotyped response patterns. [7]

The scientific community quickly adopted the self-administration paradigm as a behavioral means to examine addictive processes and adapted it to non-human primates. Thompson and Schuster (1964) studied the relative reinforcement properties of morphine in restrained rhesus monkeys using intravenous self-administration. Significant changes in response to other types of reinforcers (i.e., food, shock avoidance) were observed in drug-dependent subjects. [8] In 1969, Deneau, Yanagita and Seevers provided macaque monkeys free access to a variety of addictive substances for investigating whether nonhuman primates would voluntarily initiate self-administration of these substances. Initiation and maintenance of self-administration produced dependence and toxicity in monkeys, thereby more closely approximating important aspects of drug addiction in humans and allowing for the first of modern self-administration studies. [9]

The procedure of testing the efficacy of a pharmacological agent as a reinforcer would soon become a standard assay. Most frequently, studies were performed in nonhuman primates to identify addictive potential, as required by the drug development process. In 1983, Collins et al. published a landmark paper in which rats were exposed to a battery of 27 psychoactive substances. The team compared test drug self-administration rates with saline vehicle self-administration rates. If animals self-administered at a rate significantly greater than vehicles, the drug was considered an active reinforcer with addictive potential. With few exceptions, the abuse liability observed in rats paralleled that observed from previous research in monkeys. In light of these similarities between the different animal models, it was identified that the addictive potential of psychoactive substances could be investigated using rats instead of nonhuman primates. [10]

Technique

Acquisition

Operant conditioning represents the behavioral paradigm underlying self-administration studies. Although not always required, subjects may be first pre-trained to perform some action, such as a lever press or nose poke to receive a food or water reward (under food- or water- restricted conditions, respectively). Following this initial training, the reinforcer is replaced by a test drug to be administered by one of the following methods: oral, inhalation, intracerebral, intravenous. Intravenous catheterization is used most commonly because it maximizes bioavailability and has a rapid onset, although is inappropriate for drugs taken orally, such as alcohol. Humans suffering from addiction often resort to intravenous drug use for similar reasons, so this route of administration increases the face validity of the construct. [11]

Maintenance

Upon presentation of the drug to the subject, a number of experimental variables might be manipulated to test hypotheses:

Dose-response relationship

Dose-response relationship in cocaine self-administering mice Dose response2.png
Dose-response relationship in cocaine self-administering mice

Both humans and animals will adjust the rate and number of drug infusions to maintain stable rewarding blood levels of drugs, like cocaine. A dilute dose of cocaine will be administered intravenously at a faster rate than a concentrated dose of cocaine. [13]

Reinforcement schedules

Continuous reinforcement: A single operant response triggers the dispense of a single dose of the reinforcer. A time-out period may follow each operant response that successfully yields a dose of reinforcer; during this period the lever used in training may be retracted preventing the animal from making further responses. Alternatively, operant responses will fail to produce drug administration allowing previous injections to take effect. Moreover, time-outs also help prevent subjects from overdosing during self-administration experiments. Fixed-ratio studies require a predefined number of operant responses to dispense one unit of the reinforcer. Standard fixed ratio reinforcement schedules include FR5 and FR10, requiring 5 and 10 operant responses to dispense a unit of reinforcer, respectively. Progressive ratio reinforcement schedules utilize a multiplicative increase in the number of operant responses required to dispense a unit of the reinforcer. For example, successive trials might require 5 operant responses per unit of reward, then 10 responses per unit of reward, then 15, and so on. The number of operant responses required per unit of reinforcer may be altered after each trial, each session, or any other time period as defined by the experimenter. Progressive ratio reinforcement schedules provide information about the extent that a pharmacological agent is reinforcing through the breakpoint. The breakpoint is the number of operant responses at which the subject ceases engaging in self-administration, defined by some period of time between operant responses (generally up to an hour). Fixed interval (FI) schedules require that a set amount of time pass between drug infusions, regardless of the number of times that the desired response is performed. This “refractory” period can prevent the animal from overdosing on a drug. Variable interval (VI) schedules of reinforcement are identical to FI schedules, except that the amount of time between reinforced operant responses varies, making it more difficult for the animal to predict when the drug will be delivered.

