The Result of Oxytocin on Methamphetamine Habit

Chun-Fu Wu , ... Fang Wang , in Neuropathology of Drug Addictions and Substance Misuse, 2016

Self-Administration

Self-administration (SA) is based on the principle of operant conditioning, in which an animal conveying out aspecific behavior (e.g., pressing a lever) is rewarded with a drug. The beliefs of animals in SA experiments is very similar to that of drug abusers, and SA is thought to exist a reliable model of psychological dependence. Report by Carson, Cornish, Guastella, Hunt, & McGregor (2010) has shown that systemically administered OT decreases MAP activation of the subthalamic nucleus and accumbens core and stimulates oxytocinergic neurons in the hypothalamus starting time assessed the result of OT on MAP SA in rats. Strikingly, it was found that OT reduced the response to intravenous MAP in a dose-dependent manner, and almost completely abolished the response at the highest dose tested. OT also reduced the ability of MAP to reinstate MAP-seeking behavior (Carson, Hunt, et al., 2010). These findings propose that OT may have a powerful inhibitory effect on the motivation to consume MAP. Interestingly, the result of OT on the SA model was dependent on the sex of the rats. OT decreased the response of active lever pressing, breakpoint, and number of infusions in females but not in males during MAP SA. Later extinction, when rats were tested in cue-, MAP-, and yohimbine-induced reinstatement tests, OT was shown to significantly decrease lever-pressing activity in both females and males, except males in cue-induced restatement (Cox, Young, See, & Reichel, 2013). Information technology is noteworthy that administration of OT by both intraperitoneal (i.p.) injection (Hicks, Cornish, Baracz, Suraev, & McGregor, 2014) and NAc microinjection (Baracz, Everett, McGregor, & Cornish, 2014) inhibited MAP-induced restatement. The furnishings of OT on MAP-induced SA are summarized in Table i.

Table ane. Upshot of OT on MAP-Induced SA

Administration Road Dose Model Constructive: ○
Ineffective: ╳ 		References
i.p. 0.3 and 1   mg/kg SA: acquisition ○ Carson, Cornish, et al. (2010) and Carson, Hunt, et al. (2010)
SA: MAP-induced reinstatement ○
i.p. 1   mg/kg SA: conquering Female: ○ Cox et al. (2013)
SA: conditioned cue-induced reinstatement Female: ○
SA: MAP prime-induced reinstatement Both sexes: ○
SA: yohimbine-induced reinstatement Both sexes: ○
i.p. 1   mg/kg SA: conquering ╳ Hicks et al. (2014)
SA: MAP-induced reinstatement ○
NAc injection 0.5.1.five,four.5   pmol SA: MAP-induced reinstatement ○ Baracz et al. (2014)

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Evolution of Medications for Heroin and Cocaine Habit and Regulatory Aspects of Abuse Liability Testing

Beatriz A. Rocha , ... Roger D. Spealman , in Animal and Translational Models for CNS Drug Discovery, 2008

Self-administration Versus Other Models for Medications Development

The cocky-assistants model clearly predicts medications that finer treat opioid dependence, and appears to exist the best current behavioral image for preclinical testing of medications to treat cocaine dependence. For opioids, clinically effective medications decrease both the subjective and reinforcing effects of opioids, merely the same is non necessarily truthful for cocaine. Several human laboratory studies have assessed the ability of medications to dampen the discriminative-stimulus and subjective effects of cocaine, hypothesizing that blocking these effects will predict utility in the clinic (come across 229 for review; 230 ). However, cocaine's subjective furnishings announced to exist more than sensitive to modulation by medications than its reinforcing effects, resulting in a high rate of false positives when but subjective effects are measured. The aforementioned appears to be largely true in animate being studies involving straight comparisons of drug bigotry and drug self-administration results.

Cocaine use is extraordinarily difficult to disrupt both in the human laboratory and in the clinic. Medications rarely decrease cocaine self-administration, even when they essentially subtract ratings of cocaine "high" or "good drug effect" (run into 231–234 ). Measures of craving are as well not a proxy for self-administration, equally peckish is far easier to disrupt than drug taking. For example, maintenance on the antidepressant, desipramine, resulted in a 40% subtract in ratings of cocaine peckish still had no consequence on the amount of cocaine self-administered in laboratory animals, 179 in human research volunteers 231 or in the clinic (e.1000., 235 ). This dissociation betwixt peckish and actual drug employ emphasizes the importance of measuring cocaine self-administration when investigating potential pharmacotherapies for drug dependence. In contrast to the large number of faux positives obtained in studies that do not assess self-administration, no medication has been found to significantly decrease the self-administration of high doses of cocaine in the human being laboratory until recently. 224 Drug self-administration studies in laboratory animals have been of significant value for identifying candidate medications that fail to modify drug cocky-administration or that display undesirable properties such as high abuse potential. 176 Human and animal cocky-administration studies appear to predict medication failure or success in the clinic with much meliorate accuracy than studies that rely solely on drug bigotry information, self-reported subjective effects, or measures of craving (run into 228 ).

