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Drug Alcohol Depend. Author manuscript; available in PMC 2016 May 25. Published in final edited form as: Drug Alcohol Depend. 2015 June 1; 151: 284–288.
The rise (and fall?) of drug discrimination research☆ Lance R. McMahon Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, United States
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Drug discrimination has unsurpassed utility among preclinical assays for examining the extent to which CNS-acting drugs share neuropharmacological mechanisms in whole animals. Drugs of abuse were routinely used in the earliest days of drug discrimination. However, over the years the scope of drug discrimination research has extended well beyond drugs of abuse. Any CNS-mediated event that can be repeated consistently, not necessarily drug-induced, has the potential to be trained as a discriminative stimulus. This commentary briefly touches upon the history of drug discrimination research, highlights some useful and novel applications, and discusses its current status in relation to drug self-administration. This commentary is written in part to address the markedly different trajectories of drug discrimination and drug self-administration research, evidenced by a larger number of published scientific papers reporting self-administration data as compared with drug discrimination data. Antecedents and consequences of this disparity are discussed.
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1. History and applications
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Drug discrimination emerged as an experimental approach in the late 1960s and early 1970s. In the earliest experiments conducted by Cathleen Morrison, Herbert Barry, and Francis Colpaert, it was demonstrated that rats could make a “correct” choice depending on the presence versus the absence of the effect of a dose of a drug (Morrison and Stephenson, 1969; Barry, 1974; Colpaert et al., 1975a,b,c). During training animals are presented with a choice between two alternative and mutually exclusive responses (e.g., pressing a left or right lever). The correct response results in delivery of a reinforcer such as food. The correct response is determined by administration of drug or saline beforehand. After administration of a dose of a drug (i.e., the training dose and training drug) the animal can only obtain reinforcers by responding on one of the two levers (e.g., right lever) and the same lever is always paired with the same dose of the same drug. The other lever (e.g., left lever) is always the correct lever following vehicle administration. Incorrect responses do not result in delivery of the reinforcer. Training proceeds until animals reliably make the correct choice, as evidenced by responding on the drug-associated lever after drug administration and the vehicle-lever after vehicle administration. Tests are the same as training sessions except that any dose of any drug can be administered. Moreover, during tests responding on
☆This material is not peer-reviewed by the Journal, but is reviewed prior to publication by the members of the CPDD Publications Committee and invited members of the College. News and Views is edited by the Chair of the CPDD Publications Committee: Gregory M. Miller, Ph.D., Harvard Medical School, New England Primate Research Center, Pine Hill Drive, Southborough, MA 01772, USA.
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either of the two levers results in delivery of a reinforcer or lever-pressing is not reinforced, i.e., tests are conducted under conditions of extinction.
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Drug discrimination has a high degree of selectivity for the primary mechanism by which a training drug produces its neuropharmacological effects in whole animals. For example, when animals that are trained to discriminate the μ opioid agonist fentanyl receive another μ opioid agonist, they respond as though they received fentanyl. In contrast, animals trained to discriminate fentanyl typically do not respond as though they received fentanyl when instead they receive a drug that is not a μ opioid agonist, though there are exceptions. Instead fentanyl-trained animals will respond on the non-drug (e.g., vehicle) associated lever (Colpaert et al., 1975a). The pharmacological selectivity of drug discrimination has been demonstrated for a number of drug classes including abused drugs such as cannabinoids (Balster and Prescott, 1992) and different classes of GABAA receptor-mediated sedative/ hypnotics (Colpaert et al., 1976) as well as non-abused drugs such as the serotonin releasing agent fenfluramine (White and Appel, 1981). Such pharmacological selectivity is highly useful for examining and classifying in vivo pharmacological mechanism(s) of CNS-acting drugs in the whole animal.
