Which Of The Following Statements Is Accurate About Self-administration Animal Models?

• Journal List
• Dialogues Clin Neurosci
• v.nineteen(3); 2017 Sep
• PMC5741108

Dialogues Clin Neurosci. 2017 Sep; nineteen(three): 247–258.

Language: English | Spanish | French

Animal models of addiction

Modelos animales de adicciones

Modèles animaux d'addiction

Rainer Spanagel

Constitute of Psychopharmacology, Central Found of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany

Abstract

In contempo years, creature models in psychiatric research have been criticized for their express translational value to the clinical situation. Failures in clinical trials have thus often been attributed to the lack of predictive power of preclinical animal models. Here, I argue that animal models of voluntary drug intake—under nonoperant and operant weather condition—and habit models based on the Diagnostic and Statistical Transmission of Mental Disorders are crucial and informative tools for the identification of pathological mechanisms, target identification, and drug evolution. These models provide excellent face validity, and it is assumed that the neurochemical and neuroanatomical substrates involved in drug-intake beliefs are similar in laboratory rodents and humans. Consequently, animal models of drug consumption and addiction provide predictive validity. This predictive power is best illustrated in alcohol inquiry, in which three canonical medications—acamprosate, naltrexone, and nalmefene—were developed by means of animal models so successfully translated into the clinical situation.

Keywords: biomarker, cocaine and alcohol habit, drug self-administration, DSM-based animate being model, face validity, predictive validity, translational neuroimaging

Abstract

Los modelos animales en investigación psiquiátrica han sido criticados en los últimos años por su limitado valor para ser trasladados a la situación clínica. Las fallas en los ensayos clínicos a menudo han sido atribuidas a la falta de poder predictivo de los modelos animales preclínicos. En este artículo se argumenta que los modelos animales de ingesta voluntaria de drogas—bajo condiciones operantes y no operantes—y los modelos de adicciones basados en el Manual Diagnóstico y Estadístico de los Trastornos Mentales constituyen herramientas cruciales due east informativas para la identificación de mecanismos patológicos, identificación de blancos y desarrollo de fármacos. Estos modelos aportan una excelente validez aparente y se asume que los sustratos neuroquímicos y neuroanatómicos involucrados en la conducta de ingesta de drogas son similares en los roedores de laboratorio y en los humanos. En consecuencia, los modelos animales de consumo de drogas y adicciones aportan validez predictiva. Este poder predictivo está mejor ilustrado en la investigación con alcohol, en la cual tres medicamentos aprobados (acamprosate, naltrexona y nalmefene) fueron desarrollados a partir de modelos animales y luego trasladados exitosamente a las situaciones clínicas.

Résumé

Ces dernières années, les modèles animaux en recherche psychiatrique ont été critiqués cascade leur valeur translationnelle limitée en state of affairs clinique. Les échecs des études cliniques ont donc souvent été attribués au manque de puissance prédictive des modèles précliniques animaux. Pour ma part j'estime que les modèles animaux de prise volontaire de substances —sous conditions opératoires et non opératoires— et les modèles d'addiction basés sur le DSM (Diagnostic and Statistical Manual of Mental Disorders) sont des outils essentiels et informatifs pour identifier les mécanismes pathologiques et les cibles thérapeutiques et pour développer les médicaments. La validité apparente de ces modèles est excellente et on considère que les substrats neuro-chimiques et neuro-anatomiques impliqués dans le comportement de prise de substance sont similaires chez les rongeurs de laboratoire et les humains. Les modèles animaux de consommation de substances et d'addiction ont donc une validité prédictive. C'est dans la recherche sur 50'alcool que cette puissance prédictive s'illustre le mieux, trois médicaments autorisés (acamprosate, nal-trexone et nalméfène) ayant été développés grâce aux modèles animaux et transférés ensuite avec succès en situation clinique.

Introduction

Over the past two decades, major advances have been fabricated in the neurobiological agreement of brain functions and psychiatric disorders. Despite this huge knowledge gain, new and clinically useful treatment developments remain limited. The fact that many preclinically validated mechanisms fail during clinical development, which has led to the full general opinion that beast models in psychiatric inquiry do not provide good predictive validity. Consequently, the strategic decision fabricated by most pharmaceutical companies has been to stop drug development programs in the field of psychiatry.¹ Still, failed trials for psychiatric disorders exercise not necessarily invalidate preclinical animal models and identified drug targets.ⁱⁱ

In the position paper past Bespalov et al,^two the authors argue that the rigor with which preclinical data is obtained—and the resulting robustness of the data—is quite low. Thus, few preclinical studies written report randomization, blinding, or sample-size calculations—factors that are critical for designing clinical trials. Furthermore, the generalizability of preclinical data is frequently not considered. This is not but an issue pertaining to laboratory conditions and animal strains, age, and sexual practice, just as well to long-term drug assistants and tolerance development—factors that are besides disquisitional to the design of clinical trials just often not considered at the preclinical level. It is therefore argued that researchers should attach greater importance to issues of data robustness and information generalizability when designing preclinical studies.

