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.

Reprinted with permission from Koob.


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).

Reprinted with permission from Basso et al. [Springer Science+Business Media].


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]).

Reprinted with permission from Stinus et al.


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.


Reward Thresholds


Electrical brain stimulation reward or intracranial self-stimulation has a long history as a measure of activity of the brain reward system and of the acute reinforcing effects of drugs of abuse. All drugs of abuse, when administered acutely, lower brain reward thresholds. Brain stimulation reward involves widespread neurocircuitry in the brain, but the most sensitive sites, defined by the lowest thresholds, involve the trajectory of the medial forebrain bundle that connects the ventral tegmental area with the basal forebrain. Although much emphasis was placed initially on the role of the ascending monoamine systems in the medial forebrain bundle, other nondopaminergic, descending systems in the medial forebrain bundle clearly play a key role.


Acute intravenous cocaine self-administration in animals lowers reward thresholds, consistent with the well-documented effects of drugs of abuse in lowering brain reward thresholds. However, with more prolonged access to the drug, the lowering of reward thresholds (i.e., rewarding effects) are replaced with elevations of reward thresholds (i.e., anti-rewarding effects) after the initial lowering of reward thresholds, presumably reflecting an acute withdrawal or opponent process-like effect. Such elevations of reward thresholds begin rapidly, can be observed within a single session of self-administration, and are greater with greater exposure to cocaine, bearing a striking resemblance to human subjective reports. Chronic administration or self-administration of all drugs of abuse produces elevations of reward thresholds during spontaneous or precipitated acute withdrawal ( Fig. 18.4 ). These elevations of threshold can be short (minutes to hours) or can last for days, depending on dose, drug, time of exposure, and precipitant.




Fig. 18.4


(A) Mean intracranial self-stimulation reward thresholds (± SEM) in rats during amphetamine withdrawal (10 mg/kg/day for 6 days). Data are expressed as a percentage of the mean of the last five baseline values prior to drug treatment. ∗ p < 0.05, compared with saline control group. (Reprinted with permission from Paterson et al. [Springer Science+Business Media].) (B) Mean intracranial self-stimulation reward thresholds (± SEM) in rats during alcohol withdrawal (blood alcohol levels achieved: 197.29 mg%). Elevations of thresholds were time-dependent. ∗ p < 0.05, compared with control group. (Reprinted with permission from Schulteis et al. ) (C) Mean intracranial self-stimulation thresholds (± SEM) in rats during cocaine withdrawal 24 h following the cessation of cocaine self-administration. ∗ p < 0.05, compared with control group. (Reprinted with permission from Markou and Koob .) (D) Mean intracranial self-stimulation reward thresholds (± SEM) in rats during naloxone-precipitated morphine withdrawal. The minimum dose of naloxone that elevated intracranial self-stimulation reward thresholds in the morphine group was 0.01 mg/kg. ∗ p < 0.05, compared with control group. (Reprinted with permission from Schulteis et al. ) (E) Mean intracranial self-stimulation reward thresholds (± SEM) in rats during spontaneous nicotine withdrawal following surgical removal of osmotic minipumps that delivered nicotine hydrogen tartrate (9 mg/kg/day) or saline. ∗ p < 0.05, compared with control group. (Data adapted from Epping-Jordan et al. ) (F) Mean intracranial self-stimulation reward thresholds (± SEM) in rats during withdrawal from an acute 1.0 mg/kg dose of Δ -tetrahydrocannabinol (THC). Withdrawal significantly shifted the reward function to the right (indicating lower reward). (Reprinted with permission from Gardner and Vorel .) Note that because different equipment systems and threshold procedures were used in the collection of the above data, direct comparisons among the magnitude of effects that were induced by these drugs cannot be made.