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Many CNS-acting drugs, including some abused drugs, bind to multiple receptor sites and have a complex pharmacology. Drug discrimination has been highly useful as a tool for examining the relative importance of multiple receptor sites of action to the in vivo effects of drugs. For example, the stimulants cocaine, amphetamine, and 3,4methylenedioxymethamphetamine (MDMA) bind to membrane-bound, pre-synaptic monoamine transporter proteins to promote the release and/or block the reuptake of monoamine neurotransmitters (Rothman et al., 2001). Drug discrimination has been used to identify not only the relative importance of monoamines, but also the relative contribution of monoamine receptor types to the in vivo effects of stimulants. Drug discrimination assays have been used to dissect the mechanisms of action of other abused drugs with complex pharmacology, including but not limited to alcohol (Grant and Colombo, 1993), gamma hydroxybutyric acid (Carter et al., 2003), and GABAA receptor modulators (Ator and Griffiths, 1983).
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Research programs in academia and private industry have exploited drug discrimination to provide critical early information on the extent to which chemical modeling and in vitro pharmacological profiles translate into whole-animal pharmacology. Richard Glennon and Roger Nichols incorporated drug discrimination in their respective academic research programs into hallucinogenic drugs and the relative contribution of serotonin 5-HT2A and other receptor subtypes to in vivo effects (Glennon and Rosecrans, 1982; Marona-Lewicka and Nichols, 1995). The laboratories of Glennon and Nichols also used drug discrimination to examine relationships between chemical structure, binding at monoamine transporters, and in vivo effects of various stimulants and appetite-suppressants (Schechter and Glennon, 1985; Oberlender and Nichols, 1988). Pre-clinical neuropharmacological research divisions of pharmaceutical companies have similarly relied upon drug discrimination. For example, Synthelabo Recherché Laboratories used drug discrimination to compare and contrast the pharmacology of benzodiazepine-related drugs (Sanger and Zivkovic, 1986). Janssen Pharmaceuticals, primarily through the pioneering efforts of Frances Colpaert, used drug
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discrimination to study a variety of drug classes including opioids, stimulants, hallucinogens, and alpha-adrenergic receptor ligands (Colpaert, 1984). Later at Pierre Fabre, Colpaert and colleagues used drug discrimination to identify serotonin 5-HT1A agonists as part of a program to develop novel analgesics (Kleven and Koek, 1998; Kleven et al., 1997).
2. Using drug discrimination to study the state of an organism
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Unique applications of drug discrimination have involved the study of physical dependence and withdrawal. Holtzmann was among the first of a handful of investigators to demonstrate that the μ opioid antagonist naltrexone could be readily discriminated by animals rendered dependent on morphine (Gellert and Holtzman, 1979). The discriminative stimulus effects of naltrexone in morphine-dependent animals were correlated in time with physical signs of withdrawal. Antagonist-discrimination procedures in drug-dependent animals have been extended to include withdrawal from benzodiazepines (Gerak and France, 1999) and cannabinoid agonists such as Δ9-tetrahydrocannabinol (Stewart and McMahon, 2010). Emmett-Oglesby, Lal, and colleagues used a different approach in studies of dependence and withdrawal: animals were trained to discriminate the GABAA receptor antagonist pentylenetetrazole, which produces convulsions at relatively large doses and anxiety-like behaviors at smaller doses. Abrupt discontinuation of chronic treatment from a variety of drugs including ethanol, GABAA receptor modulators, and nicotine was demonstrated to share discriminative stimulus effects with pentylenetetrazole; these results were interpreted as reflecting anxiety that occurs during drug withdrawal (Emmett-Oglesby et al., 1990).