Furthermore, at that place are also concerns well-nigh the pattern of clinical trials and divergences in master and secondary outcomes of preclinical and clinical studies, insufficient target engagement in the human being condition, likewise-depression dosing in order to avert unwanted side effects, and augmented placebo effects; these may in many cases be the reasons for failure in clinical trials.ⁱⁱⁱ

Despite these obvious concerns, the generally held opinion is that animate being models in psychiatric research practice not provide translatable information for the clinical situation and are therefore misleading. Is this conclusion correct for psychiatric disorders, and in detail for booze-use and substance-utilise disorders? Although for some complex human mental disorders, such as schizophrenia, this conclusion might be right, it is argued here that animal models of voluntary drug intake and addiction models based on the Diagnostic and Statistical Transmission of Mental Disorders (DSM) are crucial and highly informative tools for the identification of pathological mechanisms, target identification, and drug development. The precondition for each animal model is a high degree of face validity, defined here as feature behavioral features that are seen both in laboratory animals and in humans.

Confront validity of creature models in addiction inquiry

Humans and laboratory animals, such as monkeys, rats, and mice, voluntarily take drugs by different routes of administration, be it orally or intravenously. If unlimited voluntary intravenous access to heroin or cocaine is provided, laboratory animals tin easily overdose to death. Lethal overdosing as well frequently happens in drug users. Mice and rats can too voluntarily drink large quantities of alcohol, which leads to potent intoxication. These characteristic features seen in drug-taking behavior in laboratory animals resemble drug-taking behavior in humans and suggests a loftier degree of face up validity. Still, face validity is frequently a consequence of anthropomorphic interpretations of an animal's behavior. If, however, behavioral features are evolutionarily developed, real face validity is inferred. For case, behavioral fear responses are critical to most species for survival and developed over millions of years. Every bit such, freezing behavior in response to a threatening stimulus, equally seen in mice and humans alike, has real face validity. Since it is generally believed that psychoactive drug use in humans is a novel characteristic of our environment and cultural development,⁴ one wonders whether drug-taking behavior in laboratory animals really resembles drug taking in humans?

Given the fact that the evolution of our human ancestors and of animals proceeded in a world rich in drugs, an alternative theory favors the idea that drug and alcohol intake by mammals and other species has always been an everyday occurrence.⁵ Thus, occasional and even long-term intake of psychoactive drugs produced past a variety of plants or booze ingestion through sugar-rich plant products susceptible to fermentation might be a behavior that has been shaped over millions of years.⁶ Interestingly, information technology was establish that hominids adapted to metabolize alcohol long before human-directed fermentation. Using a paleogenetics arroyo, Carrigan and colleagues⁷ resurrected digestive booze dehydrogenases (ADH4) from our primate ancestors to explore the history of primate-alcohol interactions and identified a unmarried mutation occurring roughly 10 million years ago that endowed our ancestors with a markedly enhanced ability to metabolize ethanol. This alter occurred around the fourth dimension that our ancestors adopted a terrestrial lifestyle. Because fruit collected from the forest floor contains college concentrations of fermenting yeast and alcohol than similar fruits hanging from copse, this transition may too be the starting time fourth dimension our ancestors were exposed to and adjusted to substantial amounts of booze. These discoveries favor the idea that from an evolutionary perspective, alcohol and drug-intake behavior has been shaped over millions of years and should be considered a part of our normal behavioral repertoire. These evolutionary roots of alcohol- and drug-taking behavior in mammals back up the real face validity of creature models of drug cocky-administration.

Animal models of drug cocky-administration

Cocky-assistants-based beast models are widely used in preclinical addiction research and are extensively reviewed by in ref 8. Equally explained, these models accept excellent confront validity, and it is assumed that the neurochemical and neuroanatomical substrates involved in drug-intake behavior are similar in laboratory rodents and humans^8,9 (which is often defined every bit construct validity). Consequently, self-administration-based animal models are helpful in unraveling the molecular and neurobiological mechanisms of drug-related behaviors and therefore critical in identifying strategies useful in the intervention of homo drug consumption; ie, they provide predictive validity. For example, pharmacological opioid-receptor blockade reduces alcohol consumption in many cocky-administration studies in different strains of rats and mice under unlike weather condition,¹⁰ which provides generalizability of preclinical data that translates to the human situation, in which the opioid-receptor blocker nalmefene besides reduces alcohol consumption.¹¹

Self-administration procedures tin exist classified co-ordinate to different criteria. From a pharmacokinetic perspective, they tin can be classified according to the route of administration by which the drug is delivered to the organism. Pharmacokinetic aspects that are determined by the road of administration are of critical importance in modeling of man drug-taking behavior. For example, researchers have used oral self-assistants procedures to model human opioid-taking behavior.¹² Still, virtually opioid users inject the drug intravenously. The oral and intravenous route of opioid administration yield completely unlike pharmacokinetics and, consequently, unlike pharmacodynamics cascades are to be expected. Therefore, the route of administration is of critical importance for modeling human beliefs.