Animal Models of Increased Drug Taking With Prolonged Access or Dependence


Escalation of Drug Self-Administration With Extended Access


A progressive increase in the frequency and intensity of drug use is one of the major behavioral phenomena that characterize the development of addiction and has face validity with the criteria of the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5): “The substance is often taken in larger amounts and over a longer period than was intended.” A framework with which to model the transition from drug use to drug addiction can be found in animal models of prolonged access to intravenous cocaine self-administration. Historically, animal models of cocaine self-administration involved the establishment of stable behavior from day to day to allow the reliable interpretation of data that are provided by within-subjects designs that explore the neuropharmacological and neurobiological bases of the reinforcing effects of acute cocaine. Until 1998, after the acquisition of self-administration, rats typically were allowed access to cocaine for 3 hours or less per day to establish highly stable levels of intake and stable patterns of responding between daily sessions. This was a useful paradigm for exploring the neurobiological substrates for the acute reinforcing effects of drugs of abuse.


However, in an effort to explore the effects of differential access to intravenous cocaine self-administration on cocaine-seeking in rats, rats were allowed access to intravenous cocaine self-administration for 1 hour or 6 hours per day. One-hour access (short access) to intravenous cocaine per session produced low and stable intake, as observed previously. In contrast, 6-hour access (long access) to cocaine produced drug intake that gradually escalated over days ( Fig. 18.5 ). Increased intake was observed in the extended-access group during the first hour of the session, with sustained intake over the entire session and an upward shift in the dose-effect function, suggesting an increase in hedonic set point. When animals were allowed access to different doses of cocaine, both the long- and short-access animals titrated their cocaine intake, but the long-access rats consistently self-administered almost twice as much cocaine at any dose tested, further suggesting an upward shift in the set point for cocaine reward in the escalated animals. Such increased self-administration in dependent animals has now been observed with cocaine, methamphetamine, nicotine, heroin, and alcohol (see Fig. 18.5 ). This model is a key element for evaluating the motivational significance of changes in the brain reward and stress systems in addiction that lead to compulsivity in addiction. Similar changes in the reinforcing and incentive effects of cocaine have been observed following extended access and include increased cocaine-induced reinstatement after extinction and decreased latency to goal time in a runway model for cocaine reward. Altogether, these results suggest that drug taking with extended access changes the motivation to seek the drug. Whether this enhanced drug taking reflects the sensitization of reward or a reward deficit state remains under discussion, but the brain reward and neuropharmacological studies that are outlined in subsequent text argue for a reward deficit state that drives the increased drug taking during extended access.




Fig. 18.5


Escalation of drug intake. (A) Effect of drug availability on cocaine intake (mean ± SEM). In long-access (LgA) rats ( n = 12) but not short-access (ShA) rats ( n = 12), the mean total cocaine intake started to increase significantly from session 5 ( p < 0.05; sessions 5 to 22 compared with session 1) and continued to increase thereafter ( p < 0.05; session 5 compared with sessions 8–10, 12, 13, and 17–22). (Reprinted with permission from Ahmed and Koob. ) (B) Effect of drug availability on total intravenous heroin self-infusions (mean ± SEM). During the escalation phase, rats had access to heroin (40 μg per infusion) for 1 h (ShA rats, n = 5-6) or 11 h per session (LgA rats, n = 5-6). Regular 1-h (ShA rats) or 11-h (LgA rats) sessions of heroin self-administration were performed 6 days per week. The dotted line indicates the mean ± SEM number of heroin self-infusions in LgA rats during the first 11-h session. ∗ p < 0.05, different from the first session (paired t -test). (Reprinted with permission from Ahmed et al. ) (C) Effect of extended access to intravenous methamphetamine on self-administration as a function of daily sessions in rats trained to self-administer 0.05 mg/kg/infusion of intravenous methamphetamine during 6-h sessions. ShA, 1-h session ( n = 6). LgA, 6-h session ( n = 4). ∗ p < 0.05, ∗∗ p < 0.01, compared with day 1. (Reprinted with permission from Kitamura et al. ) (D) Nicotine intake (mean ± SEM) in rats that self-administered nicotine under a fixed-ratio (FR) 1 schedule in either 21-h (long access [LgA]) or 1-h (short access [ShA]) sessions. LgA rats increased their nicotine intake on an intermittent schedule with 24–48 h breaks between sessions, whereas LgA rats on a daily schedule did not. The left shows the total number of nicotine infusions per session when the intermittent schedule included 24-h breaks between sessions. The right shows the total number of nicotine infusions per session when the intermittent schedule included 48-h breaks between sessions. # p < 0.05, compared with baseline; ∗ p < 0.05, compared with daily self-administration group. n = 10 per group. (Reprinted with permission from Cohen et al. ) (E) Ethanol self-administration in ethanol-dependent and nondependent animals. The induction of ethanol dependence and correlation of limited ethanol self-administration before and excessive drinking after dependence induction following chronic intermittent ethanol vapor exposure is shown. ∗∗∗ p < 0.001, significant group × test session interaction. With all drugs, escalation is defined as a significant increase in drug intake within-subjects in extended-access groups, with no significant changes within-subjects in limited-access groups.