Second-order reinforcement schedules build on basic reinforcement schedules by introducing a conditioned stimulus that has previously been paired with the reinforcer (such as the illumination of a light). Second-order schedules are built from two simpler schedules; completion of the first schedule results in the presentation of an abbreviated version conditioned stimulus, following completion of a fixed-interval, the drug is delivered, alongside the full-length conditioned stimulus. Second-order schedules result in a very high rate of operant responding at the presentation of the conditioned reinforcer becomes reinforcing in its own right. Benefits of this schedule include the ability to investigate the motivation to seek the drug, without the interference of the drug's own pharmacological effects, maintaining a high level of responding with relatively few drug infusions, reduced risk of self-administered overdose, and external validity to human populations where environmental context can provide a strong reinforcing effect for drug use. [14]

Extinction and reinstatement

Extinction involves the discontinuation of a particular reinforcer in response to operant behavior, such as replacing a reinforcing drug infusion with a saline vehicle. When the reinforcing element of the operant paradigm is no longer present, a gradual reduction in operant responses results in the eventual cessation or “extinction” of the operant behavior. Reinstatement is the restoration of operant behavior to acquire a reinforcer, often triggered by external events/cues or exposure to the original reinforcer itself. Reinstatement can be broken into a few broad categories:

Drug-induced reinstatement: exposure to a reinforcing drug after the extinction of drug-seeking operant behavior can often reinstate drug-seeking, and can even occur when the new drug of exposure is different from the original reinforcer. This is thought to be strongly linked to drug sensitization [15] Cue-induced reinstatement: environmental cues associated with drug administration can trigger drug reinstatement by acting as conditioned stimuli, even during drug abstinence [16]

1. Environmental surroundings, as well as drug-associated behavior or actions, can function as environmental cues.

2. Stress-induced reinstatement: in many cases, a stressor can reinstate drug-seeking in a drug-abstinent animal. This can include (but is not limited to) acute stressors such as foot-shock or social defeat stress. In many cases, it appears that social stress can potentiate drug reinstatement just as strongly as exposure to the drug itself [17]

Apparatus

Self-administration apparatus SelfAdmin-2.jpg
Self-administration apparatus
Back-mount intravenous mouse catheter for drug self-administration Mouse catheter for self-administration.jpg
Back-mount intravenous mouse catheter for drug self-administration

Animal self-administration experiments are typically performed in standard operant conditioning chambers adapted for the catheters used to deliver a drug intravenously. The catheter is secured to the animal by a harness or backplate and is tethered to a protective leash that extends upward through a hole in the top of a chamber, where it attaches to a rotating swivel on a mechanical arm that allows the subject to move around freely. The chamber houses two levers: one whose depression results in the delivery of a drug, the other whose depression does nothing. Activity on these levers can be used to measure drug administration (via activity at the drug-inducing lever) as well as changes in nonspecific behavior that reflect short- and long-term effects of the drug (via activity at the non-inducing lever). The sterile intravenous catheter used to deliver the drug into the bloodstream of the subject is typically composed of flexible plastic, silastic tubing, and nylon mesh placed subcutaneously. [19] It is attached to a mechanical pump that can be calibrated to deliver a specific amount of drug upon depression of one of the levers in the chamber. Other chamber modifications are required if the drug is to be delivered orally or via inhalation, such as liquid containers or an aerosol distribution mechanism. [20] [21]