From a behavioral perspective, drug cocky-assistants can exist classified into operant and nonoperant procedures. Drug self-administration based on operant and nonoperant responses differ in procedural characteristics, merely may also differ in their sensitivity to the manipulation of specific brain substrates.¹³

Nonoperant drug self-administration

Nonoperant procedures are restricted to oral self-administration. This kind of procedure is very common in the context of alcohol inquiry, simply has also been used with other drugs of abuse, such as cannabinoids, nicotine, cocaine, amphetamine, and opioids.¹² Nonetheless, when those drugs are orally cocky-administered, they show reduced motivational efficacy.¹² As the oral road of administration in humans applies mainly to alcohol, 3,4-methylenedioxymethamphetamine (MDMA), and related designer drugs that are usually taken every bit pills, it is incongruous to use a nonoperant-based procedure of self-assistants to model man cannabis, nicotine, cocaine, or opioid use—drugs that are either inhaled or intranasally or intravenously applied. Therefore, the following paragraphs will focus solely on oral alcohol self-administration procedures.

In nonoperant booze self-administration, two bottles are usually offered to a laboratory animal in its dwelling house cage, with one containing an aqueous solution of alcohol and some other bottle containing water. Different factors tin can affect alcohol consumption, such as the number of bachelor bottles, the temporal accessibility to alcohol, the alcohol concentration, etc. In full general, information technology has been shown that alcohol consumption increases when more than ii bottles with different concentrations of alcohol solutions are presented or when subjects are given restricted admission to them.¹⁴ Alcohol concentration is a critical issue in these procedures, because low or overly high concentrations can be orally consumed or rejected because of their mild-sweet or aversive tasting properties, respectively. Moreover, equally the corporeality of ingested fluid is limited by physiological constraints, as well low of an alcohol concentration may result in negligible brain booze levels. Thus, it is usually considered that ethanol concentrations beneath 4% (v/v) are not pharmacologically relevant and that a concentration in the range of 10% to 12% is a suitable standard for consumption by rats and mice. In contrast, when initially offered, well-nigh rodent strains volition most likely not drink much of a highly concentrated booze solution. Consequently, several procedures take been developed for "training" rodents to orally self-administer pharmacologically relevant amounts of booze, including the presentation of ascending concentrations of ethanol, the addition of a sweetness flavour amanuensis (ie, sucrose) that tin can be progressively faded out or not, or the inclusion of a fourth dimension menstruation of forced exposure to ethanol.^12,14 Using these procedures, laboratory rodents drink up to 40% alcohol solutions and can become highly intoxicated. An alternative strategy has been the development of rodent strains with a high inborn booze consumption/preference,^15,16 but this strategy reduces data generalizability, and results from these genetically selected animal strains may therefore non translate well to the human situation. However, rodent strains for high versus low alcohol consumption and recombinant inbred rodent strains are powerful tools to identify genetic adventure alleles that predispose to excessive alcohol consumption.¹⁷

Another very efficient procedure to induce excessive oral alcohol consumption is the exposure to intermittent booze vapor. Long-term intermittent intoxication with alcohol vapor leads to long-lasting neuronal and behavioral adaptations that persist fifty-fifty in the absence of the drug.¹⁸ Although this model is based on experimenter-controlled intoxication—as opposed to largely voluntary drinking in humans—it has been valuable in identifying potential molecular mechanisms underlying excessive alcohol consumption.^19,20 This rat model of excessive alcohol consumption after intermittent vapor exposure was besides instrumental in the discovery that enhanced corticotropin-releasing-hormone (CRH) signaling within the amygdala is a key molecular mechanism mediating excessive booze consumption and alcohol seeking.^21,22 However, the human being application of two different selective pharmacological CRH-receptor one (CRH-R1) antagonists failed in clinical trials,^23,24 establishing doubt in the translational and predictive value of this rat model of excessive alcohol drinking. In this context, one must admit that intermittent alcohol vapor exposure over several weeks lacks face up validity for the human drinking situation and may equally such produce false-positive signals that do not translate to excessive human drinking behavior.

The measures in nonoperant models of alcohol self-administration are the amount of pure ethanol consumed, alcohol preference, and total fluid intake. The contempo introduction of drinkometer systems forth with advanced mathematical time-series analysis of drinking information^25,26 are providing additional data on booze consumption. In detail, microdrinking patterns, cyclic and ultradian drinking patterns, can be identified.^27,28 Knowledge on individual microdrinking patterns may assist to forecast excessive drinking episodes and, as such, hold great potential for the development of new preventive strategies to reduce drinking. The utilize of a drinkometer arrangement also allows the measurement of additional behavioral features, such as licking and wanting, that are relevant to the development of alcohol-use disorders.^25,28,29