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Nonhuman Primate Models of Drug and Alcohol Habit

Donna Thou. Platt , James Yard. Rowlett , in Nonhuman Primates in Biomedical Inquiry (Second Edition), Book 2, 2012

The Self-Administration Model

Self-assistants models in laboratory animals are especially useful for determining the biological basis of drug and alcohol addiction, as well as for evaluating the effectiveness of potential candidate medications. In self-administration procedures, subjects perform a response, called an operant, which results in the commitment of a drug or booze. Drug or booze commitment is typically via the intravenous or oral route, although smoking/inhalation techniques besides have been adult.

The effectiveness of drug or alcohol in maintaining self-assistants beliefs depends on the precise scheduling weather condition under which information technology is delivered, and it is important that self-assistants experiments be conducted using a schedule of reinforcement appropriate for the type of question being asked (Spealman and Goldberg, 1978). For case, a uncomplicated fixed-ratio schedule may exist the all-time choice if the aim is to make up one's mind whether a particular drug maintains self-administration behavior. Under this type of schedule, drug or alcohol delivery occurs each time the subject completes a fixed number of responses (Figure 18.1).

Figure eighteen.1. Intravenous cocky-administration of drugs by nonhuman primates.

The acme console depicts the key elements of a cocky-administration system for squirrel monkeys. The monkey sits in a restraint chair, with access to response levers and stimulus lights. Pressing the lever is programed to event in reinforcer delivery—the reinforcer beingness an intravenous injection of drug or a nutrient pellet. The monkey wears a jacket to protect the catheter. Events are controlled by a estimator with associated interface hardware. The bottom panel depicts data from a typical self-administration experiment. Four adult male squirrel monkeys (Saimiri sciureus) were trained to press a response lever x times in society to receive an injection of 0.03   mg/kg/injection of cocaine. Dissimilar doses of cocaine were tested, along with the cocaine vehicle (V). Data are mean number of injections/1-h session (± SEM). The cocaine dose-response function is an inverted U-shaped function typical of cocky-administration studies. In general, the ascending limb of the office is thought to correspond the reinforcing furnishings; whereas the descending limb of the function is idea to stand for response rate-impairing effects.

A progressive-ratio schedule, under which the number of responses required for each drug/alcohol commitment increases systematically until responding falls below some pre-established level, is meliorate suited to a comparison of the relative effectiveness of dissimilar drugs as reinforcers. Second-gild schedules, in which persistent behavior is maintained past drug-associated stimuli, are useful for studying the reinforcing effects of widely spaced drug deliveries or for investigating the command of drug-taking behavior by ecology stimuli paired with drug injections. Finally, nether pick procedures, animals have the opportunity to choose between 2 or more reinforcers; the most common arroyo being the concurrent availability of drug or alcohol with a non-drug reinforcer, such as food. Compared to cocky-administration procedures that have only a single reinforcer available, these procedures may gauge more closely the conditions under which humans take drugs, namely complex environments in which a variety of alternative reinforcers are available. Choice procedures may exist peculiarly useful for the study of factors that promote drug/alcohol option and abuse.

Rats and mice serve as subjects in many of the self-administration studies of drug and alcohol addiction. Rodent models have some clear advantages over larger and more expensive primate models such as cost and ease of access. Moreover, the availability of genetically modified mice also offers models with unique molecular specificity. Complementary to these advantages of rodent models, nonhuman primates offering distinct and appealing features. The similarity in anatomy (including brain size, organization, and functionality), physiology, beliefs, and genetics betwixt nonhuman primates and humans provides a strong rationale for the use of nonhuman primates to span the gap betwixt rodent and human studies. Focusing on these similarities, this chapter's goal is to illustrate the value of nonhuman primates in studies of addiction to build on data generated in rodent studies and to ultimately increase understanding of the neurobiological and behavioral bases of drug and alcohol habit.