Significant findings

Self-administration studies have long been considered the “standard” in addiction research using both animal and human models. Conducting self-administration studies in animal models provides a much greater level of experimental flexibility than in humans because investigating the effects of novel pharmacological drug treatments poses significantly fewer ethical and practical barriers. In 1999, Pilla and colleagues published in Nature a study documenting the efficacy of a partial D3-agonist (BP-897) in reducing environmental cue-induced cocaine craving and vulnerability to relapse. [22] An interesting aspect of this study was the use of second-order reinforcement schedules to identify a dissociation in the effects of BP-897 in that the drug inhibits cue-induced cocaine-seeking but has no primary reinforcement effect. This latter condition is important for any pharmacological agent to be used in the treatment of addiction—drugs used to treat addiction should be less reinforcing than the drug whose addiction they treat and optimally have no reinforcing effects. [23]

MiR-212 regulates cocaine intake.jpg

A 2010 study published in Nature showed an upregulation of microRNA-212 in the dorsal striatum of rats previously exposed to cocaine for extended periods. [24] Animals infected with a viral vector overexpressing miR-212 in the dorsal striatum produced the same initial levels of cocaine intake; however, drug consumption progressively decreased as net cocaine exposure increased. The authors of the study noted that viral-infected animals exhibited decreased operant responding during the post-infusion time-out period and proposed that this demonstrated a reduction in compulsive drug-seeking behavior.(Hollander et al.) miR-212 acts through Raf1 to enhance the CREB response; CREB-TORC is known to negatively regulate the reinforcing effects of cocaine. (Hollander et al.) This study provides one example (miR-212, owing to its amplification of CREB) of a self-administration study that may provide potential therapeutic targets for the treatment of cocaine addiction. One of the most important advances to emerge from self-administration studies comes from a behavioral model for addiction in animals. [25] This model relies on observation of three separate phenomena to classify a rat as “addicted:” 1) 'Persistence in drug-seeking: Depends on the attempts of rats to obtain drug during time-out or no-periods in the self-administration apparatus. 2) Resistance to punishment: Measured by how much rats maintain rates of self-administration when cocaine infusion is paired with an electric shock. 3) Motivation for the drug: Measured by the breakpoint in progressive ratio reinforcement.

The researchers used an additional test to further support the classification of a rat as “addicted” by measuring relapse rates during reinstatement paradigms. Human drug addicts reportedly relapse at a rate of >90% as measured from the initial diagnosis. Rats that responded at high rates after some form of cue-induced reinstatement could be considered likely to relapse. This model provided an important advancement for the method of self-administration because it allows animal models to better approximate the physiological and behavioral aspects of drug addiction in humans.

Self-administration experiments can also be paired with methods such as in vitro electrophysiology or molecular biology to understand the effects of addiction on neural circuitry. Self-administration studies have allowed researchers to locate a staggering number of changes in brain signaling that occur in addiction. [26] One example of such a study involved examining synaptic plasticity in rats undergoing the behavioral shift to addiction. [27] Using the criteria for classifying rats as “addicts” or “non-addicts” as put forth by Deroche-Gamonet et al., it was found that addicted rats display a prolonged and persistent impairment in mGluR2/3-dependent Long-Term Depression. Despite exposure to the same self-administration paradigm, control rats recovered this form of synaptic plasticity. The authors of the study propose an important explanation for their results in that this specific loss of plasticity over an extended period is responsible for the progressive loss of controlled drug use. This represents a potential molecular mechanism by which addicts might differ from non-addicts and undergo pathological learning processes during the development of addiction.

Much like animal studies, human experiments that pair self-administration studies with additional neuroscientific techniques provide unique insight into the disease of addiction. Human self-administration studies have gained momentum with the widespread use of fMRI technology to measure BOLD signals. Brain imaging coupled with human self-administration studies with the laboratory have led to the development of a three-stage model of human neurocircuitry of addiction: Binge/Intoxication, Preoccupation/Anticipation, and Withdrawal/Negative Effect. [28] Koob, Lloyd, and Mason reviewed the laboratory models approximating each stage of the model of human addiction. The binge-intoxication phase traditionally has been modeled by drug or alcohol self-administration; the psychological effects of addiction might be modeled by the increased motivation for self-administration observed in drug-dependent animals. Self-administration studies capably model the somatic effects of addiction, but many of the most deleterious effects related to drug addiction can be considered psychological in nature. Models like the one published by Deroche-Gamonet and colleagues in 2004 better approximate the effects of addiction on physiology and psychology, but animal models are inherently limited in their ability to reproduce human behavior.