Reprinted with permission from Edwards et al.


Withdrawal-Induced Drinking


Historically, animal models of negative reinforcement that is associated with alcohol dependence have proven difficult, especially with rodents. The induction of physical dependence could enhance the preference for alcohol, c


c References 39, 40, 68, 146, 153, 160, 187, 206.

but other reports did not support enhanced preference for alcohol in dependent animals. Over the past 30 years, reliable and useful models of alcohol consumption in dependent rats and mice have been developed in several laboratories. For example, in a major advance, alcohol first was established as a reinforcer, and then the animals were made dependent. The animals were maintained through a liquid diet or continuous alcohol vapor exposure at blood alcohol levels that produced mild-to-moderate physical withdrawal symptoms when the alcohol was removed, but significant motivational signs were observed, measured by changes in brain stimulation reward during acute withdrawal from alcohol. Therefore, any somatic withdrawal symptoms that the rats experienced would be predictably quite mild and would not be expected to physically interfere with their ability to respond. Animals showed reliable increases in self-administration of alcohol during withdrawal, in which the amount of intake approximately doubled and the animals had blood alcohol levels from 0.10 to 0.15 gm% after 12 hours of self-administration.


Further development of this model showed that animals that were exposed intermittently (14 hours on/10 hours off) to the same amount of alcohol as continuously exposed animals showed even more dramatic increases in self-administration during acute withdrawal (see Fig. 18.5 ). Systematic exploration of the parameters that determine the maximum increase in alcohol self-administration and blood alcohol levels showed that animals that were exposed to intermittent alcohol via alcohol vapor chambers developed dependence more rapidly. The intermittent paradigm has produced dependent animals that achieved blood alcohol levels of 0.15 gm% in a 30-minute session and display increased responding on a progressive-ratio schedule, indicative of increased motivation to consume alcohol.


Motivational Changes Associated With Increased Drug Intake During Extended Access or Dependence


The hypothesis that compulsive drug use is accompanied by a chronic perturbation in brain reward homeostasis has been tested in an animal model of the escalation of drug intake with prolonged access combined with measures of brain stimulation reward thresholds. Animals that were implanted with intravenous catheters and allowed differential access to intravenous self-administration of cocaine or heroin showed increases in drug self-administration from day to day in the long-access group but not in the short-access group. The differential exposure to drug self-administration had dramatic effects on reward thresholds that progressively increased in long-access rats but not in short-access or control rats across successive self-administration sessions ( Fig. 18.6 ). Elevations of baseline reward thresholds temporally preceded and were highly correlated with the escalation of cocaine intake. Postsession elevations of reward thresholds failed to return to baseline levels before the onset of each subsequent self-administration session, thereby deviating progressively more from control levels. The progressive elevation of reward thresholds was associated with the dramatic escalation of cocaine consumption that was observed previously. After escalation had occurred, an acute cocaine challenge facilitated brain reward responsiveness to the same degree as before but resulted in higher absolute brain reward thresholds in long-access compared with short-access rats. Similar results have been observed with extended access to heroin, in which rats that were allowed 23-hour access to heroin showed a time-dependent elevation of reward thresholds that paralleled the increases in heroin intake (see Fig. 18.6 ).




