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Buccafusco JJ, editor. Methods of Behavior Analysis in Neuroscience. 2nd edition. Boca Raton (FL): CRC Press; 2009.

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Methods of Behavior Analysis in Neuroscience. 2nd edition.

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Chapter 9Intravenous Drug Self-Administration in Nonhuman Primates

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9.1. INTRODUCTION

The abuse of psychoactive drugs such as cocaine and heroin has spanned several decades and continues to be widespread in the United States. Currently, research efforts have focused on the development of therapeutics to treat drug abuse. Drug self-administration studies have done much to help us understand the behavioral and pharmacological mechanisms underlying drug abuse. An understanding of these mechanisms will in turn aid in the development of effective therapeutic agents.

Important to the study of drug effects on behavior is the understanding that drugs can function as stimuli to control behavior [1]. Based on the principles of operant conditioning, presentation of a stimulus as a consequence of behavior may either increase or decrease the probability that a behavior will occur again [2]. If the presentation of a stimulus increases the probability that a behavior will recur, then that stimulus is defined as a positive reinforcer [2]. Stimuli such as food and water function as positive reinforcers, and data from self-administration studies indicate that most drugs of abuse, most notably psychostimulants and opioids, can also function as positive reinforcers under the appropriate schedule contingencies. Drug self-administration procedures in animals have been used extensively to evaluate the reinforcing effects of drugs. The first studies examining the reinforcing effects of drugs in the 1950s and 1960s focused on morphine self-administration in morphine-dependent animals [3,4]. Later studies demonstrated that dependence was not necessary to initiate self-administration [5,6]. Since these early studies, self-administration procedures have been used as a model of drug taking that can be studied under controlled laboratory conditions and applied to human drug use.

Drug self-administration studies in animals have contributed substantially to our knowledge of the neuropharmacological mechanisms controlling drug abuse. For example, studies with opioids have shown that drugs with high affinity for μ-opioid receptors function as positive reinforcers [7,8], whereas opioids with high affinity for κ-opioid receptors generally do not [8,9]. Additionally, the self-administration of psychomotor stimulants and opioids has been found to be affected by the administration of antagonists either systemically or centrally (cf [10,11].). If administration of an antagonist shifts the dose-response function for a self-administered drug to the right, then it can be assumed that the site of action of the antagonist is important for the reinforcing effects of the drug [12–15]. In addition to the administration of antagonists, self-administration of drugs has been affected by lesions of certain brain neurotransmitter systems (cf [10,11].). Studies have also found that animals will self-administer drugs directly into certain brain areas, suggesting a neuropharmacological mechanism for their reinforcing effects (cf [10].).

Over the years, drug self-administration procedures in animals have been found to be valid and reliable for determining the abuse liability of drugs in humans. It is well established that animals will self-administer most drugs that are abused by humans [16,17]. In particular, studies in nonhuman primates have made a significant contribution to the field of drug abuse research. Nonhuman primates are ideal subjects since they are phylogenetically more closely related to humans than are other species [18]. Potential species differences in drug metabolism also illustrate the importance of nonhuman primate models in substance abuse research. Thus, we can apply information obtained from nonhuman primates to problems of human drug abuse with greater accuracy. This chapter discusses methods of self-administration in non-human primates, including different preparations and schedules of drug reinforcement. While the focus is primarily on self-administration of psychoactive stimulants such as cocaine, the methodology and general principles apply to other pharmacological classes including opiates, benzodiazepines, and alcohol.

9.2. SURGICAL PROCEDURES

Protocols for intravenous drug self-administration require the surgical implantation of a chronic intravenous catheter to permit infusion of the drug solution. Typically, a superficial vessel, such as the external jugular or femoral vein, is accessed via a surgical cut-down procedure [19]. Using appropriate anesthesia, either inhaled anesthetics (e.g., isoflurane) or injected ketamine in combination with a benzodiazepine, and under aseptic conditions, one end of a catheter is implanted into the vessel while the other end is routed subcutaneously to a point of access. If the distal end of the catheter is externalized, an appropriate jacket is used to prevent the animal from damaging the preparation [20], and the catheter is sealed with a stainless-steel obturator when not in use. An alternative means of access involves the attachment of the distal end of the catheter subcutaneously to a vascular access port [21]. A Huber needle designed to minimize insult to the skin or port membrane is inserted perpendicular to the port to allow for injection of drug solution. Lastly, a tethering system can be used to protect the catheter while providing convenient access [5,22]. The preparation requires continuous housing in an experimental chamber, and restraint by a harness and a spring arm attached to the top or back of the chamber. However, movement of the animal within the chamber is not restricted by the tethering system. The distal end of the catheter is routed subcutaneously to exit between the monkey’s scapulae, and is threaded through the spring arm. For each of the preparations, the catheter is connected via plastic tubing to a motor-driven syringe located outside the test chamber during experimental sessions. At least twice weekly, catheters are flushed with sterile saline or water, and filled with heparinized saline (100 units of heparin per mL of saline). All solutions that come in contact with the catheter are prepared with sterile components and stored in sterile glassware.

