Animal Models of Substance Use Disorders: Motivational Perspective

Acknowledgments

The author would like to thank Michael Arends for his assistance with manuscript preparation.

Definitions Relevant to Animal Models

Drug addiction, also known as substance use disorder, is a chronically relapsing disorder that is characterized by (1) compulsion to seek and take the drug, (2) loss of control in limiting intake, and as defined by the present author and others, (3) emergence of a negative emotional state (e.g., dysphoria, anxiety, irritability) when access to the drug is prevented.

Drug addiction has been conceptualized as a disorder that involves elements of both impulsivity and compulsivity, in which impulsivity can be defined behaviorally as “a predisposition toward rapid, unplanned reactions to internal and external stimuli without regard for the negative consequences of these reactions to themselves or others.” Compulsivity can be defined as elements of behavior that result in perseveration in responding in the face of adverse consequences or perseveration in the face of incorrect responses in choice situations. The compulsivity element could be considered analogous to some of the symptoms of substance use disorder that is outlined by the American Psychiatric Association (i.e., continued substance use despite knowledge of having had a persistent or recurrent physical or psychological problem and a great deal of time spent in activities necessary to obtain the substance).

Collapsing the cycles of impulsivity and compulsivity yields a composite addiction cycle that comprises three stages—binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation (craving). Impulsivity often dominates at early stages, and compulsivity dominates at terminal stages. As an individual moves from impulsivity to compulsivity, a shift occurs from positive reinforcement that drives the motivated behavior to negative reinforcement that drives the motivated behavior ( Fig. 18.1 ). Negative reinforcement can be defined as the process by which the removal of an aversive stimulus (e.g., negative emotional state of drug withdrawal) increases the probability of a response (e.g., dependence-induced drug intake). These three stages are conceptualized as interacting with each other, becoming more intense, and ultimately leading to the pathological state known as addiction. The present review focuses on the role of animal models of dependence that are associated with the negative emotional state of the withdrawal/negative affect stage of the addiction cycle (see Fig. 18.1 ).

Fig. 18.1, Diagram describing the three stages of the addiction cycle—preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect—from a psychiatric perspective with the different criteria for substance dependence incorporated from the DSM-5. Bolded symptoms from the DSM reflect changes during the three stages of the addiction cycle.

The diagnostic criteria for addiction that are described by the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) ⁸ have evolved over the past 30 years, with a shift from an emphasis on and necessary criteria of tolerance and withdrawal to other criteria that are directed more at compulsive use, craving, and relapse. The number of criteria that are met by individuals who meet the criteria for addiction varies with the severity of addiction, the stage of the addiction process, and the drug in question, but the criteria are well represented by symptoms that coalesce around the withdrawal/negative affect and preoccupation/anticipation stages (see Fig. 18.1 ).

Important for the present chapter is the distinction between physical or somatic signs of withdrawal and motivational signs of withdrawal. Both reflect dependence in the classic sense, but only the motivational signs of withdrawal are argued herein to be relevant to the syndrome of addiction (see discussion of somatic vs. motivational withdrawal in subsequent text of this chapter). Thus, although historically the diagnostic criteria have focused on physical (somatic) signs of withdrawal, more motivational signs have been neglected, and the argument of the present treatise is that motivational signs of withdrawal remain a critical aspect of the addiction process.

Different drugs produce different patterns of addiction, with an emphasis on different components of the addiction cycle. The classic drugs of addiction are opioids. A pattern of intravenous or smoked drug taking evolves, including intense intoxication, the development of tolerance, escalation of intake, and profound dysphoria, physical discomfort, and somatic withdrawal signs during abstinence. Intense preoccupation with obtaining opioids (craving) develops that often precedes the somatic signs of withdrawal and is linked not only to stimuli that are associated with obtaining the drug but also to stimuli that are associated with withdrawal and internal and external states of stress. A pattern develops in which the drug must be taken to avoid the severe dysphoria and discomfort of abstinence. Other drugs of abuse follow a similar pattern but may involve more the binge/intoxication stage (e.g., psychostimulants and alcohol) or less binge/intoxication and more withdrawal/negative affect and preoccupation/anticipation stages (e.g., nicotine and cannabinoids).

Animal Models of Withdrawal

Somatic Signs

Two drugs, opioids and alcohol, provide classic examples of the somatic signs of withdrawal and have served as models for measures of withdrawal per se. Indeed, as discussed earlier, these somatic measures are basically a “red herring” for the more motivational measures of withdrawal from the perspective of negative reinforcement, drug seeking, and craving that are associated with acute and protracted abstinence. However, the somatic signs of withdrawal are an index of neuroadaptational changes that reflect sufficient drug intake to produce motivational measures, given that motivational measures occur at lower doses and earlier than somatic signs.