Operant drug cocky-administration

Dissimilar operant schedules are routinely used in drug and addiction research. The about common schedule of reinforcement is the stock-still ratio (FR) schedule. Under a FR schedule, the drug is delivered each fourth dimension a preselected number of responses have been completed; eg, under an FR1 schedule, a unmarried active-lever response results in the delivery of a pocket-size, previously defined quantity of a drug. Under a progressive ratio (PR) schedule, the required ratio increases afterward a predefined, unremarkably arithmetic, progression. The most common index of performance under a PR schedule is the breaking betoken, defined every bit the highest response rate achieved to obtain a single reinforcer. PR measurements are indicators for the motivation of a field of study to obtain a drug. For example, the harder a subject field is willing to piece of work nether a PR, the higher the breaking point will be, which is then indicative of an incentive motivation for the drug. Not all drugs are equally cocky-administered under FR or PR schedules, and several factors change reinforcing efficacy, such every bit nutrient restriction, previous drug exposure, stress, etc. FR1 performance is less afflicted by those factors than by other schedules of reinforcement. Therefore, when the objective is to assess the potential liability of a drug or its initial intake every bit a result of its unconditioned psychopharmacological effects, the FR1 procedure may be a offset choice. However, when considering changes in later stages of drug intake, such as the evolution of addicted beliefs interval schedules in which the drug follows a response afterward a given period of time has elapsed may be more appropriate.^eight,xxx Especially in stock-still-interval (FI) schedules, high response rates can be achieved even by drug doses that unremarkably disrupt performances nether FR schedules. This is seen in a multifariousness of species and over a wide range of FI values^thirty; therefore, FI schedules should be used to study the evolution of addictive behavior. FR and FI schedules of drug injection can also exist combined in secondorder schedules. On a 2nd-lodge schedule, a subject field responds according to 1 schedule for a brief presentation of a stimulus, such every bit a light. Responding past the subject on this initial schedule is and then reinforced according to another schedule of reinforcement. 2nd-order schedules of drug injection permit the study of more circuitous behavioral sequences than do simple schedules and may more accurately reflect the human drug-intake state of affairs.³¹ Derived from studies of conditioned reinforcement, an important feature of second-order schedules is that responding is maintained by conditioned stimuli. They are thus well-suited to examine cue-induced drug-seeking behavior, including its behavioral, neural, and neurochemical basis.³² Experiments with 2d-lodge schedules have, for instance, been instrumental for the discovery of the so-called spiraling striatonigrostriatal circuitry,³³ which is critically involved in the development and performance of drug habits that are a key characteristic of drug addiction.

Another important modification in operant drug self-administration procedures is the reinstatement model of drug-seeking,³⁴ which became a standard model to assess some properties of addictive behavior and to test potential anticraving and antirelapse compounds.³⁵

Reinstatement and incubation of drug-seeking: animal models that are indicative of craving

In a typical drug reinstatement experiment, an animal is trained to cocky-administer a drug, and the beliefs is then subjected to extinction—that is, the animal is tested under weather condition of nonreinforcement until operant responding appears to be extinguished. When the animal reaches some criterion of unresponsiveness, various stimuli are presented. A stimulus is said to reinstate the drug-seeking behavior if information technology causes renewed responding, ie, lever pressing, without any further response-contingent drug reinforcement. At least 3 events can reinstate responding: (i) drug priming, that is, the injection of a small-scale dose of the drug; (two) stress; and (iii) conditioned stimuli. Importantly, after the presentation of a conditioned cue or stress, drug-seeking responses are measured nether a drug-free condition. This allows the written report of drug-seeking beliefs without the interference produced by the psychoactive furnishings of the drug (ie, a drug that increases locomotor beliefs could produce spurious increases in lever pressing), and the increase in the number of operant responses compared with that observed during extinction is inferred to be an enhancement of the subject area's drug-seeking beliefs.

An alternative method to written report drug-seeking behavior relates to the conditioned place preference (CPP) paradigm.^8,36 In a typical CPP experiment, subjects are injected daily with the drug and paired with a distinguishable compartment in a conditioning box. A second compartment is paired with vehicle injections. Afterwards several days of conditioning, a drug-conditioned identify preference is achieved. Then, this acquired preference is extinguished with repeated saline injections in both the previously drug-paired compartment and the saline-paired compartment. Following the extinction phase, the reinstatement of CPP is initiated by drug priming. In comparison with reinstatement testing in an operant self-assistants paradigm, this modified CPP procedure allows rapid screening of drug-seeking behavior, eg, in transgenic mice,³⁷ with the disadvantage that stress- or cue-induced drug-seeking responses cannot exist assessed.

The reinstatement of drug-seeking behavior can be used to study the neurobiological and molecular basis of drug peckish and cue reactivity, as there appears to be a good correspondence betwixt the events that induce drug-seeking in laboratory animals and those that provoke peckish and cue reactivity in humans.³⁵ Data derived from over 1200 studies using the reinstatement model suggest that the neuronal substrates that mediate drug-, stress-, and cue-induced reinstatement are non identical.³⁵ The reinstatement model as well allows drug testing for potential anticraving backdrop,³⁵ but the predictive validity is all the same questionable. All reinstatement procedures include an extinction phase; all the same, homo addicts usually do not undergo extinction, and no systematic study has been conducted to assess its possible consequences on the predictive validity of these procedures. Most important, in this model, the operant response is reinstated, but the subjects, strictly speaking, practise not relapse because they do non actually resume drug consumption. Thus, reinstatement testing of drug-seeking behavior is to some caste indicative of drug craving and cue reactivity, but not relapse behavior, in human being drug users. Since drug craving in humans involves a very strong urge to seek out the drug, a more than advisable animal model to assess craving-like responses in laboratory animals involves the incubation procedure developed by Shaham and coworkers.^38,39