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Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse

Leonard L. Howell , S. Stevens Negus , in Advances in Pharmacology, 2014

two.ane Drug self-assistants

In drug self-administration procedures, drug delivery serves as the consistent stimulus ( Katz, 1989; Negus & Banks, 2011; Young & Herling, 1986). More specifically, conditions are established such that, in the presence of some discriminative stimulus (e.g., a stimulus light), emission of a response (due east.g., pressing a response lever) produces delivery of a drug dose (due east.g., i.v. delivery via a chronic i.v. catheter). A drug is considered to role as a reinforcer if some drug dose maintains higher response rates than vehicle, and many drugs of abuse including psychostimulants role as reinforcers in drug cocky-administration procedures. The high concordance betwixt preclinical measures of drug reinforcement and clinical measures of abuse liability has encouraged use of drug self-assistants for practical applications such as corruption liability assessment by regulatory agencies like the U.S. Drug Enforcement Agency (Ator & Griffiths, 2003; Carter & Griffiths, 2009). Moreover, drug self-administration by laboratory animals has articulate parallels to human patterns of drug abuse that likewise involve sequences of beliefs culminating in drug consumption. For all these reasons, drug reinforcement in assays of drug cocky-administration is often viewed every bit the most significant "abuse-related" effect acquiescent to preclinical study, and candidate medications can be evaluated for the degree to which they reduce self-administration of a target drug of abuse such as cocaine (Comer et al., 2008; Haney & Spealman, 2008; Mello & Negus, 1996).

Experiments to examine medication effects on drug self-administration can include many nuances (Mello & Negus, 1996). Three of those will exist mentioned here. First, to be clinically efficacious, medication furnishings should exist sustained rather than transient, because drug addiction is a chronic disorder that often demands chronic treatment. Assessment of the persistence of medication furnishings requires experimental designs that apply chronic medication commitment. Second, to be clinically prophylactic, medications should reduce consumption of the driveling drug without producing undesirable effects. Although toxicology screens play a central function in safety cess, useful insights to condom can also be provided by comparing medication effects on drug cocky-administration with furnishings on responding maintained by a nondrug reinforcer such as food. Some level of prophylactic is implied by a profile of medication furnishings that includes selective reduction in drug self-administration with lesser effects on responding maintained by another reinforcer. Finally, medication furnishings on drug self-administration may vary equally a office of the schedule of reinforcement used to maintain drug self-assistants. This result has been discussed in detail elsewhere (eastward.thou., Negus & Banks, 2011) and is across the scope of this review. However, as a general rule, the forcefulness of preclinical evidence for medication efficacy depends in part on the breadth of conditions across which a medication reduces drug self-assistants.

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Impulse and Reward Deficit Disorders: Drug Discovery and Development

Christian Heidbreder , in Creature and Translational Models for CNS Drug Discovery, 2008

Cocky-administration

The self-administration model has probably one of the highest face validities equally virtually all drugs of abuse, merely also natural reinforcers, such as nutrient or sucrose are self-administered by laboratory animals. The key event relates to the reinforcement contingencies used and the resulting interpretation of the data. The fixed-ratio (FR) paradigm of self-administration has been classically viewed every bit measuring the fact of reinforcement, but not the caste of reinforcing efficacy. 67, 78–80 Yokel and Wise 81, 82 proposed that, considering animals compensate past increasing their rate of self-administration (under low FR reinforcement weather condition) following decreases in unit corporeality of self-administered drug, such increased rates of FR self-assistants must reverberate decreased reinforcer efficacy. Even so, 6-hydroxydopamine (half-dozen-OHDA) lesions of the mesoaccumbens DA system 83 derange that interpretation as partial depletion of nucleus accumbens DA produced partial inhibition of cocaine self-administration. Since the reinforcing efficacy of cocaine is believed to correlate with its enhancement of nucleus accumbens DA, 67, 79, 80, 84–87 the decreased FR drug cocky-administration seen during recovery from the 6-OHDA-induced DA depletion has been interpreted as reflecting decreased reinforcer efficacy. Notwithstanding, how can the same alteration in reinforcing efficacy of cocaine (i.e., decreased efficacy) manifest itself as past opposite patterns of FR drug self-administration (i.east., by either increased or decreased FR drug self-administration)? 88 The reply is that drug cocky-administration under depression response-cost FR reinforcement conditions is an ambiguous measure of reinforcing efficacy, and possibly even an inaccurate mensurate that is insensitive to changes in reinforcing efficacy. 78, 83

The progressive ratio (PR) break-point shift paradigm was specifically developed to measure shifts in reinforcing efficacy and motivation to self-administer drugs. 78, 89–92 For example, cocaine cocky-administration nether PR atmospheric condition in rats has been shown to be dose-dependent, 78, 89, 90 to exist sensitive to manipulations affecting brain reward systems, 78, 89, xc to yield dose–response functions that reflect addictive potential, 78, 90, 93, 94 and to mensurate non only the reinforcing efficacy of cocaine, just also cocaine-induced craving. 90, 91, 95 This paradigm benefits from translational value into clinical trials as the reinforcing furnishings of cocaine, D-amphetamine, caffeine, and methylphenidate are influenced by behavioral demands following drug administration in humans. 96–98

