Abstract

Substance abuse and addiction are enormous public health concerns that affect society and public policy in multiple areas, including health care, education, worker productivity, criminal law, and prison systems.
The World Health Organization reported that 76.3 million persons worldwide have alcohol use disorders and at least 15.3 million have drug use disorders.
 Use of injected drugs has been reported in 136 countries, of which 93 reports HIV infection among this population.

The costs of this situation The common feature of substance dependence is a group of behavioural and physiologic symptoms indicating the continued use of the substance despite significant problems resulting from such use.
Drug addiction exists when drug procurement and use begins to govern the subject's (human or animal) behaviour and the drug appears to control the subject's motivational status. Substance dependence is often linked to other mental health illnesses. Among adults 18 y or older with serious psychologic distress, 22.1% were dependent on to society are substantial.
 The National Institute on Drug Abuse estimated the total economic cost of alcohol and drug abuse at $245.7 billion for 1992.
 In addition to health care costs and the costs of lost productivity, costs are incurred by the criminal justice system, efforts to reduce the supply of drugs, and the provision of social welfare. Crime-related costs alone account for 59% of total societal costs.accounting for more than 10% of combined federal, state, and local expenditures for all purposes. prevention, treatment, and addiction research. According to the NIH Office of Budget, research awards supported by the National Institute on Drug Abuse in the fiscal year 2008 totalled just over $750 million (http://officeofbudget.od.nih.gov/spending_hist.html).
Substance-related disorders are divided into 2 groups: substance-use disorders include substance dependence and substance abuse, and substance-induced disorders, which include intoxication, withdrawal, substance-induced delirium, persisting dementia. 
Pain lasting more than 24 h affects more than 25% of Americans each year and costs approximately $100 billion in lost productivity, lost income, and health care. chronic pain with addictive medications and the spillover abuse of prescription drugs by persons without medical indications have led to widespread prescription drug abuse. As mentioned elsewhere in this overview, animal studies have demonstrated that the rewarding effect is not dependent on preexisting conditions; that is, exposure to the drug is sufficient to motivate drug-taking behaviour. In other words, some of the typical behaviours associated with drug abuse in humans are not necessary for drug reinforcement to occur; rather they involve biologic processes common to mammalian species. better understood medical issues such as heart disease, diabetes, and cancer. In this overview, we aim to present important aspects of substance abuse research, describe various animal models that have been developed to study specific aspects of drug addiction and substance abuse disorders, and delve into important veterinary, husbandry, and ethical (IACUC) issues associated with substance abuse research

Animal Models of Substance Abuse and Addiction

Recently, the conceptual framework for modelling addiction in animals has focused on modelling different phases of the addiction process, such as drug initiation or acquisition, and on the factors that affect or predict vulnerability to drug addiction. 

Drug self-administration paradigm.

In addition, similar patterns of drug intake have been reported in humans and animals for ethanol, opioids, nicotine, and cocaine self-administration. These parallel results between the human and animal drug literature This ‘reward pathway’ is comprised of several brain regions, the most prominent being the ventral tegmental area, nucleus accumbens, and prefrontal cortex. 
The ventral tegmental area has dopaminergic projections to both the nucleus accumbens and prefrontal cortex.


the reward pathway, particularly in the nucleus accumbens, and if dopamine release is prevented (for example, by pharmacologic blockage or lesions), drug reinforcement is blocked. Importantly, this pathway is known to be activated in response to drugs of abuse as well as natural rewards, such as food and sex.
Reinforcement or the rewarding effects of drugs of abuse, and thus dopaminergic signalling in the reward pathway, appear to be critically involved in addiction, but the strength of this involvement may vary with stage of the addiction process.
Studies in animals have revealed that drug initiation, or acquisition, can be blocked by dopamine antagonists or by inducing lesions in the reward pathway. However, accumulating evidence indicates that after chronic drug exposure, systems and signalling pathways outside the reward pathway (for example, dopaminergic and nondopaminergic signalling in cortical areas, other striatal areas, amygdala, hippocampus; for review see reference 100) become involved in driving drug-taking and -seeking behaviours. On the basis of the idea that this reward pathway is critical for drug reinforcement, much of the hunt for pharmacotherapeutic agents to combat drug addiction has focused on dopaminergic signalling. Although the rationale for using dopaminergic agents appears to be obvious, the plethora of research in this area has failed to produce an accepted effective pharmacotherapy.
 This failure is due, in part, to severe adverse effects, including nausea, headaches, hypertension, tachycardia, and psychosis-like symptoms, experienced after the administration of dopaminergic agents.
Although addiction involves drug reinforcement, it also involves drug craving and a loss of control over use.