The use of the self-administration methodology to model human drug addiction provides powerful insight into the physiological and behavioral effects of the disease. While self-administration experiments in humans or animals each pose unique barriers to complete understanding of addiction, the scientific community continues to invest a great deal of effort in both avenues of research in the hopes of improving understanding and treatment of addiction.

Related Research Articles

Operant conditioning, also called instrumental conditioning, is a learning process where voluntary behaviors are modified by association with the addition of reward or aversive stimuli. The frequency or duration of the behavior may increase through reinforcement or decrease through punishment or extinction.

<span class="mw-page-title-main">Reinforcement</span> Consequence affecting an organisms future behavior

In behavioral psychology, reinforcement refers to consequences that increase the likelihood of an organism's future behavior, typically in the presence of a particular antecedent stimulus. For example, a rat can be trained to push a lever to receive food whenever a light is turned on. In this example, the light is the antecedent stimulus, the lever pushing is the operant behavior, and the food is the reinforcer. Likewise, a student that receives attention and praise when answering a teacher's question will be more likely to answer future questions in class. The teacher's question is the antecedent, the student's response is the behavior, and the praise and attention are the reinforcements.

Motivational salience is a cognitive process and a form of attention that motivates or propels an individual's behavior towards or away from a particular object, perceived event or outcome. Motivational salience regulates the intensity of behaviors that facilitate the attainment of a particular goal, the amount of time and energy that an individual is willing to expend to attain a particular goal, and the amount of risk that an individual is willing to accept while working to attain a particular goal.

Rat Park was a series of studies into drug addiction conducted in the late 1970s and published between 1978 and 1981 by Canadian psychologist Bruce K. Alexander and his colleagues at Simon Fraser University in British Columbia, Canada.

In internal medicine, relapse or recidivism is a recurrence of a past condition. For example, multiple sclerosis and malaria often exhibit peaks of activity and sometimes very long periods of dormancy, followed by relapse or recrudescence.

Substance dependence, also known as drug dependence, is a biopsychological situation whereby an individual's functionality is dependent on the necessitated re-consumption of a psychoactive substance because of an adaptive state that has developed within the individual from psychoactive substance consumption that results in the experience of withdrawal and that necessitates the re-consumption of the drug. A drug addiction, a distinct concept from substance dependence, is defined as compulsive, out-of-control drug use, despite negative consequences. An addictive drug is a drug which is both rewarding and reinforcing. ΔFosB, a gene transcription factor, is now known to be a critical component and common factor in the development of virtually all forms of behavioral and drug addictions, but not dependence.

Extinction is a behavioral phenomenon observed in both operantly conditioned and classically conditioned behavior, which manifests itself by fading of non-reinforced conditioned response over time. When operant behavior that has been previously reinforced no longer produces reinforcing consequences the behavior gradually stops occurring. In classical conditioning, when a conditioned stimulus is presented alone, so that it no longer predicts the coming of the unconditioned stimulus, conditioned responding gradually stops. For example, after Pavlov's dog was conditioned to salivate at the sound of a metronome, it eventually stopped salivating to the metronome after the metronome had been sounded repeatedly but no food came. Many anxiety disorders such as post traumatic stress disorder are believed to reflect, at least in part, a failure to extinguish conditioned fear.