Although the PR suspension-point shift paradigm measures the reinforcing efficacy and motivation to self-administer drugs, the sequential build-up of the drug following repeated self-administration may lead to unwanted results including dumb instrumental responding that might exist misinterpreted as impairment of reinforcement or incentive motivation. To address this potential issue conditioned reinforcement paradigms have been developed. These paradigms typically combine instrumental and Pavlovian (classical) conditioning procedures. For case, self-administration under 2nd-order schedules for both natural and drug reinforcers have examined how a response sequence is maintained by intermittent reinforcement of instrumental beliefs (typically a lever press) past the environmental stimulus that has acquired conditioned reinforcement backdrop. 99–101 One of the most attractive features of this paradigm is that it may potentially dissociate brain mechanisms underlying drug-seeking versus drug-taking behaviors. 102

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Gimmicky Aspects of Biomedical Research

Gianluigi Tanda , ... Jonathan L. Katz , in Advances in Pharmacology, 2009

C Self-Administration

Drug cocky-administration is a behavioral procedure in which responses of a subject area directly produce drug injections. The consequent features of the many variants of the process involve training a subject area to emit a unproblematic response that produces an intravenous injection of the compound. Often subjects are trained with 1 known compound, such as cocaine, and tested with various doses of unknown compounds, besides equally vehicle. When rates of response are greater than those maintained with vehicle injection, the chemical compound is said to have reinforcing effects (see Katz, 1989, for further details). Behavior maintained by drug self-injection is often considered the golden standard for the study of the reinforcing effects, and thus the abuse liability, of drugs.

The reinforcing effects of cocaine have been extensively documented (Forest et al., 1987). The reinforcing furnishings of BZT analogs were initially compared to those of cocaine in two studies. In the first, rhesus monkeys were trained to self-administer cocaine, and BZT and its iii′-Cl- and 4′-Cl-analogs were after tested. Rates of responding maintained by BZT and its analogs were relatively depression compared to those maintained by cocaine (Woolverton et al., 2000). In this report drugs were delivered after each 10th lever press (fixed-ratio 10-response or FR 10 schedule).

The reinforcing effects of 3′-Cl-, 4′-Cl-, and 3′,4′-diCl-BZT were further tested in a second study and compared to those of cocaine and GBR 12909 under the FR x schedule (Woolverton, Hecht, Agoston, Katz, & Newman, 2001). The rate of self-administration obtained nether the FR schedule with 3′-Cl- and four′-Cl-BZT, only not with iii′,4′-diCl-BZT, was greater than vehicle, but much lower than that maintained by cocaine or past GBR 12909 in the aforementioned monkeys. The rate of self-administration of 3′,4′-diCl-BZT was non greater than that maintained by vehicle. In a second part of the written report, rhesus monkeys were trained to answer under a progressive-ratio schedule, in which the number of responses required for self-administration increases progressively until the subject stops responding. The number of responses completed before the subject stops responding is often considered a measure out of the effectiveness of a compound as a reinforcing stimulus (Hodos, 1961). Cocaine and GBR 12909 were the most effective reinforcers, and the BZT analogs were the to the lowest degree efficacious, with the rank order as follows: cocaine> GBR 12909 >3′-Cl-BZT = 4′-Cl-BZT >3′,four′-diCl-BZT. In a more contempo study using rats, progressive-ratio performance maintained by cocaine was greater than that maintained by AHN ane-055, which was only marginally greater than that maintained by vehicle (Ferragud et al., 2009).

Recently, the reinforcing effects of N-substituted BZT analogs were assessed in rats responding under an FR five schedule and compared to those of standard DAT inhibitors (Hiranita, Soto, Newman, & Katz, 2009). The DAT inhibitor, methylphenidate, maintained responding like cocaine (Fig. 4A), whereas the SERT and NET inhibitors, citalopram and nisoxetine, respectively, did non (Fig. 4B). Under the same experimental conditions, neither AHN two-005 nor JHW 007 maintained rates of responding above those maintained by vehicle (Fig. 4C). AHN 1-055 maintained i.five. self-assistants beliefs, though maximal rates of responding were at a low level as compared to cocaine or methylphenidate (Fig. 4C). Reinforcing effects of AHN ane-055 were besides demonstrated past Ferragud et al. (2009) using an FR i-response injection schedule. In addition, after a 2-week period in which subjects did not accept the opportunity to respond, the responding previously maintained by AHN 1-055 was reduced to the rates previously obtained with vehicle whereas responding previously maintained by cocaine persisted.