In humans, drug craving can occur in response to environmental stimuli previously associated with drug use, even later on extended periods of forbearance. In rats, cue-elicited cocaine seeking has been shown to increase progressively during the first two months of abstinence from drug self-administration³⁸ (Figure 1) This phenomenon, referred to as the incubation of cocaine seeking, is consequent with the hypothesis that in humans, craving increases over time and remains high after a prolonged period of abstinence.^xl Time-dependent changes in neuroplasticity in several structures of the mesolimbic brain reward system take been demonstrated during cocaine withdrawal and probably mediate the incubation of cocaine seeking.^41,42 It is remarkable that the incubation phenomenon of drug seeking was outset discovered in laboratory rats and later as well demonstrated to occur in smokers,⁴³ alcoholics,⁴⁴ and cocaine addicts⁴⁵—such a straight translation to the human situation indicates loftier face, construct, and predictive validity of the incubation model of drug craving.

Experimental timeline for measuring incubation of drug-seeking behavior (peckish) in rats. Behavioral training and testing is co-ordinate to Grimm et al.³⁸ Cocaine-self-administration grooming consists of sixteen daily (24-hour interval 2 to twenty-four hours 1 viii) 6-60 minutes sessions during which nose poking at the active pigsty nether a fixed ratio 1 (FR1) of response is reinforced by 0.5 mg/kg/infusion of cocaine. Cocaine availability is signaled by illumination of the blue light. Each earned infusion is coupled to the presentation of ii discrete cues (light and tone). During forced forbearance (30 days), rats remain in the home cage. Cue-induced reinstatement of cocaine seeking is tested at withdrawal days 1 and thirty during a ii-hour session in the operant chamber. The kickoff hour consists of extinction of olfactory organ-poking beliefs, in which active nose poking is neither rewarded nor paired with the detached light/tone cues. The second hour comprises cue-induced reinstatement and starts with turning on the blue light and one noncontingent presentation of the lite/tone cues followed by contingent presentations of the light/tone cues in the absence of cocaine delivery. CSA, cocaine self-administration; D, solar day; WD, withdrawal day.

The incubation model has been used for studying neurobiological aspects of craving. Nigh notable are adaptations in the glutamate system. In detail, calcium permeable GluR2-lacking -αamino-3-hydroxy-five-methyl-4-isoxazolepropionic acid (AMPA) receptors—which showroom higher conductance than calcium-impermeable GluA2-containing AMPA receptors—are produced in the nucleus accumbens during prolonged abstinence from cocaine self-administration. These compensatory changes in AMPA-receptor subunit limerick change the properties of neuronal networks and exacerbate affliction processes by increasing the reactivity of accumbens neurons to cocaine-associated cues that promote craving.⁴¹ At the neural-circuit level, glutamatergic projection neurons from the basolateral amygdala to the nucleus accumbens that impinge on silent synapses—which are excitatory synapses that contain Northward-methyl-D-aspartate (NMDA) receptors with absent-minded or labile AMPA receptors—play a critical function in the incubation phenomenon.⁴⁶ Thus, increased silent synapses are seen shortly after cocaine cocky-administration but not after prolonged abstinence. The unsilencing process that occurs with prolonged cocaine abstinence is associated with the insertion of calcium-permeable AMPA receptors. Re-silencing those synapses, by in vivo optogenetic stimulation, causes downregulation of calcium permeable AMPA receptors and abolishes the incubation of cocaine craving.⁴⁶ These results are consistent with a causal office of calcium-permeable AMPA receptors in the nucleus accumbens in cocaine craving.⁴¹

Although drug peckish may not be directly responsible for all compulsive drug use,⁴⁷ it is a core feature of substance-use disorders and often precedes relapse. Fauna models that are based on diagnostic criteria defined in DSM-IV/five and that likewise involve the measurement of relapse behavior are discussed below.

DSM-based creature models of relapse and addictive behavior

The electric current psychiatric diagnostic classification systems—DSM-v and International Nomenclature of Diseases, tenth revision (ICD10)—are based upon clinical observations and symptom reports by patients and are by nature congenital on anthropomorphic terms. Thus, it is argued that gimmicky psychiatry uses a syndrome-based disease classification that is not based on mechanisms and does not guide handling.⁴⁸ As a result, a number of dissimilar psychiatric diagnoses largely overlap in terms of their symptoms, underlying neurobiological mechanisms, and genetic take a chance factors. For example, cue-mediated craving involves largely overlapping neuronal substrates of reactivity to drug, nutrient, and sexual cues⁴⁹ and is therefore not exclusive for addictive disorders, but rather resembles the intersection of information pathways for processing reward, emotional responses, nondeclarative memory, and obsessive-compulsive beliefs. This highlights the ambiguities associated with the nomenclature of mental disorders by DSM-5 or ICD10.