9.3. SCHEDULES OF REINFORCEMENT

9.3.1. Initial Training

Drug self-administration involves operant behavior that is reinforced and maintained by drug delivery. Animals acquire drug injections by emitting a discrete response, such as pressing a lever or key. The number and pattern of responses required for each injection are defined by the schedule of reinforcement. Availability of drug under a given schedule typically is signaled by an environmental stimulus, such as the illumination of a stimulus light located proximal to the response lever. Schedule parameters and stimulus conditions are controlled by computers, while responses emitted by the animal are recorded simultaneously. The primary dependent measures are number of drug injections and rate of responding during each session. As with behavior maintained by nondrug reinforcers such as food, responding maintained by drug injections is determined by the schedule parameters and the behavioral history of the animal.

Daily experimental sessions are conducted in the home cage or in a standard primate chair either custom designed [22] or commercially available [24,25]. If a primate chair is used, location of the chair within a ventilated, sound-attenuating chamber will minimize distractions and interference from daily laboratory activities. Typically, responding is initiated using a 1-response, fixed-ratio schedule so that each response in the presence of a stimulus light will result in the intravenous injection of a drug solution. The drug dose is determined by the concentration and volume of solution, and should be sufficient to maintain reliable drug self-administration in a well-trained animal. The saliency of the drug injection is enhanced by a change in the stimulus lights during the injection period. It is critical to avoid excessive drug intake and toxicity during training sessions. Drug intake can be limited by scheduled timeout periods following each injection, during which stimulus lights are extinguished and responding has no scheduled consequence. Defined limits on the number of injections per session are also recommended. Once the animal has acquired the lever press response and behavior is reliably maintained by drug injections, the response requirement can be gradually increased under a variety of intermittent schedules of reinforcement.

9.3.2. Fixed-Ratio Schedules

The most basic schedule of reinforcement is the fixed-ratio (FR) schedule, which defines the number of responses required per drug injection. Once responding on the lever is engendered, the response requirement is gradually increased to the terminal value. Nonhuman primates rapidly acquire drug self-administration behavior under FR schedules, and stable daily performances can be obtained in several weeks. FR schedules typically generate high response rates and a “break and run” pattern of responding characterized by a brief pause in responding after each drug injection, followed by an abrupt change to a steady high rate of responding until the next FR is completed. It is important to note that total session intake of drug is a direct function of response rate under FR schedules. Typically, higher unit doses are required to maintain behavior at higher FR values. Drug intake can be limited by scheduling timeouts following each injection and by restricting the total number of drug injections per session. The duration of the timeout value following each injection can also have significant effects on behavior.

9.3.3. Fixed-Interval Schedules

In contrast to FR schedules, fixed-interval (FI) schedules are time based and specify a minimal inter-injection interval. They represent a suitable alternative to FR schedules because they engender high levels of behavioral output. Typically, a stimulus light is illuminated in the test chamber during the FI to serve as a discriminative stimulus. Once the FI has elapsed, a single response is required for drug delivery. A limited hold can be imposed following the FI to restrict the time period during which a response is reinforced, resulting in higher rates of responding. Temporal control over behavior is enhanced if a timeout is scheduled following each injection. Once responding on the lever is engendered at a very short FI (1–5 sec), the interval is gradually increased to the terminal value. In contrast to the “break and run” pattern engendered by FR schedules, FI schedules engender a “scalloped” pattern of responding characterized by little or no responding early in the interval and increased rates of responding as the interval elapses. Nonhuman primates often require several months of training before a stable pattern of responding develops. Also, response rate can vary markedly with little or no change in the total number of injections per session. It is important to emphasize that quantitative aspects of self-administration are dictated by the schedule of reinforcement. For example, nicotine maintained i.v. self-administration under an FR schedule in rhesus monkeys, but at response rates much lower than those maintained by cocaine [26]. In contrast, nicotine maintained i.v. self-administration in squirrel monkeys under an FI schedule with peak response rates much more similar to those maintained by cocaine. Hence, the apparent strength of nicotine to maintain behavior was markedly influenced by the schedule of reinforcement.