FIGURE 4. Substitution of different doses of cocaine or other monoamine uptake inhibitors and BZT analogs in rats trained to self-administrate cocaine (0.32 mg/kg/injection). Ordinates: responses per 2nd. Abscissae: injection dose (mg/kg/injection). Each point represents the mean (vertical bars stand for SEM) of 6 to 11 subjects. Panel A: cocaine (filled circles) and methylphenidate (open circles). Panel B: cocaine (filled circles) and citalopram (open circles) or nisoxetine (triangles). Console C: cocaine (filled circles) and AHN 1-055 (open circles), AHN 2-055 (triangles upward), or JHW 007 (triangles down). Modified from Hiranita et al. (2009).

Pre-session treatments with methylphenidate (p.o.) shifted the dose–response curve for cocaine cocky-administration leftward (Fig. 5A), suggesting that methylphenidate did not antagonize the reinforcing effects of cocaine, but rather added to them (Hiranita et al., 2009). At variance with methylphenidate, AHN 2-005 and JHW 007 (p.o.) shifted the cocaine dose–response curve downwards (Fig. 5C and D), suggesting an combative effect of these compounds on cocaine cocky-administration (Hiranita et al., 2009). The effects of AHN one-055 were more than complex, with intermediate doses of the compound increasing responding at lower doses of cocaine, merely decreasing responding for the higher cocaine doses. Likewise, higher doses of AHN ane-055 shifted the cocaine dose–response curve downwards, thus significantly decreasing and antagonizing cocaine-maintained self-administration behavior (Fig. 5B). Importantly, the BZT analog-induced changes in cocaine self-administration were obtained at p.o. doses that had no effects on responding maintained by food reinforcement under conditions like to those used for the studies of cocaine-maintained responding (Ferragud et al., 2009; Hiranita et al., 2009).

FIGURE 5. Furnishings of pre-session treatment with methylphenidate and Northward-substituted BZT analogs on cocaine self-administration. Ordinates: responses per second. Abscissae: injection dose (mg/kg/injection). Each point represents the mean with SEM (n = 6 to 10). Methylphenidate, AHN one-055, AHN ii-005, or JHW 007 were administered orally at 60, 180, 240, or 300   min before sessions, respectively. Modified from Hiranita et al. (2009).

A slower onset of action as compared to cocaine and other psychostimulants may explain the lower efficacy of BZT analogs equally reinforcers. Because of the importance of contingency between the response and the effect of the compound, dull onset of activity results in delays in reinforcement. A substantial literature in behavioral science confirms delay in reinforcement as a factor that decreases the effectiveness of all reinforcers (Skinner, 1938), also as cocaine (eastward.g., Beardsley & Balster, 1993).

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Therapeutic Areas I: Primal Nervous System, Pain, Metabolic Syndrome, Urology, Gastrointestinal and Cardiovascular

A.H. Newman , R.B. Rothman , in Comprehensive Medicinal Chemistry II, 2007

vi.07.three.i Cocky-Administration/Reinstatement Model

Self-administration in animals requires an operant behavior (e.k., lever press) for the intravenous injection of a drug. A drug or NCE is considered to be reinforcing when either the rate of responding on the drug-correct lever exceeds that of the control or vehicle-paired lever, or if the response rate of the drug-receiving brute is greater than that of a yoked-control animal. In one case self-administration behavior is established, the experimenter tin can increment the number of lever presses required for a drug injection and thereby mensurate the reinforcing properties of the drug. When the number of lever presses required exceeds the 'piece of work' that the animal is willing to do to receive an injection, extinction of lever-pressing/self-assistants volition ensue. Several schedules of reinforcement can be employed. The fixed ratio (FR) schedule requires the brute to press the lever a fixed number of times before receiving a drug injection. The fixed interval (FI) schedule is used to determine how many presses an beast will make in a fixed interval of time. The most ordinarily used schedule is the progressive ratio (PR) in which a progressively larger number of lever presses are required to receive the same drug injection. The highest response requirement a drug will sustain is chosen the 'pause signal' and this has been used to measure drug reinforcement properties. Furthermore, the attenuation of the pause point has been used to evaluate potential medications or other weather that might decrease the reinforcing effects of the drug. 33 Most drugs driveling past humans are more often than not self-administered by animals and laboratory-based self-administration in humans has also been used to written report drug addiction. 34

In addition, this model can be extended to a reinstatement model of relapse. 35 In the reinstatement model, the fauna is trained to self-administer the drug of abuse. One time this beliefs is established, the drug injections are replaced with saline injections. In time, the brute will no longer printing the lever for a drug injection and this is called 'extinction.' Several investigators take demonstrated that drug- or cue-induced reinstatement of drug taking beliefs (e.yard., lever pressing) tin can be induced by a single priming injection of the drug of abuse or a cue that had previously been paired with the drug injection, during training. In improver, aversive conditions used every bit a model of stress, such every bit human foot shock, can besides reinstate lever pressing beliefs. This examination has face validity as a model for relapse to drug use by humans and has been suggested to farther model the effects of stress on drug taking behavior. 35 Farther, the attenuating furnishings by sure medication candidates in this model have prompted intense interest in detail mechanisms for drug evolution, such as DA D3 and mGluR5 receptors (meet Department 6.07.7). 36,37