Fig. 18.6


(A) Relationship between elevation in of intracranial self-stimulation (ICSS) reward thresholds and cocaine intake escalation. ( Left ) Percent change from baseline response latencies (3 h and 17–22 h after each self-administration session; first data point indicates 1 h before the first session). ( Right ) Percent change from baseline ICSS thresholds. ∗ p < 0.05, compared with drug-naive and/or ShA rats (tests for simple main effects). (Reprinted with permission from Ahmed et al. ) (B) Unlimited daily access to heroin escalated heroin intake and increased reward thresholds. ( Left ) Heroin intake (± SEM; 20 μg per infusion) in rats during limited (1 h) or unlimited (23 h) self-administration sessions. ∗∗∗ p < 0.001, main effect of access (1 or 23 h). ( Right ) Percent change from baseline ICSS thresholds (± SEM) in 23 h rats. Reward thresholds, assessed immediately after each daily 23 h self-administration session, became progressively more elevated as exposure to self-administered heroin increased across sessions. ∗ p < 0.05, main effect of heroin on reward thresholds. (Reprinted with permission from Kenny et al. ) (C) Escalation of methamphetamine self-administration and ICSS in rats. Rats were daily allowed to receive ICSS in the lateral hypothalamus 1 h before and 3 h after intravenous methamphetamine self-administration with either 1- or 6-h access. ( Left ) Methamphetamine self-administration during the first hour of each session. ( Right ) ICSS measured 1 h before and 3 h after methamphetamine self-administration. ∗ p < 0.05, ∗∗ p < 0.01, ∗∗∗ p < 0.001, compared with session 1; # p < 0.05, compared with LgA 3 h after.

From Jang et al.


Another reflection of the change in motivation that is associated with dependence is a measure of reinforcement efficacy, measured by changes in progressive-ratio responding. In the progressive-ratio procedure, rats are first allowed to reach baseline responding for cocaine under a fixed-ratio 1 schedule of reinforcement. For a progressive-ratio schedule, the response requirement (i.e., the number of lever responses that are required to receive a drug injection, or “ratio”) increases using an exponential function, such as 5 (0.2·infusion number) −5, yielding response requirements of 1, 2, 4, 6, 9, 12, 15, 20, 25, 32, 40, 50, 62, 77, 95, 118, 146, 178, 219, and 268, etc. Sessions on this schedule are terminated when more than three times the animal’s longest baseline interresponse time has elapsed since the last self-administered cocaine injection. Animals normally respond for 11–15 injections of cocaine, and the breakpoint is defined as the highest completed ratio in a session. The dependent measure in progressive-ratio experiments is the total number of injections that are obtained per session and the breakpoint. Extended access to drugs that results in escalated intake is also associated with an increase in breakpoint for cocaine on a progressive-ratio schedule, suggesting enhanced motivation to seek cocaine or the lower efficacy of cocaine reward. Similar results have been observed with methamphetamine and withdrawal-induced drinking in rats that were made dependent with alcohol vapor ( Fig. 18.7 ).




Fig. 18.7


(A) Dose-response function of cocaine self-administration in rats under a progressive-ratio schedule. Test sessions under a progressive-ratio schedule ended when rats did not achieve reinforcement within 1 h. The data are expressed as the number of injections per session on the left axis and ratio per injection on the right axis. ∗ p < 0.05, compared with short-access (ShA) rats at each dose of cocaine. (Reprinted with permission from Wee et al. ) (B) Responding for heroin under a progressive-ratio schedule of reinforcement in ShA and long-access (LgA) rats. ∗ p < 0.05, LgA significantly different from LgA. (Modified with permission from Barbier et al. ) (C) Dose-response for methamphetamine under a progressive-ratio schedule. Test sessions under a progressive-ratio schedule ended when rats did not achieve reinforcement within 1 h. ∗ p < 0.05, ∗∗ p < 0.01, LgA significantly different from ShA. (Modified with permission from Wee et al. ) (D) Breakpoints on a progressive-ratio schedule in LgA rats that self-administered nicotine with 48 h abstinence between sessions. LgA rats on an intermittent schedule reached significantly higher breakpoints than LgA rats that self-administered nicotine daily. The data are expressed as mean ± SEM. ∗ p < 0.05. n = 9 rats per group. (Reprinted with permission from Cohen et al. ) (E) Mean (± SEM) breakpoints for alcohol while in nondependent and alcohol-dependent states. ∗∗ p < 0.01, main effect of vapor exposure on alcohol self-administration.