For opioids, somatic withdrawal signs in humans are dramatic and dose-dependent and duration-of-abstinence-dependent and include a number of overt measurable signs, such as yawning, lacrimation, rhinorrhea, perspiration, gooseflesh, tremor, dilated pupils, anorexia, nausea, emesis, diarrhea, weight loss, and elevations of temperature and blood pressure. In animals (rodents), opioid withdrawal signs are well characterized when precipitated by the administration of a competitive opioid receptor antagonist, such as naloxone. A weighted scale was developed and widely adopted that included graded signs of weight loss, diarrhea, escape attempts, wet dog shakes, abdominal constrictions, facial fasciculations/teeth chattering, salivation, ptosis, abnormal posture, penile grooming/erection/ejaculation, and irritability ( Table 18.1 ). When the somatic signs of opioid withdrawal are directly compared with more motivational measures, the motivational measures are more sensitive and show more efficacy in defining the withdrawal state. Spontaneous withdrawal shows many of the same signs, but they are significantly less intense (see Table 18.1 ).

Table 18.1

Somatic withdrawal signs

Opioid Withdrawal
Rats	Humans
Weight loss Diarrhea Escape attempts Wet dog shakes Abdominal constrictions Facial fasciculations Teeth chattering Salivation Ptosis Abnormal posture Penile grooming Erection/ejaculation Irritability	Weight loss Diarrhea Yawning Lacrimation Rhinorrhea Perspiration Gooseflesh Tremor Dilated pupils Anorexia Nausea Emesis Hyperthermia Increased blood pressure

Alcohol Withdrawal
Rats	Humans
Hyperactivity Tail tremors Tail stiffness Akinesia Spastic rigidity Convulsions	Tremor Increased heart rate Increased blood pressure Increased body temperature Anorexia Convulsions Hyperthermia Delirium tremens

For alcohol, the somatic signs of withdrawal in humans are equally dramatic but also life-threatening and are characterized by tremor, increases in heart rate, increases in blood pressure, increases in body temperature, anorexia, and convulsions. In its severest form, alcohol withdrawal can result in pronounced hyperthermia that can evolve into delirium tremens, a state of marked sympathetic hyperactivity, hyperthermia (which can be fatal), and hallucinations. In animals (rodents), alcohol withdrawal signs are characterized by hyperactivity, tail tremors, tail stiffness, head tremors, general tremors, ventromedio-distal flexion, wet shakes, teeth chattering, akinesia, spastic rigidity, and induced and spontaneous convulsions (see Table 18.1 ). With alcohol, the withdrawal is only spontaneous because no known competitive antagonist can precipitate withdrawal. Similar to opioids, withdrawal from alcohol is dose- and duration-of-abstinence-dependent, with peak withdrawal ranging from 10 to 16 hours with high-dose blood alcohol levels at the time of withdrawal (300–400 mg/dL).

Motivational Signs

Animal models of the withdrawal/negative affect stage include increases in anxiety-like responses, measures of conditioned place aversion (rather than preference), and elevations of brain stimulation reward thresholds in response to precipitated withdrawal or spontaneous withdrawal from chronic administration of a drug ^a

a References 43, 49, 104, 133, 161, 162.

( Table 18.2 ).

Table 18.2

Animal Models Associated With the Different Stages of the Addiction Cycle

Stage of Addiction Cycle	Animal Model
Binge/intoxication	Drug/alcohol self-administration Conditioned place preference Brain stimulation reward thresholds
Withdrawal/negative affect	Anxiety-like responses Conditioned place aversion Brain stimulation reward Escalation of drug self-administration with extended access or dependence
Preoccupation/anticipation	Drug-induced reinstatement Cue-induced reinstatement Stress-induced reinstatement Protracted abstinence

Anxiety-Like Symptoms

A common response to acute withdrawal and protracted abstinence from all major drugs of abuse is the manifestation of anxiety-like responses. Animal models have revealed anxiety-like responses to all major drugs of abuse during acute withdrawal, with the dependent variable often a passive response to a novel and/or aversive stimulus, such as the open field or elevated plus maze, or an active response to an aversive stimulus, such as defensive burying of an electrified metal probe. Withdrawal from repeated administration of cocaine produces an anxiogenic-like response in the elevated plus maze and defensive burying test, both of which are reversed by administration of corticotropin-releasing factor (CRF) antagonists ( Fig. 18.2 ). Precipitated withdrawal in opioid dependence and nicotine dependence also produces anxiety-like effects. Spontaneous alcohol withdrawal produces anxiety-like behavior. ^b

b References 13, 23, 75, 129, 137, 183, 185.