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Animal Models of Addiction

Leigh Five. Panlilio , ... Steven R. Goldberg , in Biological Inquiry on Habit, 2013

Indirect Behavioral Assessments of Cannabinoid Reward

Drug self-administration procedures provide the most direct behavioral measure of drug reinforcement. Withal, several indirect measures too provide valuable information about drug reinforcement and other habit-related phenomena. Due to the fact that reliable procedures for cannabinoid self-administration have merely been established in the final decade and drug self-administration procedures in general are more challenging to implement, the indirect techniques are more widely used and have made a large contribution to our knowledge of cannabinoids.

Conditioned place preference procedures provide an indirect measure of whether a drug has a reinforcing event. In these procedures, the effects of a drug are paired with the distinctive cues of one compartment of a 2-compartment apparatus. Dissimilar self-administration procedures, in which the brute but receives the drug if it performs a certain response, the drug is given automatically in place-conditioning studies, ordinarily as an intraperitoneal injection delivered just before the fauna is placed into ane of the compartments for 15–xxx   min. After the drug furnishings have been paired with one compartment and placebo injections have been paired with the other compartment several times each, a test is performed in which the animal is allowed to enter either compartment. If the fauna spends more time in the drug-paired compartment during the test, it is inferred that the drug has reinforcing effects that accept transferred to the cues nowadays in the drug-paired compartment. An reward of this kind of procedure is that it tin can also detect aversive effects of a drug, which are inferred if the beast avoids rather than prefers the drug-paired compartment. A number of conditioned place preference studies have been performed in rats and mice with THC. In general, the findings betoken that low doses of THC tin can be reinforcing, but higher doses tend to take aversive furnishings.

Drug discrimination procedures provide a means of assessing the interoceptive furnishings of a drug in animals, which are presumably analogous to the subjective furnishings reported by humans. In a typical procedure, during each daily training session a rat is injected intraperitoneally with either THC or placebo, and then placed into a sleeping room that has 2 levers. On days when THC is injected, pressing 1 of the levers (e.g. the left lever) produces food pellets; on days when placebo is injected, pressing the opposite lever produces food pellets. After a number of such preparation sessions, the rat learns to accurately detect whether it has received THC and to answer exclusively on the correct lever. At this point, tests tin can be performed to determine if another drug has furnishings similar to the training drug (i.e. causes the rat to choose the drug-advisable lever). If a drug does share furnishings with THC, this suggests that information technology might accept the potential to be driveling. Testing tin can also be performed to determine whether a handling drug can block the effects of the training drug, such that the rat chooses the placebo-appropriate lever even though it has received THC. If the handling blocks the interoceptive effects of THC, this suggests that it might exist able to prevent the reinforcing furnishings of THC. However, the drawback of using drug discrimination procedures equally a model of the rewarding effects of a drug is that the interoceptive furnishings of a drug can have several different components, some of which might not be related to advantage. When this procedure is used as an indirect model of reinforcing furnishings, the results do not always agree with the results obtained with self-assistants procedures. Such discrepancies appear to exist more than likely with certain noncannabinoid training drugs than with cannabinoids such as THC. Even so, drug discrimination procedures are best used in combination with other measures of reward to ensure validity of the results.

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Handbook of Stress and the Brain

Michela Marinelli , Pier Vincenzo Piazza , in Techniques in the Behavioral and Neural Sciences, 2005

Self-administration of psychostimulants

Animal drug cocky-administration is 1 of the best models of human being drug taking. Nonhuman primates and rodents self-administer nigh drugs that are addictive in humans ( Weeks, 1962; Pickens and Harris, 1968; Schuster and Thompson, 1969) and, like humans, they testify large individual differences in drug responding (Piazza et al., 1989).

Several studies in rodents have shown that suppressing or reducing basal levels of circulating corticosterone decreases the reinforcing effects of psychostimulants every bit measured past intravenous self-administration. For instance, suppression of glucocorticoids by adrenalectomy prevents the conquering of cocaine self-assistants over a wide range of cocaine doses (Goeders and Guerin, 1996a, 1996b). Detailed dose–response studies have shown that adrenalectomy induces a vertical downward shift of the dose–response bend to cocaine (Deroche et al., 1997b) during the maintenance stage indicating that, regardless of the cocaine dose, drug intake is always lower in adrenalectomized animals than in controls. These findings suggest that reducing circulating levels of glucocorticoids decreases the reinforcing efficacy of cocaine (Piazza et al., 2000). The subtract in drug furnishings is reversed dose-dependently by exogenous administration of corticosterone; the response to cocaine is fully restored when stress-like levels of corticosterone are reached (Fig. two), suggesting that lack of GR activation is mediating the effects of adrenalectomy.