Reprinted with permission from Walker and Koob.




Protracted Abstinence


Relapse to drugs of abuse often occurs even after physical and motivational withdrawal signs have ceased, suggesting perhaps that the neurochemical changes that occur during the development of dependence can persist beyond the overt signs of acute withdrawal. In individuals with alcohol use disorder, numerous symptoms that can be characterized by negative emotional states persist long after acute physical withdrawal from alcohol. Fatigue and tension have been reported to persist up to 5 weeks postwithdrawal. Anxiety has been shown to persist up to 9 months, and anxiety and depression have been shown to persist in up to 20%–25% of alcoholics for up to 2 years postwithdrawal. These symptoms, post-acute withdrawal, tend to be affective in nature and subacute and often precede relapse. A factor analysis of Marlatt’s relapse taxonomy found that negative emotion, including elements of anger, frustration, sadness, anxiety, and guilt, was a key factor in relapse, and the leading precipitant of relapse in a large-scale replication of Marlatt’s taxonomy was negative affect. In secondary analyses of participants in a 12-week clinical trial with alcohol dependence and not meeting criteria for any other Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition (DSM-IV), mood disorder, the association with relapse and a subclinical negative affective state was particularly strong. This state has been termed “protracted abstinence” and has been defined in humans as a Hamilton Depression rating ≥8 with the following three items consistently reported by subjects: depressed mood, anxiety, and guilt.


Animal work has shown that prior dependence lowers the dependence threshold such that previously dependent animals that are made dependent again exhibit more severe physical and motivational withdrawal symptoms than groups that receive alcohol for the first time. This supports the hypothesis that alcohol experience and the development of dependence in particular can lead to relatively permanent alterations of responsiveness to alcohol. However, relapse often occurs even after physical withdrawal signs have ceased, suggesting that the neurochemical changes that occur during the development of dependence can persist beyond the final overt signs of withdrawal (motivational withdrawal syndrome).


A history of dependence in male Wistar rats can produce a prolonged elevation of alcohol self-administration in daily 30-minute sessions after acute withdrawal and detoxification. This increase in self-administration of alcohol is accompanied by increases in blood alcohol levels and persists for up to 8 weeks postdetoxification. The increase in self-administration is also accompanied by increased behavioral responsivity to stressors and increased responsivity to antagonists of the brain CRF systems. The persistent increase in alcohol self-administration has been hypothesized to involve an allostatic-like adjustment such that the set point for alcohol reward is elevated. These persistent alterations of alcohol self-administration and residual sensitivity to stressors can be arbitrarily defined as a state of “protracted abstinence.” Protracted abstinence, defined as such in the rat, spans a period after acute physical withdrawal has disappeared when elevations of alcohol intake over baseline and increased behavioral responsivity to stress persist (2–8 weeks postwithdrawal from chronic alcohol).