9.3.4. Second-Order Schedules

Environmental stimuli that are paired with reinforcement can substitute for the reinforcer itself through Pavlovian conditioning. Moreover, these conditioned stimuli can reinforce behavior that results in their presentation through the process of second-order conditioning [27]. When a stimulus light that has been paired with drug injection is presented following an operant response, the frequency of that response increases [28,29]. Second-order schedules involve a contingency arrangement under which a series of responses under a schedule of conditioned reinforcement is treated as a unit response under a second schedule that is simultaneously in effect. Second-order schedules of drug self-administration can generate very high behavioral outputs for a single injection of drug. If the stimuli are presented early in the drug-taking history of the animal, they can also enhance the acquisition of drug self-administration. In a typical example of a second-order schedule, responding is initiated using a 1-response FR schedule so that each response in the presence of a stimulus light (e.g., red) will produce an intravenous drug injection and the brief illumination of a different stimulus light (e.g., white), followed by a timeout. The ratio value is gradually increased as responding increases. When the schedule value reaches a terminal value, drug injection no longer follows completion of each FR and, instead, is arranged to follow an increasing number of FR components during a predetermined interval of time. As the interval duration is extended during training, a greater number of FR components will be completed per drug injection. Ultimately, the terminal schedule will arrange for drug injection following the first FR component completed after the FI has elapsed. Drug administration is accompanied by a change in the stimulus light (e.g., from red to white), followed by a timeout. The drug-paired stimulus light is also presented briefly upon completion of each FR component. Daily sessions can consist of several consecutive FIs depending on the interval and session duration. By using this second-order procedure and limiting the daily session to approximately 1 hr, any direct effects the self-administered drug might have on rate and pattern of responding will be absent during the first component and minimized during the experimental session. Hence, performance measures can be related directly to the reinforcing effects of the drug. Cumulative records typical of performance engendered by a second-order FI schedule with FR components nicely illustrate that introducing an imbedded schedule of conditioned reinforcement results in much higher and persistent rates of self-administration with the same dose of cocaine and the same FI value [30].

9.3.5. Progressive-Ratio Schedules

Progressive-ratio self-administration procedures are designed to quantify the reinforcing effects of drugs and to determine their reinforcing strength. Reinforcing strength is often referred to as the maximum reinforcing effect of a drug or other reinforcer [31]. Generally, it has been inferred from the strength of the behavior maintained by the drug. In a progressive-ratio procedure, the number of responses required to obtain a reinforcer progressively increases over the duration of the session. Eventually, responding for the reinforcer will cease when the response requirement becomes too great. This point, termed a break point, is a measure of a drug’s reinforcing efficacy. Under a progressive-ratio schedule, the response requirement can increase either following the delivery of the drug [32] or at the beginning of each daily session [33,34]. If the response requirement increases following the delivery of the drug, it will be incremented within a daily session, and completion of the response requirement one time will result in the delivery of drug. If the response requirement increases at the beginning of a daily session, it will be fixed over the duration of a daily session. The same response requirement will be in effect for several days (i.e., until stability criteria are met) before progressing to the next response requirement, allowing multiple determinations of self-administration at a particular response requirement. More recent progressive-ratio procedures combine both of these approaches and require that the animal respond a given number of times at a particular response requirement before proceeding to the next response requirement within a daily session [35,36]. Thus, these procedures have the advantage of collecting multiple determinations of self-administration at a particular response requirement within a daily session while still allowing the response requirement to be increased within the session. A cumulative record typical of performance engendered by a progressive-ratio schedule is shown in Figure 9.1.

Figure 9.1. A cumulative record of lever pressing maintained in a rhesus monkey under a progressive-ratio schedule of cocaine (0.

Figure 9.1

A cumulative record of lever pressing maintained in a rhesus monkey under a progressive-ratio schedule of cocaine (0.1 mg/kg/injection) self-administration over a daily session. The daily session consisted of five components, each made up of four trials (more...)