Fig. 2. Compared with controls (sham-operated animals), suppression of corticosterone by adrenalectomy (ADX) decreases responding for cocaine during a cocky-administration task. The furnishings of ADX are reversed dose–dependently past corticosterone replacement (corticosterone added to the drinking solution of the animals; ADX + Cort). The response to cocaine is fully restored when animals receive a replacement treatment reproducing stress levels of corticosterone.

 Modified from Deroche et al. (1997b). Copyright © 1997

The hypothesis that GRs are implicated in psychostimulant self-assistants behavior have been confirmed by recent findings showing a decrease in cocaine cocky-administration in mice lacking brain GRs (Deroche-Gamonet et al., 2003). Thus, similarly to adrenalectomized animals, these mice evidence a downwardly shift in the dose-response curve for cocaine. In improver, in rats, administration of the GR antagonist mifepristone also decreases cocaine self-administration in a progressive ratio schedule of reinforcement, suggesting that occludent of GRs reduces motivation to self-administer cocaine (Deroche-Gamonet et al., 2003).

Like reduction in drug responding was observed following pharmacological occludent of corticosterone secretion. Thus, treatment with the corticosterone synthesis inhibitor metyrapone reduces cocky-administration of cocaine, both during the acquisition and maintenance phase (Goeders and Guerin, 1996a, 1996b). Another corticosterone synthesis inhibitor, ketoconazole, has similar effects and reduces acquisition of self-assistants when it decreases circulating levels of glucocorticoids (Goeders et al., 1998). These furnishings are not due to nonspecific decreases in motor behavior or motivation, equally these treatments do not modify seeking behavior in food-related tasks (Piazza et al., 1994). Every bit mentioned previously, however, a note of caution should be employed when analyzing the effects of corticosterone synthesis inhibitors such as metyrapone or ketoconazole; these drugs could have nonspecific effects and should be used mostly to confirm studies that used other methods of manipulating the HPA axis.

Information technology is noteworthy to mention that, similar to the locomotor effects of psychostimulant drugs, drug-induced increases in hormone levels are not a critical factor for intravenous drug self-administration. Thus, self-administration of psychostimulants dramatically increases glucocorticoid secretion (Baumann et al., 1995; Broadbear et al., 1999a, 1999b; Mantsch et al., 2000; Galici et al., 2000; Goeders, 2002), but blockade of this increase does not modify responding for cocaine (Deroche et al., 1997b; Broadbear et al., 1999c). In addition, animals have been shown to self-administer cocaine at doses that do not change circulating levels of glucocorticoid hormones (Broadbear et al., 1999b), which further corroborates the notion that drug-induced glucocorticoid secretion is non important to maintain drug cocky-administration behavior.

The fact that drug-induced glucocorticoid secretion is irrelevant for the maintenance of drug self-administration could explain the apparent discrepancies between studies on rats, showing that blockade of corticosterone secretion reduces psychostimulant cocky-assistants, and those on humans and on not-homo primates, showing that blockade of glucocorticoid secretion has no effects on cocaine cocky-assistants (Broadbear et al., 1999c), or on the subjective effects of smoked cocaine (Ward et al., 1998, 1999). Indeed, in rodent studies, glucocorticoid levels are e'er reduced to values that are well below those seen in control conditions. Instead, in primate studies, glucocorticoid levels are never brought below those observed in control subjects: the pharmacological treatments are merely aimed in preventing drug-induced increases in hormone levels, which, as mentioned above, are irrelevant for self-administration behavior. These are important considerations suggesting that differences in the literature might exist perceived erroneously as inter-species differences, whereas they simply reflect differences in the attained glucocorticoid levels: blockade of drug-induced hormone secretion has no effects on drug responding, whereas blockade of basal or stress-like levels decreases drug self-administration.