Significant self-administration of high amounts of alcohol that are similar to those that are observed in alcohol-preferring animals and during protracted abstinence has been observed using other methods. Here, the animals exhibited tolerance but no somatic withdrawal. Rats that received passive intragastric infusion of alcohol for 3–6 days at levels that are observed in alcohol-preferring strains (3.3–12.2 g/kg/day) and were allowed access to intragastric self-infusion maintained high levels of alcohol self-administration (4–7 g/kg/day). Intermittent access to 20% alcohol (three 24-hour sessions per week for 6 weeks) using a two-bottle choice procedure induced high alcohol consumption in rats to levels up to 5–6 g/kg/day. However, blood alcohol levels in 30-minute two-bottle choice sessions in the intermittent 20% animals were significantly lower (averaging approximately 60 mg% in Wistar rats) than those that were observed in dependent animals (see above). Protracted abstinence has also been linked to elevations of brain reward thresholds, increased sensitivity to cues that are associated with withdrawal (conditioned place aversions to opioids), and increases in the sensitivity to anxiety-like behavior (alcohol) that have been shown to persist after acute withdrawal symptoms have subsided in animals with a history of dependence. 123,173,178,184,185.


Stress-induced reinstatement of drug-seeking and stress-induced reinstatement of anxiety-like states during protracted abstinence represent models of the persistent preoccupation/anticipation (craving) stage of the addiction cycle. Protracted abstinence, largely described in alcohol dependence models, appears to involve overactive glutamatergic and CRF systems. Rats that were made dependent with chronic continuous exposure to alcohol exhibited anxiety-like behavior on the elevated plus maze at 4 weeks postwithdrawal. CRF receptor antagonists that are injected intracerebroventricularly or systemically block the potentiated anxiety-like responses to stressors that are observed during protracted abstinence from chronic alcohol. d


d References 22, 23, 67, 130, 185, 204.

In one example, rats that were tested on the elevated plus maze 3–5 weeks postwithdrawal did not exhibit an anxiogenic-like response at baseline, but an anxiogenic-like response was provoked by mild restraint stress only in rats with a history of alcohol dependence ( Fig. 18.8 ). This stress-induced anxiogenic-like response was reversed by a competitive CRF receptor antagonist (see Fig. 18.8 ).


Fig. 18.8


Effect of restraint stress on exploratory behavior in the elevated plus maze 6 weeks after exposure to an alcohol liquid diet over a 3-week period. Control rats received a sucrose-containing liquid diet. Rats were injected intracerebroventricularly with 10 μg of [D-Phe , Nle , CαMeLeu ]rCRF 12–41 (D-Phe-CRF 12–41 ; n = 8-11 per group) or vehicle ( n = 7 or 8 per group) and subsequently placed in restraint tubes or returned to their home cages for 15 min. The mean (± SEM) percentage of time spent in the open arms of the elevated plus maze was measured. ∗ p < 0.05, Tukey test compared with all other groups.

Reprinted with permission from Valdez et al.


In human studies, situations of stress are the most likely triggers for relapse to drug-taking. In parallel, there is evidence of stress-induced reinstatement in animal studies. In animals that are made dependent, stressors have a greater impact. Animal models of stress-induced reinstatement show that stressors elicit strong recovery of extinguished drug-seeking behavior in the absence of further drug availability. The delivery of acute intermittent footshock induced the reinstatement of cocaine-seeking behavior after prolonged extinction, and this was as effective as a priming injection of cocaine. Such effects are also observed after a 4- to 6-week drug-free period and appear to be drug-specific, in which food-seeking behavior was not reinstated. Other stressors that have been shown to be effective in reinstating drug seeking include food deprivation, restraint stress, tail pinch stress, swim stress, conditioned fear, social defeat stress, and administration of the α 2 -adrenergic receptor antagonist yohimbine (an activator of the sympathetic nervous system). e


e References 94, 98, 100, 138, 139, 154, 168, 170.

Stress-induced reinstatement is mediated by norepinephrine and CRF, with a focus on the bed nucleus of the stria terminalis (for review, see reference 166 and 167).