 

Vulnerability to drug abuse.

Animal models of the initiation or acquisition phase have been developed, and they have been useful in identifying biological and behavioural factors in vulnerability to the reinforcing effects of drugs of abuse that may apply to prevention efforts in humans.15 Optimally, acquisition of drug self-administration is investigated in drug-naive and experimentally naive animals that are maintained under food-satiated conditions and tested under low-dose conditions
. Under these conditions, individual differences are maximized, and some rats acquire self-administration whereas others do not.
Often the ratio of active to inactive lever press responses is used in conjugation with the intake criteria. All of the study animals are included in the analysis, regardless of whether they acquire self-administration or not, and the focus is on how rapidly acquisition of self-administration takes place and the percentage of animals in each group that acquire drug self-administration.
For example, in a study that examined the effects of feeding condition and palatability of the diet, rates of acquisition became slower with increasing levels of food satiation, particularly when the food options were enriched.
  regions associated with drug reward, genetic strain, innate saccharin preference, levels of impulsivity, age, and sex. For example, we previously showed that female rats acquire cocaine and heroin self-administration at a faster rate than do male rats and that a greater percentage of female rats acquire cocaine self-administration than do male rats.

The transition from controlled use to compulsive and uncontrolled drug 


use response was reinforced under a fixed-ratio 1 schedule) were characterized by dysregulated and binge patterns of use.
confined to the dark phase of the light: dark cycle. However, under extended access conditions (that is, 4 discrete trials per hour, 1.5 mg/kg per infusion), rats self-administer high levels of cocaine in a pattern that is dysregulated from the diurnal cycle (that is, responding occurs at high levels during both dark and light phases).
Importantly, both increased motivation for cocaine and increased drug-seeking behaviour additional key features of cocaine addiction—occur after excessive drug self-administration when examined after an abstinence period.responding for cocaine when assessed after a 7-d abstinence period. Similar results have recently been reported after extended access to self-administered heroin and methamphetamine by using similar procedures. These parallel results between extended access drug self-administration paradigms in animals and drug-addicted humans validate their use as an animal model of addiction and suggest that these models of extended drug access may be useful in determining predictive factors during the transition from controlled to uncontrolled drug use.
Although few studies have examined individual differences by using extended access drug self-administration procedure, one factor that is known to predict vulnerability is sex. For example, results from studies from our laboratory have revealed that female rats take more cocaine under extended-access conditions and appear to require less drug exposure than do male rats to display increased motivation for cocaine  Other factors include sweet preference and level of reactivity to novelty, both of which appear to influence the appearance of drug escalation or dysregulation as well as motivational changes after extended-access self-administration

Relapse to drug use.

Various types of stimuli can precipitate drug craving and relapse to drug use.
 These factors include environmental stressors, internal cues such as reexposure to small ‘priming’ doses of the drug, and external cues such as specific places and people that were associated with drug use.
 Animal models of relapse have been developed and have provided important information on the neurobiological mechanisms underlying vulnerability to relapse to drug abuse.
One model that has been used to investigate mechanisms underlying relapse is the reinstatement paradigm.
 With this procedure, animals are trained to self-administer a drug and once stable responding is achieved, it is extinguished by discontinuing drug delivery.
After responding reaches some criterion of unresponsiveness, the ability of various stimuli to reinstate drug-seeking is determined under conditions of nonreinforcement (that is, responses are no longer reinforced by the drug).  The results from preclinical studies have revealed that the conditions that reinstate drug seeking in laboratory animals are similar to those that trigger relapse in humans and include exposure.
 Results from reinstatement studies have revealed a number of factors that predict vulnerability during this phase, including responsiveness to the acute and chronic locomotor-activating effects of psychostimulants, locomotor responses