Brain stimulation reward (BSR) is a pleasurable phenomenon elicited via direct stimulation of specific brain regions, originally discovered by James Olds and Peter Milner. BSR can serve as a robust operant reinforcer. Targeted stimulation activates the reward system circuitry and establishes response habits similar to those established by natural rewards, such as food and sex. Experiments on BSR soon demonstrated that stimulation of the lateral hypothalamus, along with other regions of the brain associated with natural reward, was both rewarding as well as motivation-inducing. Electrical brain stimulation and intracranial drug injections produce robust reward sensation due to a relatively direct activation of the reward circuitry. This activation is considered to be more direct than rewards produced by natural stimuli, as those signals generally travel through the more indirect peripheral nerves. BSR has been found in all vertebrates tested, including humans, and it has provided a useful tool for understanding how natural rewards are processed by specific brain regions and circuits, as well the neurotransmission associated with the reward system.

<span class="mw-page-title-main">Reward system</span> Group of neural structures responsible for motivation and desire

The reward system is a group of neural structures responsible for incentive salience, associative learning, and positively-valenced emotions, particularly ones involving pleasure as a core component. Reward is the attractive and motivational property of a stimulus that induces appetitive behavior, also known as approach behavior, and consummatory behavior. A rewarding stimulus has been described as "any stimulus, object, event, activity, or situation that has the potential to make us approach and consume it is by definition a reward". In operant conditioning, rewarding stimuli function as positive reinforcers; however, the converse statement also holds true: positive reinforcers are rewarding.The reward system motivates animals to approach stimuli or engage in behaviour that increases fitness. Survival for most animal species depends upon maximizing contact with beneficial stimuli and minimizing contact with harmful stimuli. Reward cognition serves to increase the likelihood of survival and reproduction by causing associative learning, eliciting approach and consummatory behavior, and triggering positively-valenced emotions. Thus, reward is a mechanism that evolved to help increase the adaptive fitness of animals. In drug addiction, certain substances over-activate the reward circuit, leading to compulsive substance-seeking behavior resulting from synaptic plasticity in the circuit.

<span class="mw-page-title-main">SB-277,011-A</span> Chemical compound

SB-277,011A is a drug which acts as a potent and selective dopamine D3 receptor antagonist, which is around 80–100 times selective for D3 over D2, and lacks any partial agonist activity.

Psychological dependence is a cognitive disorder and a form of dependence that is characterized by emotional–motivational withdrawal symptoms upon cessation of prolonged drug use or certain repetitive behaviors. Consistent and frequent exposure to particular substances or behaviors is responsible for inducing psychological dependence, requiring ongoing engagement to prevent the onset of an unpleasant withdrawal syndrome driven by negative reinforcement. Neuronal counter-adaptation is believed to contribute to the generation of withdrawal symptoms through changes in neurotransmitter activity or altered receptor expression. Environmental enrichment and physical activity have been shown to attenuate withdrawal symptoms.

<span class="mw-page-title-main">FOSB</span> Protein

Protein fosB, also known as FosB and G0/G1 switch regulatory protein 3 (G0S3), is a protein that in humans is encoded by the FBJ murine osteosarcoma viral oncogene homolog B (FOSB) gene.

<span class="mw-page-title-main">2-Methyl-6-(phenylethynyl)pyridine</span> Chemical compound

2-Methyl-6-(phenylethynyl)pyridine (MPEP) is a research drug which was one of the first compounds found to act as a selective antagonist for the metabotropic glutamate receptor subtype mGluR5. After being originally patented as a liquid crystal for LCDs, it was developed by the pharmaceutical company Novartis in the late 1990s. It was found to produce neuroprotective effects following acute brain injury in animal studies, although it was unclear whether these results were purely from mGluR5 blockade as it also acts as a weak NMDA antagonist, and as a positive allosteric modulator of another subtype mGlu4, and there is also evidence for a functional interaction between mGluR5 and NMDA receptors in the same populations of neurons. It was also shown to produce antidepressant and anxiolytic effects in animals, and to reduce the effects of morphine withdrawal, most likely due to direct interaction between mGluR5 and the μ-opioid receptor.