Despite all of this criticism of our current psychiatric diagnostic classification system and contempo efforts toward a new diagnosis system, such equally the Research Domain Criteria project (RDoC),^l we should realize that DSM-5 and ICD10 are used worldwide and will certainly be used in the coming decades. Therefore it is argued that if nosotros are making our diagnoses according to DSM-5, it is logical that we must gear our research toward DSM-five. Therefore, our brute models should be based on DSM-5 criteria—is this possible? Modeling the unabridged spectrum of a complex human mental disorder, such as addiction, in animals is not possible because of its complication. However, nosotros tin can translate anthropomorphic terminology into considerately and behaviorally measurable parameters and can thereby model at least some primal criteria of the disorder. Peculiarly when it comes to relapse behavior, this is a straightforward endeavour, equally a relapse is divers as the recurrence of a past condition, namely excessive and uncontrolled drug intake later a stage of abstinence. In particular, the alcohol-deprivation model provides excellent face up validity to relapse behavior seen in alcoholics.

The alcohol-deprivation-effect model for relapse

In animals with voluntary access to booze for a sure flow of fourth dimension and that are so deprived of alcohol for several days/weeks/months, the representation of alcohol leads to a robust but temporally limited increase in alcohol intake over baseline drinking, a relapse-like drinking referred to as the alcohol deprivation effect (ADE).⁵¹ The ADE can be accomplished under both operant⁵² and nonoperant home-cage free-selection drinking conditions.^14,53 There are several experimental and biological factors that influence the magnitude and duration of the ADE. As said, concurrent access to more than than one alcohol concentration (eg, 5%, ten%, and xx% v/v ethanol solutions vs water) enhances the magnitude and elapsing of the ADE.¹⁴ The magnitude of the ADE as well depends on the duration of access to alcohol and on the length of abstinence. It has been demonstrated that just long-lasting alcohol consumption, for at to the lowest degree 6 to 8 weeks, will lead to a reliable ADE, and that at least 2 days of withdrawal are needed to increment booze consumption by more than than fifty%.^fourteen Data from dissimilar rat strains and alcohol-preferring rat lines testify that levels of baseline booze intake do not correlate with the robustness of the ADE, suggesting that baseline alcohol drinking behavior and relapse-like drinking behavior are controlled, at least in office, via different brain systems.^9,53

Long-term booze consumption with repeated impecuniousness phases in rats—a model of compulsive drinking in a relapse state of affairs

This animal model is designed to demonstrate compulsive drinking during a relapse state of affairs. Booze, unlike cocaine or opioids, is a weak reinforcer and as such requires long-term exposure to induce compulsiveness during a relapse situation. Such conditions might exist hard to reach with relatively short operant training procedures. Therefore, voluntary long-term oral alcohol consumption is a prerequisite for the evolution of compulsive drinking; ie, rats must have free admission to alcohol for at to the lowest degree viii months. In addition, this access should be interrupted repeatedly with forced abstinence phases. At the end of this procedure, compulsive drinking during an ADE tin exist measured. For this purpose, two procedures are used—taste adulteration testing with quinine and monitoring of the cyclic drinking rhythmicity. In the taste adulteration test, the taste of alcohol solutions is altered with bitter quinine; alternatively, animals could exist offered a highly palatable sucrose solution instead of water.^14,54 An animal is expected to naturally choose a more palatable (or less aversive) fluid as a drinking source. Those animals that exhibit an ADE despite alcohol taste adulteration with quinine or a competitive pick of a highly palatable fluid are classified as compulsive animals in this experimental setting. It has been demonstrated that taste adulteration reduced post-abstinence drinking in Wistar rats after a short-term alcohol feel, suggesting at least fractional control of the beliefs at this stage.⁵⁵ However, long-term chronic alcohol consumption repeatedly interrupted with deprivation phases was shown to lead to an fauna'due south complete loss of control over behavior, every bit gustatory modality adulteration procedures no longer modified the ADE.⁵⁵ This behavior resembles the continuation of drug use despite clear prove of overtly harmful consequences and fail of alternative interests. Another sign of compulsive alcohol drinking is an alteration of the normal circadian drinking pattern.^25,28 Orcadian disturbances have been reported in human addicts.⁵⁶ In long-term drinking rats repeatedly deprived of alcohol for several weeks, re-exposure leads to increased drinking frequency and a loss of diurnal drinking rhythmicity during the first postal service-forbearance days. Specifically, rats bear witness increased wanting of more highly concentrated booze solutions to more rapidly attain loftier blood alcohol concentrations.^25,28,29

Many drug targets and more than 50 different putative anti-relapse compounds have already been tested in this model.⁵⁷ In alcoholics, medications that reduce relapse rates, such as naltrexone and acamprosate, also reduce compulsive drinking during an ADE,^58,59 demonstrating the predictive power of this animal model. Drugs such as agomelatine or melatonin, which normalize circadian drinking action during the ADE,²⁸ could easily be transferred to the clinical situation. Agomelatine is clinically used as an antidepressive medication and is already approved in many countries.^lx Given that there is a loftier comorbidity between alcoholism and depressive behavior, general practitioners tin easily prescribe agomelatine for this comorbid condition.