9.4. RESEARCH APPLICATION AND DATA INTERPRETATION

The primary focus of drug self-administration research in nonhuman primates has been to establish the reinforcing properties of drugs of abuse and to identify neurochemical mechanisms underlying drug use. A better understanding of the neurochemical basis of drug self-administration is essential for the development of treatment medications for human drug abusers. The key feature of drug-reinforced behavior is control of behavior by response-contingent drug delivery [37]. Hence, drug-reinforced behavior should be distinguished from drug self-administration. A number of control procedures have been described to demonstrate that increases in behavior that result in drug delivery are caused specifically by the reinforcing effects of the drug [6]. The most commonly used procedure is to substitute saline for the drug solution and determine whether the behavior undergoes extinction. The rate and pattern of responding maintained by drug delivery depends on a number of variables including the schedule of reinforcement, drug dose, the volume and duration of injection, and the duration of drug self-administration sessions. Drug self-administration studies have consistently obtained an inverted U-shaped dose-effect curve relating the unit dose of drug delivered per injection and response rate or number of injections delivered. The dose-effect function reflects a combination of reinforcing effects and unconditioned stimulus effects such as sedation or marked hyperactivity. Typically, the ascending limb of the dose-effect curve reflects the reinforcing effects, and response rate increases with drug dose. In contrast, the descending limb of the curve reflects a nonspecific disruption of operant behavior as excessive drug accumulates over the session, and response rate decreases with drug dose. It should be noted that the dose-effect curve relating the unit dose of drug delivered per injection and drug intake in mg/kg is typically a monotonic increasing function. Lastly, an inverse relationship has been obtained between infusion duration and reinforcing effects [38,39]. The longer the infusion time required to deliver a constant volume of drug solution, the less effectively the drug functions as a reinforcer. However, the latter relationship is typically not observed until the infusion duration is extended to a minute or more.

A study by Glowa et al. [40] illustrates the use of an FR schedule of drug self-administration to characterize the effectiveness of a dopamine reuptake inhibitor to alter the reinforcing effects of cocaine in rhesus monkeys. A standard tethered-catheter, home-cage system was used for i.v. drug delivery [5]. Animals were trained to self-administer cocaine under an FR 10 schedule of drug delivery during 90-min daily sessions. Pretreatment with the high-affinity dopamine reuptake inhibitor, GBR 12909, dose-dependently decreased rates of cocaine-maintained responding, and the effect was larger when lower doses of cocaine were used to maintain responding. Moreover, the rate-decreasing effects of GBR 12909 were greater on cocaine-maintained responding than on food-maintained responding under a multiple schedule of drug and food delivery. The results obtained were consistent with previous reports demonstrating that drugs with dopamine agonist effects can decrease cocaine-maintained responding [41,42]. This type of drug interaction has been attributed to a satiation of cocaine-maintained responding by pretreatment with a drug having dopaminergic effects. The latter approach to cocaine medication development has been referred to as substitute agonist pharmacotherapy [43]. Hence, response-independent delivery of a dopamine reuptake inhibitor may have decreased cocaine self-administration by substituting for the reinforcing effects of response-produced cocaine. This interpretation is supported by studies showing that GBR 12909 will substitute for cocaine as a reinforcer in squirrel monkeys [44–46].

Note that Glowa et al. [40] incorporated several important design features in their self-administration study. First, multiple unit doses of cocaine were self-administered on separate occasions in order to establish a complete dose-effect curve for cocaine. Hence, pretreatment effects of GBR 12909 could be assessed over a broad range of cocaine doses. Second, multiple pretreatment doses of GBR 12909 were administered in order to establish dose-dependency of pretreatment effects and to identify the optimal pretreatment dose that lacked overt behavioral toxicity. Lastly, the specificity of pretreatment effects on cocaine-maintained behavior was assessed by comparing drug effects on food-maintained behavior. The multiple schedule that alternated cocaine and food as maintaining events during separate components was well suited for this application. Moreover, cocaine dose was manipulated to match response rate to that obtained during the food component of the multiple schedule. The finding that GBR 12909 suppressed cocaine-maintained responding at doses that had little or no effect on food-maintained responding under identical schedules and comparable response rates provides convincing evidence that GBR 12909 selectively attenuated the reinforcing effects of cocaine.

A study by Woolverton [47] provides another example of cocaine self-administration under an FR schedule in rhesus monkeys. The objective was to characterize the effectiveness of dopamine antagonists to alter the reinforcing effects of cocaine. A standard tethered-catheter, home-cage system was used for i.v. drug delivery. Animals were trained to self-administer cocaine under an FR 10 schedule of drug delivery during 2-hr daily sessions. When responding was stable, the animals were pretreated with the D1 antagonist SCH 23390, or the D2 antagonist pimozide. Intermediate doses of pimozide generally increased cocaine self-administration, whereas SCH 23390 either had no effect or decreased cocaine self-administration. High doses of both antagonists decreased the rate of cocaine self-administration, but also produced pronounced catalepsy. Hence, the latter effects could not be attributed to a selective interaction with the reinforcing effects of cocaine. The author concluded that the selective increase in responding maintained by cocaine following pimozide pretreatment suggested a role for the D2-receptor in cocaine self-administration.