Fig. 18.2, Effect of intracerebroventricular administration of the corticotropin-releasing factor (CRF) antagonist D-Phe CRF 12–41 on anxiogenic-like effects in the defensive burying paradigm following chronic cocaine administration. Rats received chronic cocaine (20 mg/kg, i.p., for 14 days) or saline (1 ml/kg, i.p.). Animals were then tested in the defensive burying paradigm 48 h after the last injection. D-Phe CRF 12–41 (0, 0.04, 0.2, and 1.0 mg/5 mL) was administered immediately after the animal touched the electrified probe and received the shock and 5 min before the testing session. The data are expressed as mean ± standard error of the mean (SEM; n = 10–14/group). The left panel shows the latency to start burying in all experimental groups (∗ p < 0.05, compared with saline/vehicle group; ∗∗ p < 0.01, compared with cocaine/vehicle group; Duncan post hoc test). The middle panel represents the total duration of burying behavior in all experimental groups (∗ p < 0.05, compared with chronically saline-treated groups; ∗∗ p < 0.01, compared with cocaine/vehicle group; Duncan post hoc analysis). The right panel represents the height of bedding material at the junction between the probe and the wall of the testing cage (∗ p < 0.05, compared with saline/vehicle group; ∗∗ p < 0.01, compared with other chronically cocaine-treated groups; Duncan post hoc analysis).

Dysphoria-Like Symptoms

Place aversion has been used to measure the aversive stimulus effects of withdrawal, mostly in the context of opioids ( Fig. 18.3 ). In contrast to conditioned place preference, rats that are exposed to a particular environment while undergoing precipitated withdrawal from opioids spend less time in the withdrawal-paired environment when subsequently presented with a choice between that environment and an unpaired environment. Such an association continues to be manifested weeks after the animals are “detoxified” (e.g., after the morphine pellets are removed ) and can be measured from 24 hours to 16 weeks later. Additionally a place aversion in opioid-dependent rats can be observed with doses of naloxone below which somatic signs of withdrawal are observed. Although naloxone itself will produce a place aversion in nondependent rats, the threshold dose that is required to produce a place aversion decreases significantly in dependent rats.

Fig. 18.3, The corticotropin-releasing factor-1 antagonist antalarmin (Ant) reduced naloxone (NAL)-precipitated place aversion conditioning in morphine (Morph)-dependent rats. Morphine dependence was induced by subcutaneous implantation of two slow-release, morphine-containing pellets, each containing 75 mg of morphine base. Placebo-pelleted rats received placebo morphine pellets that were implanted subcutaneously. Separate groups of morphine-dependent rats that received naloxone (15 μg/kg, subcutaneously) immediately prior to conditioning (Morph-Nal) were also injected 30 min before naloxone on days 6, 8, and 10 with antalarmin (2.5, 5, 10, or 20 mg/kg, intraperitoneally; n = 8–12/group). Although antalarmin at doses of 2.5 and 5 mg/kg was ineffective, doses of 10 and 20 mg/kg blocked the place aversion that was produced by naloxone in morphine-dependent rats and returned values to levels that were observed with naloxone in placebo-pelleted rats and in morphine-no naloxone (Morph-Nal 0) rats. ∗ p < 0.05, within each dose group treatment (Wilcoxon signed-rank test). NS refers to no significant place preference or place aversion with the Wilcoxon signed-rank test. ## p < 0.01, compared with Morph-Nal 15 group (between-group comparisons, Mann-Whitney test [ΔD]).

The place aversion to opioids does not require the maintenance of opioid dependence for its manifestation, and a variation of this approach is to explore the place aversion that is produced following a naloxone injection after a single acute injection of morphine. Acute opioid dependence has been defined as the precipitation of withdrawal-like signs by opioid receptor antagonists following a single opioid dose or short-term administration of an opioid receptor agonist. Rats exhibit a reliable conditioned place aversion that is precipitated by a low dose of naloxone after a single morphine injection that reflects a motivational component of acute withdrawal. Similar acute withdrawal-like effects have been observed using anxiety-like responses following bolus injections of alcohol.

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