To summarize, the model of long-term alcohol consumption with repeated deprivation phases allows distinguishing between addicted and non-fond animals and examining the transition from controlled drug use to compulsive drug wanting. A similar model has been developed for cocaine habit in rats.

A DSM-based beast model of cocaine habit

A diagnosis of cocaine addiction is given when an private shows multiple signs of loss of control over drug utilise. Signs of loss of control can be indicated by the following: (i) the inability to refrain from drug seeking; (ii) loftier motivation for the drug; and (iii) maintained drug apply despite negative consequences. These three signs establish the clinical-based theoretical background of the multisymptomatic 0/3 criteria (0/3crit) model of cocaine addiction.^61-65 Matching prevalence rates of cocaine-addicted individuals,⁶² xv% to 20% of a rat accomplice loses control over cocaine intake subsequently prolonged training, showing aficionado-like beliefs (3crit), whereas the majority of animals maintain control over cocaine intake, showing nonaddict-like beliefs (0crit). Hence, the 0/3crit model of habit is a multidimensional experimental approach aimed at identifying subpopulations of rats possessing vulnerability (3crit) and resilience (0crit) toward cocaine-habit-similar beliefs. In the 0/3crit model, the three clinical signs of loss of control listed above are modeled by 3 corresponding addiction-like criteria: (i) persistence in drug seeking when the drug is signaled but not bachelor; (two) motivation to self-administrate cocaine nether a PR schedule of reinforcement; and (iii) maintenance of cocaine drug seeking and taking despite punishment by an electric footshock (Figure 2) 0crit and 3crit rats represent the two opposite extremes in each of these behaviors. The 0crit rats show nonaddict-like behavior, characterized past refraining from drug seeking when cocaine is not bachelor, a lack of motivation to produce increasing effort to get their dose, and abstention of cocaine self-administration during penalisation. On the contrary, 3crit rats show addict-like behavior, being unable to refrain from drug seeking when cocaine is unavailable, requires increasing effort, or is punished.^62,64 Therefore, the 0/3crit model of habit allows us to correlate behavioral subdimensions of cocaine habit with specific brain alterations, either on the molecular^65,66 or neuroanatomical level.⁶⁷ Although very time- and labor-intensive, drug testing in the 0/3crit model provides valuable preclinical information for drug development,⁶⁸ and similar to the findings in the ADE model, melatonin reduces motivation for cocaine cocky-administration and prevents relapse behavior in cocaineaddicted rats.⁶⁹

Behavioral characterization of 0crit and 3crit rats in the multisymptomatic model of cocaine addiction. 3crit rats bear witness higher responding than 0crit rats in each criteria. (A) Persistence of cocaine seeking expressed by the sum of agile nose pokes during no-drug periods in a session. (B) Motivation for cocaine intake expressed every bit the break signal during a progressive ratio session. (C) Resistance to punishment when cocaine seeking and cocaine taking are paired with a footshock. (D) 0crit and 3crit rats practice not differ in number of selfadministered cocaine injections. Information are shown as mean ± SEM; ****P<0.0001 with respect to 0crit. CSA, cocaine self-administration; SEM standard mistake of the mean.

Virtually strikingly, the 0/three crit model of addiction provided new insight into the neurobiological understanding of a transition into a pathological country. During the acquisition of cocaine self-assistants, NMDA-receptor-mediated long-term depression (LTD) in the nucleus accumbens is essential for learning new rewardresponse associations. Once the learning has been consolidated and with further cocaine cocky-assistants, LTD is suppressed in all rats. However, after prolonged cocaine self-administration, LTD is progressively recovered in animals that maintain a controlled drug intake (0crit), whereas it is persistently lost in animals undergoing the transition to addiction (3crit).⁶⁵ This persistent impairment in LTD could explain the loss of command on drug intake observed in 3crit rats. LTD in the nucleus accumbens is considered of import in rescaling synapses that are enhanced during acquisition of cue-reward associations, assuasive those synapses to encode time to come associations and restore flexibility to neuronal circuits. The persistent disability to rescale synapses in 3crit rats may render drug-seeking behavior consistently resistant to modulation by environmental contingencies, finally resulting in loss of control over drug intake. Thus, the major behavioral difference between 3crit and 0crit, ie, between fond vs nonaddicted subjects, is their capacity to adjust their drug intake equally a function of environmental contingencies. Nonaddicts can terminate seeking drugs if they know that the drug is not available, if it requires an excessively loftier workload, or if taking the drug results in negative consequences. Addicts have lost this power and continue to seek drugs independently of ecology conditions. In conclusion, the transition to addiction is associated, at least in the nucleus accumbens, with a course of anaplasticity, ie, the incapacity of addicted subjects to counteract initial drug-induced impairments.⁶⁵ The anaplasticity of addicted rats is relevant to revising conceptualizations of the transition to addiction, currently seen as the progressive development of specific encephalon adaptations that lead to loss of control over drug intake. In fact, anaplasticity means the loss of neuronal and molecular adaptations that characterize an addicted brain—a new concept that can exist applied to most encephalon pathologies.