Strengths of the Woolverton [47] study design included multiple unit doses of cocaine and multiple pretreatment doses of both dopamine antagonists. Extinction of cocaine self-administration when saline was substituted for cocaine was also characterized. Note that response rate for cocaine increased following pretreatment with the D2-selective antagonist. The latter effect is interpreted as a behavioral compensation to overcome the attenuation of the reinforcing effects of cocaine by pimozide. Since drug intake is a direct function of response rate under FR schedules, an increase in rate will result in greater session intake of cocaine, which may effectively surmount the dopamine antagonist effects of pimozide. The finding that the pattern of responding following pimozide was virtually identical to that seen in the first session of extinction supports the view that pimozide was attenuating the reinforcing effects of cocaine. However, alternative interpretations were acknowledged, largely because specificity of pretreatment effects on cocaine-maintained behavior was not assessed by comparing drug effects on behavior maintained by nondrug reinforcers.

Nader et al. [48] used an FI schedule of drug self-administration to characterize the effectiveness of a novel cocaine analog to alter the reinforcing effects of cocaine in rhesus monkeys. A standard tethered-catheter, home-cage system was used for intravenous drug delivery. Animals were trained to self-administer cocaine under an FI 5-min schedule during 4-hr daily sessions. Under this schedule, the first response after 5 min produced a 10-sec cocaine injection. Pretreatment with the high-affinity dopamine reuptake inhibitor 2β-propanoyl-3β-(4-tolyl)-tropane (PTT) dose-dependently decreased rates of cocaine-maintained responding and total session intake of cocaine. The reinforcing effects of PTT were also evaluated in a separate group of animals. When substituted for cocaine, PTT maintained response rates that were similar to those maintained by saline and significantly lower than rates maintained by cocaine. The results demonstrated that a long-acting dopamine reuptake inhibitor could effectively decrease cocaine self-administration in nonhuman primates. Also, failure of PTT to maintain rates of self-administration greater than those obtained during extinction conditions suggested that PTT may have limited abuse liability.

The study of Nader et al. [48] was consistent with previous findings using dopamine reuptake inhibitors to decrease cocaine self-administration under FR schedules of drug self-administration [37]. Hence, a generality of pretreatment effects has been demonstrated across experimental conditions, further supporting a substitute agonist approach to cocaine medication development. Both studies included multiple unit doses of cocaine and multiple pretreatment doses of the dopamine reuptake inhibitors. In addition, assessment of the reinforcing properties of PTT provided critical information concerning the abuse liability of the candidate medication. The fact that PTT did not reliably maintain self-administration behavior, whereas GBR 12909 has been shown to function effectively as a reinforcer in monkeys [44–46], illustrates the potential importance of pharmacokinetic factors in drug self-administration studies. It is possible that low rates of PTT self-administration were a result of its relatively long duration of action at inhibiting dopamine uptake. Hence, its long duration of action compared with cocaine may have required lower session intake to produce cocaine-like reinforcing effects. It should be noted, however, that the rate of onset appears to play a more prominent role in the reinforcing effects of psycho-stimulants than does duration of action [49–51].

Human drug use often involves a ritualized sequence of behaviors that occurs in a specific environment. The environmental stimuli associated with drug use are believed to play a major role in the maintenance of drug-seeking behavior [29]. Second-order schedules of drug self-administration have been used in nonhuman primates to maintain extended sequences of responding between drug injections [20,45,46,52] analogous to patterns of drug use in humans. The second-order schedule is well suited for drug-interaction and drug-substitution experiments because response rate increases as a direct function of the unit dose administered at low and intermediate doses (Figure 9.2). Note that high doses of drug can disrupt performance during the latter components of a session as multiple doses accumulate. In drug-interaction experiments, changes in the positioning of the cocaine dose-effect curve leftward or rightward will indicate altered potency of cocaine to function as a reinforcer. A downward shift in the cocaine dose-effect curve will indicate an insurmountable attenuation of cocaine self-administration. In drug-substitution experiments, maximum rates of responding maintained over a range of drug doses can be used to compare reinforcing effectiveness.