<span class="mw-page-title-main">MTEP</span> Chemical compound

3-( ethynyl)pyridine (MTEP) is a research drug that was developed by Merck & Co. as a selective allosteric antagonist of the metabotropic glutamate receptor subtype mGluR5. Identified through structure-activity relationship studies on an older mGluR5 antagonist MPEP, MTEP has subsequently itself acted as a lead compound for newer and even more improved drugs.

<span class="mw-page-title-main">Conditioned place preference</span> Pavlovian conditioning

Conditioned place preference (CPP) is a form of Pavlovian conditioning used to measure the motivational effects of objects or experiences. This motivation comes from the pleasurable aspect of the experience, so that the brain can be reminded of the context that surrounded the "encounter". By measuring the amount of time an animal spends in an area that has been associated with a stimulus, researchers can infer the animal's liking for the stimulus. This paradigm can also be used to measure conditioned place aversion with an identical procedure involving aversive stimuli instead. Both procedures usually involve mice or rats as subjects. This procedure can be used to measure extinction and reinstatement of the conditioned stimulus. Certain drugs are used in this paradigm to measure their reinforcing properties. Two different methods are used to choose the compartments to be conditioned, and these are biased vs. unbiased. The biased method allows the animal to explore the apparatus, and the compartment they least prefer is the one that the drug is administered in and the one they most prefer is the one where the vehicle is injected. This method allows the animal to choose the compartment they get the drug and vehicle. In comparison, the unbiased method does not allow the animal to choose what compartment they get the drug and vehicle in. Instead, the researcher chooses the compartments.

<span class="mw-page-title-main">RTI-113</span> Chemical compound

RTI(-4229)-113 is a stimulant drug which acts as a potent and fully selective dopamine reuptake inhibitor (DRI). It has been suggested as a possible substitute drug for the treatment of cocaine addiction. "RTI-113 has properties that make it an ideal medication for cocaine abusers, such as an equivalent efficacy, a higher potency, and a longer duration of action as compared to cocaine." Replacing the methyl ester in RTI-31 with a phenyl ester makes the resultant RTI-113 fully DAT specific. RTI-113 is a particularly relevant phenyltropane cocaine analog that has been tested on squirrel monkeys. RTI-113 has also been tested against cocaine in self-administration studies for DAT occupancy by PET on awake rhesus monkeys. The efficacy of cocaine analogs to elicit self-administration is closely related to the rate at which they are administered. Slower onset of action analogs are less likely to function as positive reinforcers than analogues that have a faster rate of onset.

<span class="mw-page-title-main">Addiction</span> Disorder resulting in compulsive behaviours

Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use often alters brain function in ways that perpetuate craving, and weakens self-control. This phenomenon – drugs reshaping brain function – has led to an understanding of addiction as a brain disorder with a complex variety of psychosocial as well as neurobiological factors that are implicated in addiction's development.

Addiction is a state characterized by compulsive engagement in rewarding stimuli, despite adverse consequences. The process of developing an addiction occurs through instrumental learning, which is otherwise known as operant conditioning.

Addiction vulnerability is an individual's risk of developing an addiction during their lifetime. There are a range of genetic and environmental risk factors for developing an addiction that vary across the population. Genetic and environmental risk factors each account for roughly half of an individual's risk for developing an addiction; the contribution from epigenetic risk factors to the total risk is unknown. Even in individuals with a relatively low genetic risk, exposure to sufficiently high doses of an addictive drug for a long period of time can result in an addiction. In other words, anyone can become an individual with a substance use disorder under particular circumstances. Research is working toward establishing a comprehensive picture of the neurobiology of addiction vulnerability, including all factors at work in propensity for addiction.

The Monkey Drug Trials of 1969 were a series of controversial animal testing experiments that were conducted on primates to study the effects of various psychoactive substances. The trials shed light on the profound effects of drug addiction and withdrawal in primates, pioneering critical insights into human substance abuse.

References

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