Rats are a better model organisation than mice to study addictive beliefs

Despite major efforts, the multisymptomatic model of cocaine addiction has not been successfully established in mice. The try to plant a model of compulsive drinking behavior during a relapse situation (equally described above) also failed in mice.⁵² Establishing such mouse models has potential value in behavioral neuroscience and genetics due to the availability of a large number of genetically modified mouse lines that could be tested in this model in guild to contribute to our understanding of the mechanisms involved in the transition from controlled to compulsive drug employ and to functionally validate genetic risk variants derived from genome-wide clan studies.⁷⁰ However, with the introduction of new gene editing tools, such every bit CRISPR/Cas9 (clustered regularly interspaced brusque palindromic repeats [CRISPR]/CRISPR-associated protein-ix nuclease),⁷¹ whatever specific rat mutant of interest tin exist generated. Thus, genetic manipulations are no longer an argument to use mice. There are also other technical considerations in favor of using rats in addiction inquiry.⁷² Brain size matters for performing in vivo electrophysiological recording in conjunction with beliefs and translational neuroimaging.The use of different modalities in magnetic resonance imaging has great potential for translation. For example, glutamate spectroscopy in alcohol-dependent rats and alcohol-dependent humans has yielded identical results: during withdrawal, both rats and humans demonstrate hyperglutamatergic activeness in different brain sites that diminishes when withdrawal symptomatology subsides.⁷³ Furthermore, intracranial surgery produces less damage to brain tissue in rats than in mice. Intravenous surgery and catheter treatment are besides more straightforward in rats; for example, it would exist impossible to maintain catheter function for months in mice as required for the multisymptomatic model of cocaine addiction. Certainly, these technical advantages come with costs. Rat breeding colonies, peculiarly with the apply of double transgenic animals, are much more cost intensive and take more space in the animal facility. The smaller size of mice likewise means that a lower amount of drug or virus can be administered, which is more cost constructive.

There are also biological factors to be considered. Rats tin more readily larn complex operant training schedules relative to mice, which often crave more preparation and higher numbers of animals per group due to larger individual variability.⁷² Considering the number of responses on the inactive lever, mice and rats should be viewed differently, since in the quondam, lever pressing per se seems to be a reinforcing action.⁸ Thus, in a reinstatement test, mice may exhibit high inactive lever responding. Rats are social animals and are the get-go choice when considering social factors in drug and addiction studies. Mice in the wild are nonsocial and spend significantly less time interacting with conspecifics and many fifty-fifty find such interactions aversive, whereas rats are social animals; in fact, rats observe social interaction even more rewarding than cocaine.⁷⁴

About importantly, the pharmaceutical industry has built its pharmacological databases upon rats, and mice can sometimes produce paradoxical drug effects when compared with humans. Ellenbroeck and Youn take recently summarized fundamental differences between rats and mice in drug evolution and habit research and conclude that rats are the optimal rodent model for studies of man addictive beliefs.⁷²

Conclusions and time to come perspectives

In my brief overview of nonoperant and operant models of drug-taking beliefs, incubation of drug-seeking, relapse, and DSM-based beast models, some readers may miss their favorite process or model. For instance, intracranial self-stimulation⁷⁵—an excellent exam procedure to measure the rewarding value of a drug or dysphoria during withdrawal⁷⁶ and to evaluate the abuse potential of a drug—has not been discussed hither. This experimental method is a "examination" that does not have a directly resemblance to the human being situation and tin can therefore not be considered as an creature model of drug use or habit. This statement also relates to the phenomenon of behavioral sensitization, which refers to the power of addictive drugs to progressively increase locomotion after repeated administration in a variety of laboratory animals.²⁹ Although this phenomenon plays an of import function in the incentive-sensitization theory of addiction,²⁹ the possible relevance of drug-induced sensitization in humans is still unclear. This does not devaluate the importance of testing the phenomenon of drug-induced sensitization, but I practise suggest that the models described here have a more direct translational value to the human situation.

Twenty years ago Alan Leshner, the erstwhile manager of the National Institute on Drug Abuse, proclaimed that "addiction is a encephalon disease and it matters."⁷⁷ Although this statement gave an enormous heave to addiction enquiry from a neuroscience perspective, it is my potent conventionalities that the whole organism has to exist taken into consideration to provide the best therapy for our patients. In the time to come, heart, liver, and other organ physiology should as well be taken into consideration when developing new animal models. Virtually of import, addiction researchers should focus more on data robustness and data generalizability when designing preclinical studies.

Acknowledgments

The author would like to thank Rick Eastward. Bernardi for text editing. This work was supported by the Deutsche Forschungsgemeinschaft (DFG): Reinhart-Koselleck Honour SP 383/five-1 and the ERANET COCADDICT grant. The author reports no conflicts of interest.

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741108/

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