Figure 9.2. Mean (± SEM) rate of responding maintained in a group of three squirrel monkeys under a second-order fixed interval 900-sec schedule of cocaine intravenous self-administration with fixed ratio 20 components.

Figure 9.2

Mean (± SEM) rate of responding maintained in a group of three squirrel monkeys under a second-order fixed interval 900-sec schedule of cocaine intravenous self-administration with fixed ratio 20 components. Data for each dose of cocaine were (more...)

A study by Howell et al. [53] provides an example of cocaine self-administration under a second-order FI schedule in squirrel monkeys. The objective was to characterize the effectiveness of a phenyltropane analog of cocaine to alter the reinforcing effects of cocaine. The distal end of the catheter was externalized and exited between the scapulae, and a nylon-mesh jacket protected the catheter when not in use. Animals were trained to self-administer cocaine under a second-order FI 15-min schedule with FR 20 components during 1-hr daily sessions. Pretreatment with the dopamine reuptake inhibitor RTI-113 significantly decreased rates of cocaine self-administration, and the effect was not surmounted by increasing the unit dose of cocaine (Figure 9.3). The latter findings are consistent with previous studies using dopamine reuptake inhibitors to decrease cocaine self-administration under FR [40] and FI [48] schedules of drug self-administration. Hence, the generality of pretreatment effects has been demonstrated over a range of experimental conditions and in two different primate species. Note that low doses of RTI-113 actually increased rates of cocaine self-administration at the low unit dose of cocaine, providing evidence of additivity of effects. The latter finding is an important consideration when conducting drug interaction studies with two drugs that have a similar mechanism of action.

Figure 9.3. Mean (± SEM) rate of responding in a group of three squirrel monkeys maintained under a second-order fixed interval 900-sec schedule of cocaine (0.

Figure 9.3

Mean (± SEM) rate of responding in a group of three squirrel monkeys maintained under a second-order fixed interval 900-sec schedule of cocaine (0.1 and 0.3 mg/injection) intravenous self-administration with fixed ratio 20 components. Cocaine (more...)

Similar to other self-administration schedules, the reinforcing potencies of drugs can be determined under progressive-ratio schedules [33,36]. For example, cocaine is 10-fold more potent than the local anesthetic procaine under a progressive-ratio procedure [36]. However, progressive-ratio procedures are most useful for determining the reinforcing strength of self-administered drugs. Drugs can be rank-ordered based on their relative reinforcing effects as determined by break point in the progressive ratio [33,36]. For example, cocaine has been found to maintain higher break-point values than diethylpropion, chlorphentermine, and fenfluramine in baboons [33]. More recently, cocaine has been found to maintain higher break-point values than procaine in rhesus monkeys (Figure 9.4) [36].

Figure 9.4. Break-point values and injections/session maintained by cocaine (closed symbols) and procaine (open symbols) under a progressive-ratio schedule in rhesus monkeys.

Figure 9.4

Break-point values and injections/session maintained by cocaine (closed symbols) and procaine (open symbols) under a progressive-ratio schedule in rhesus monkeys. Data are the mean (± SEM) for the number of monkeys indicated in parentheses above (more...)

As mentioned above, break point typically is used as the dependent measure to assess reinforcing effectiveness under a progressive-ratio procedure. However, break-point data violate the assumption of homogeneity of variance necessary for reliable statistical analysis. Variability is greater at high break-point values than at low break-point values, making it difficult to determine effects based on drug dose at high break points [54,55]. Therefore, some researchers have applied a data transformation to break-point data before analysis (see Rowlett et al. [55]). In addition, the number of injections per session has been found to be a reliable measure of reinforcing strength and does not violate the assumption of homogeneity of variance [36,55]. With intravenous self-administration paradigms, it is important to consider that effects other than reinforcing effects may influence responding for drug injections when high doses of a drug are available. Downward turns in dose-response curves have been explained by drug accumulation. To address this issue in the progressive ratio, researchers have used a timeout after each injection. The idea is that the timeout will allow the effects of the drug to dissipate before another injection can be obtained. A timeout length of 30 min is effective for studying cocaine in the progressive-ratio procedure [36,55].