Neurobiological Bases of Increased Drug Taking During Extended Access or Dependence


In a within-system adaptation, repeated drug administration elicits an opposing reaction within the same system in which the drug elicits its primary reinforcing actions. For example, if the synaptic availability of the neurotransmitter dopamine is responsible for the acute reinforcing actions of cocaine, then the within-system opponent process neuroadaptation would be a decrease in the synaptic availability of dopamine. In a between-system adaptation, repeated drug administration recruits a different neurochemical system, one that is not involved in the acute reinforcing effects of the drug but that when activated or engaged acts in opposition to the primary reinforcing effects of the drug. For example, chronic cocaine may activate the neuropeptide dynorphin, and dynorphin produces dysphoria-like effects that would be opposite to those of dopamine.


Within-System Changes: Dopamine


Within-system neuroadaptations to chronic drug exposure include decreases in function of the same neurotransmitter systems in the same neurocircuits that are implicated in the acute reinforcing effects of drugs of abuse during drug withdrawal in animal studies. Decreases in activity of the mesolimbic dopamine system and decreases in serotonergic neurotransmission in the nucleus accumbens are well documented. Imaging studies in drug-addicted humans have consistently shown long-lasting decreases in the numbers of dopamine D 2 receptors in drug abusers compared with controls. Additionally, cocaine abusers have lower dopamine release in response to a pharmacological challenge with a stimulant drug. Decreases in the number of dopamine D 2 receptors, coupled with the decrease in dopaminergic activity, in cocaine, nicotine, and alcohol abusers results in the lower sensitivity of reward circuits to stimulation by natural reinforcers. These findings suggest an overall reduction of the sensitivity of the dopamine component of reward circuitry to natural reinforcers and other drugs in drug-addicted individuals.


Psychostimulant withdrawal in humans is associated with fatigue, depressed mood, and psychomotor retardation and in animals is associated with lower motivation to work for natural rewards and a decrease in locomotor activity, behavioral effects that may involve decreases in dopaminergic function. Animals during amphetamine withdrawal exhibited decreased responding on a progressive-ratio schedule for a sweet solution, and this decreased responding was reversed by the dopamine receptor partial agonist terguride, suggesting that low dopamine tone contributes to the motivational deficits that are associated with psychostimulant withdrawal.


Under this conceptual framework, other within-system neuroadaptations would induce greater sensitivity of receptor transduction mechanisms in the nucleus accumbens. The activation of adenylate cyclase, protein kinase A, cyclic adenosine monophosphate response-element binding protein, and ΔFosB has been observed during drug withdrawal. The ΔFosB response is hypothesized to represent a neuroadaptive change that extends long into protracted abstinence.


Between-System Changes: Role of Corticotropin-Releasing Factor


A prominent role for the activation of brain stress systems and inhibition of anti-stress systems in acute withdrawal and protracted abstinence has been established. The neurobiological systems in the brain that constitute the brain stress systems that are engaged by the addiction process include CRF, dynorphin, norepinephrine, hypocretin, vasopressin, glucocorticoids, and neuroinflammatory factors. Perhaps the most compelling data derive from studies of the extrahypothalamic CRF system. CRF controls hormonal and behavioral responses to stressors, but the extrahypothalamic CRF system is hypothesized to mediate behavioral responses to stressors. In addiction, CRF plays a key role via both the hypothalamic-pituitary-adrenal axis and extrahypothalamic CRF stress system, with a common response of elevated adrenocorticotropic hormone, corticosterone, and amygdala CRF during acute withdrawal f


f References 35, 81, 85, 115, 127, 136, 144, 145.

( Fig. 18.9 ). Data that support the role of CRF in mediating the negative emotional responses that are associated with acute and protracted abstinence have largely been generated by preclinical studies with animal models. The negative emotional-like states that are associated with acute withdrawal and protracted abstinence from all major drugs of abuse in animal models can be reversed by CRF receptor antagonists. The effects of CRF antagonists have been localized to the central nucleus of the amygdala. Critically, activation of the hypothalamic-pituitary-adrenal axis may be an early dysregulation that is associated with excessive drug taking that ultimately produces a “kindling” or sensitization of the extrahypothalamic CRF systems.
Jan 19, 2020 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Animal Models of Substance Use Disorders: Motivational Perspective
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