Information showing that suppression of corticosterone decreases self-administration behavior are in contrast with studies showing that adrenalectomy does non modify cocaine-induced place preference (CPP) (Suzuki et al., 1995), a response that is often considered equally an alphabetize of the rewarding effects of drugs of abuse (Carr et al., 1989; Hoffman, 1989; Tzschentke, 1998). It is possible that this discrepancy could depend on the fact that the 2 behaviors seem to depend on different neuronal substrates. Thus, the dopamine system largely mediates psychostimulant cocky-administration (Roberts et al., 1980) but information technology does not mediate the effects if CPP induced by cocaine injected intreaperitoneally (Spyraki et al., 1982). Interestingly, CPP induced by intravenous administration of cocaine is dopamine-dependent (Spyraki et al., 1982), but, to our knowledge, the effects of glucocorticoids on this beliefs have non been studied. Another possible explanation for the discrepancy between the function of glucocorticoid in CPP versus self-administration is that CPP might not be the about suitable paradigm to study changes in the intensity of the reinforcing or rewarding issue of drugs (for review, see Bardo and Bevins, 2000). In fact, this examination can evaluate changes in the threshold dose of psychostimulants required to produce conditioning, but once the response is induced, the intensity of its furnishings does non modify significantly equally a function of drug dose (Costello et al., 1989). Therefore, this paradigm is mostly suited to evaluate horizontal shifts in dose-response functions, just non vertical ones. On the other manus, drug self-assistants shows dose-dependent responding, thus allowing assay of both horizontal and vertical shifts in dose-response functions. Given the fact that adrenalectomy induces a vertical shift in the dose-response to cocaine cocky-administration (Deroche et al., 1997b), it is understandable that this manipulation has no effects of cocaine-induced place workout.

Concerning the role of stress levels of glucocorticoids on cocky-administration, it has been shown that stress enhances cocky-administration behavior (for review see Kreek and Koob, 1998; Lu and Shaham, 2004). Again, different stressors such every bit tail compression (Piazza et al., 1990a), foot-daze (Goeders and Guerin, 1994), social isolation (Schenk et al., 1987a, b), social stress (Haney et al., 1995; Miczek and Mutschler, 1996; Tidey and Miczek, 1997) and food brake (Carroll et al., 1979; Papasava and Vocaliser, 1985; Papasava et al., 1986; Macenski and Meisch, 1999; Marinelli et al., 2002) all increase intravenous self-assistants of amphetamine and cocaine. These furnishings have been observed for different doses of the drugs, during the conquering phase, the retention 1, as well as in progressive ratio schedules. As in the case of locomotor activity, the increase in self-assistants induced by stress seems to depend on stress-induced corticosterone secretion. The effects of stress levels of corticosterone have but been examined following handling with ketoconazole, a corticosterone synthesis inhibitor. Repeated handling with ketoconazole decreases the rate of conquering of cocaine self-administration equally well as the proportion of rats meeting acquisition benchmark following food restriction stress (Campbell and Carroll, 2001). The effects of corticosterone reduction are non related to changes in motivation or motor behavior, because operant responding for food is non decreased in groups whose corticosterone levels have been modified (Micco et al., 1979; Piazza et al., 1994). As mentioned previously, studies on nonspecific corticosterone synthesis inhibitors should be viewed cautiously, as their effects could besides depend on other non-specific backdrop of these drugs.

The furnishings of stress levels of glucocorticoids on drug self-administration have besides been analyzed by studying the effects of repeated administration of loftier, stress-like levels of glucocorticoids on drug responding. These studies have shown that repeated exposure to high levels of glucocorticoids reproduces the effects of stress on drug responding. Thus, rats repeatedly treated with corticosterone have been shown to acquire cocaine cocky-administration at a lower dose compared with vehicle-treated controls (Mantsch et al., 1998), and the intravenous injection of corticosterone prior to a self-administration session also increases drug responding in animals that would not readily acquire cocaine self-administration (Piazza et al., 1991a).

Over again, every bit in the case of locomotor activity, it is very important to specify that nearly studies on drug self-administration have observed increases in drug responding post-obit repeated or prolonged exposure to high, stress-like levels of glucocorticoids (Goeders and Guerin, 1996b; Deroche et al., 1997b; Mantsch et al., 1998), although see (Piazza et al., 1991a). It is therefore possible that long-term exposure to high levels of these hormones is required for the development of stress-induced increment in drug responding, whereas acute increment in glucocorticoids might not be sufficient. Indeed, a single exposure to loftier levels of glucocorticoids does not modify the subjective responses to amphetamine in humans (Wachtel et al., 2001).

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Animate being Behavior

Matt Carter , Jennifer Shieh , in Guide to Research Techniques in Neuroscience (Second Edition), 2015

Self-Assistants

Cocky-administration is a form of operant conditioning (Box 2.five) in which animals are trained to perform a item action, such every bit pressing a lever, to receive a rewarding stimulus, such as an addictive drug. Animals are free to perform the action freely and repetitively, demonstrating the intrinsically rewarding properties of the stimulus. In a continuous reinforcement paradigm, an animal performs a single action to receive a rewarding stimulus, whereas in a fixed ratio paradigm, an beast performs a set amount of actions (such as 5 lever presses). In a progressive ratio prototype, the creature must perform an action more and more to receive the rewarding stimulus (for example, pressing a lever one time, then 2 times, then 4 times, and so viii times, etc.), and the scientist measures the breakpoint at which the animate being no longer works to receive the advantage.

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