In addition to progressive-ratio procedures, choice procedures are used to study the reinforcing strength of drugs. The choice paradigm allows animals access to two reinforcers and evaluates the preference of one reinforcer over the other. Typically, animals choose between a food and a drug reinforcer or two drug reinforcers [56,57]. Reinforcing strength can be determined based on the preference of one reinforcer over the other. For example, rhesus monkeys given a choice between a high and a low dose of cocaine will prefer the higher cocaine dose [57]. A study by Johanson and Aigner [58] suggested a difference in the maximum reinforcing effects of cocaine and procaine using a choice procedure. They evaluated the preference for an i.v. injection of cocaine versus an i.v. injection of procaine in rhesus monkeys. At equipotent doses for reinforcing effects, monkeys chose i.v. injections of cocaine more than 80% of the time [52]. These results are consistent with those of the Woolverton [33] progressive-ratio study mentioned above. Thus, choice paradigms are reliable for studying reinforcing efficacy.

Lastly, behavioral economics provides a means to quantify the reinforcing effects of drugs independent of dose [59]. Such studies apply microeconomic concepts including consumer demand and labor supply theories to help understand how behavior is maintained by various reinforcers, referred to as “commodities” in economic parlance. Behavioral economic studies use total daily consumption of a commodity, rather than response rate, as the primary indicator of demand for that commodity. In drug self-administration experiments, subjects regulate their consumption by responding to obtain multiple presentations of the commodities of interest. The function generated by assessing consumption across increasing “cost” of a commodity is known as a “demand curve,” and these functions generally reveal that consumption decreases as the cost of a commodity increases. Cost is manipulated by increasing the work requirement—in the simplest case, increasing the FR value required to receive an injection. As the FR value is increased, consumption levels decrease, reflecting the behavioral sensitivity to price. By comparing consumption at a given price, relative to the level of consumption at the lowest price (i.e., at FR 1), one can gauge the “elasticity of demand” of a given commodity [60]. Demand is “inelastic” when consumption is defended across large increases in price. In contrast, demand is “elastic” when consumption declines rapidly with increasing price. An example of the relationship between demand and onset of drug action was demonstrated with the drugs fentanil, alfentanil, and remifentanil. All three compounds are full agonists at μ opioid receptors and have immediate onsets of action following i.v. administration, but the durations of action for these compounds differ markedly, with remifentanil having the shortest duration of action and fentanil having the longest duration of action. Despite differences in durations of action, and apparent differences in the absolute rates of responding maintained by these three compounds in self-administration experiments, demand curve analysis suggests that these drugs do not differ in their reinforcing effectiveness [61]. Thus, duration of action does not seem to contribute to the reinforcing effectiveness of opioids, or, perhaps, for other drug classes as well.

9.5. DISCUSSION

Nonhuman primate models of drug self-administration provide a rigorous, systematic approach to characterize the reinforcing effects of psychoactive drugs. The longevity of nonhuman primates is an important consideration, allowing for long-term studies to be conducted and repeated-measures designs to be employed. A single venous catheter can be readily maintained for over a year, and multiple implants permit the conduct of self-administration experiments for several years in individual subjects. Long-term studies with repeated measures are well suited for comprehensive drug-interaction experiments. While rodent models of drug self-administration have substantially contributed toward an understanding of neuropharmacology, the nonhuman primate represents an animal model with unique relevance to understanding the neurochemical basis of substance abuse in humans. For example, the complexity of the topographical organization of the striatum and its connections with surrounding areas in primates [62–64] complicates extrapolations from rodents to primates. Moreover, a large number of brain regions respond differently to acute drug administration in monkeys [65] compared to rodents [66,67]. Both the topography of altered brain metabolism and the direction of metabolic responses differ markedly [65,67]. The metabolic effects reported in monkeys are more consistent with data on functional activity in humans [68,69]. These findings, in conjunction with documented species differences in drug metabolism [18], illustrate the importance of nonhuman primate models in substance abuse research.

Research efforts that have used nonhuman primate models of drug self-administration have focused primarily on the identification of neurochemical mechanisms that underly drug reinforcement, and the development of pharmacotherapies to treat drug addiction. In clinical evaluations of new medications, a decrease in drug self-administration is the goal of treatment [70–72]. Preclinical evaluations of pharmacotherapies require the establishment of stable baseline patterns of drug self-administration prior to drug-interaction studies. Subsequently, the treatment medication is administered as a pretreatment before the conduct of self-administration sessions. It is critical to study several doses of the treatment medication to determine an effective dose range and a maximally effective dose that lacks overt behavioral toxicity. The effects of the treatment medication typically are evaluated first in combination with a dose of the self-administered drug on the ascending limb of the dose-effect curve that maintains high rates of self-administration. However, a complete dose-effect curve should be characterized for the self-administered drug because pretreatment effects can differ depending on the unit dose of the drug self-administered. A rightward shift in the dose-effect curve suggests that drug pretreatment is antagonizing the reinforcing effects of the self-administered drug. A downward displacement of the dose-effect curve indicates an insurmountable attenuation of the reinforcing effects. Alternatively, a leftward shift is consistent with an enhancement of the reinforcing effects. Medications that shift the dose-effect curve downward and decrease self-administration over a broad range of unit doses are most likely to have therapeutic utility. Medications that shift the dose-effect curve to the right and simply alter the potency of the self-administered drug may prove to be ineffective at higher unit doses. Clinically, most medications are administered on a chronic basis and may require long-term exposure before therapeutic effects are noted [73,74]. Accordingly, preclinical studies should include repeated daily exposure to the medication to characterize peak effectiveness and to document continued effectiveness over multiple sessions [75]. Figure 9.5 illustrates the effects of chronic amphetamine treatment on cocaine self-administration in rhesus monkeys. Note that amphetamine maintained its effectiveness to reduce cocaine self-administration over multiple weeks. Also, there was an initial disruption of food-maintained behavior, but responding for food returned to baseline values over the first week of amphetamine treatment. It is also critical to reestablish baseline levels of drug self-administration between successive exposures to the medication to ensure that the catheter preparation is functional and that persistent effects of the pretreatment drug do not interfere with the interpretation of drug interactions obtained.

Figure 9.5. Time course of effects of saline or d-amphetamine (0.

Figure 9.5

Time course of effects of saline or d-amphetamine (0.01–0.1 mg/kg per hr) on responding for 0.01 mg/kg per injection cocaine and food pellets. Abscissae: consecutive days of treatment. Left ordinate: number of cocaine injections (0.01 mg/kg per (more...)

The primary treatment outcome measures in drug self-administration studies are rate of responding and the number of drug injections delivered per session. Both measures are influenced by the schedule of reinforcement, drug dose, the volume and duration of injection, and the duration of the self-administration session. Moreover, most drugs that are self-administered have direct effects on rate of responding that may be distinct from their reinforcing effects. For example, cocaine injections may increase rate of responding early in the session, but suppress behavior later in the session as total drug intake accumulates. Another important consideration in evaluating medication effectiveness is the selectivity of effects on drug self-administration. If the drug pretreatment decreases drug self-administration at lower doses or to a greater extent than behavior maintained by a nondrug reinforcer such as food, the outcome is indicative of selective interactions with the reinforcing properties of the self-administered drug. In contrast, a nonspecific disruptive effect on operant behavior will likely suppress drug- and food-maintained responding to a comparable extent. Lastly, the reinforcing properties and abuse potential of the medication should be evaluated by substituting a range of doses of the medication for the self-administered drug. Since reinforcing effects in preclinical studies are correlated with abuse liability in humans, reliable self-administration of the medication is usually considered undesirable.

While this chapter focuses on the i.v. route of drug self-administration, the reinforcing properties of drugs have been studied effectively in nonhuman primates via the oral and inhalation routes. For example, orally delivered cocaine can function as a reinforcer in rhesus monkeys, and persistent and orderly responding is obtained when dose and FR size are varied [76]. Orally delivered phencyclidine and ethanol also maintain self-administration behavior in rhesus monkeys under progressive-ratio schedules [77]. However, establishing drugs as reinforcers via oral administration can be difficult because of metabolic effects associated with the gastrointestinal system and delayed onset of CNS activity associated with slow absorption and distribution. In addition, drug solutions often have a bitter taste that may be aversive to nonhuman primates. Accordingly, complex induction procedures are frequently used to establish oral self-administration of drug solutions. Studies that have demonstrated cocaine’s ability to function as a reinforcer have used a fading procedure from an initial baseline of ethanol-maintained responding [76], although concurrent access to cocaine and vehicle solution is sufficient to establish oral self-administration [78]. Lastly, cocaine and heroin are self-administered by rhesus monkeys via smoke inhalation under FR and progressive-ratio schedules [79–81]. Although initial training is difficult because of the aversive characteristics of smoke, and drug dose is difficult to quantify, rhesus monkeys can rapidly learn to self-administer the drugs via the inhalation route. Given the above considerations, the advantages of intravenous self-administration procedures are clearly evident. Drug dose is easily manipulated and quantified, metabolic effects in the gastrointestinal system and slow absorption are avoided, and onset of CNS activity is rapid. Importantly, orderly and reliable dose-effect curves are obtained that are sensitive to pharmacological manipulation.

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