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Other relatively novel applications have eliminated drugs entirely from discrimination training conditions. Rats have been trained to discriminate between food satiation and food deprivation by Jewett and colleagues. This approach has been used to examine various peptides and neurotransmitters involved in feeding and to identify drugs that potentially modify appetite (Jewett et al., 2009). An early review of drug discrimination suggested possible applications to a variety of other internally mediated events that could be studied in conjunction with drugs such as pain, inflammation, and hypertension (Lal, 1977). Experimental support for the discrimination of pain was provided by a study demonstrating that rats could discriminate aspirin more readily in the presence of chronic pain (Weissman, 1976). However, the full potential of discriminating such internally mediated events has not been realized, perhaps due to the challenges associated with maintaining stability of such stimuli.
3. Drug discrimination as an alternative or adjunct to self-administration in Author Manuscript
abuse liability assessment Self-administration and drug discrimination are complimentary approaches for examining abuse liability and underlying pharmacological mechanisms. Known drugs of abuse can serve as training drugs and then tests can be conducted with novel drugs. Alternatively, a novel drug can be trained and then evaluated by testing known drugs of abuse. In either case, overlapping discriminative stimulus effects suggests that there is the potential for overlapping abuse liability. An example of the use of both approaches involves studies with synthetic analogs of cathinones that are abused in various formulations including products Drug Alcohol Depend. Author manuscript; available in PMC 2016 May 25.
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marketed and sold as “bath salts”. Known drugs of abuse such as MDMA and methamphetamine were demonstrated to substitute when the synthetic cathinone 3,4methylenedioxypyrovalerone (MDPV) was trained (Fantegrossi et al., 2013), whereas MDPV was demonstrated to substitute when either cocaine or amphetamine were used as training drugs (Gatch et al., 2013). Because discriminations of known drugs of abuse can be maintained for several years or more depending on the species, and dose–response functions for drugs can be obtained in a few weeks, drug discrimination can provide rapid feedback on possible abuse liability.
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In non-humans as in humans, some drug classes are not robustly self-administered. Hallucinogens such as lysergic acid diethylamide and 1-(2,5-dimethoxy-4-methylphenyl)-2aminopropane (DOM) are not typically self-administered by non-human species. Drug discrimination has provided an excellent alternative for classifying these and other drugs on the basis of hallucinogenic activity mediated by 5-HT2A receptors. Likewise, cannabinoid agonists are not robustly self-administered in non-humans, although exceptions have been noted, especially in squirrel monkeys (Tanda et al., 2000). Discrimination of Δ9tetrahydrocannabinol has provided an alternative to self-administration for assessing pharmacological actions of Δ9-tetrahydrocannabinol that could mediate both the abuse liability and subjective effects of cannabinoids (Balster and Prescott, 1992). Moreover, drug discrimination has been a valuable resource for assessing the in vivo pharmacology of drugs with unique physicochemical properties. Volatile gasses such as toluene are abused via inhalation and there is no convenient alternative route of administration for pre-clinical studies. Shelton and colleagues have devised methods to precisely control the amount of volatile gas administered to rodents and have used this technology to examine the discriminative stimulus effects of toluene and other volatile gasses (Richardson and Shelton, 2015).
4. Disparity in drug discrimination vs. self-administration publication trends: antecedents and consequences A PUBMED search with the keywords “drug self-administration” yields a much larger number of publications (maximum 1847 in 2013) as compared with the keywords “drug discriminative stimulus” (maximum 117 in 1999). Trends over time have also differed. Hits per year for the keywords “drug self-administration” exhibit a steady increase over time, with 2014 being an exception. Conversely, hits per year for the keywords “drug discriminative stimulus” have been stable or declining for at least 10 years. The disparity is illustrated further in Fig. 1. What are the potential factors and consequences of these trends?
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The popularity of drug self-administration is due in part to a high degree of face validity for drug use and abuse. Without too much trouble one can readily see the similarity between humans engaging in various drug-taking behaviors and animals completing an operant response (e.g., lever press) to obtain drug. Conceptualizing drugs of abuse as reinforcers like food and sex has intuitive appeal. The predictive validity of drug self-administration for drug abuse liability is also better than most other pre-clinical assays. Both humans and nonhumans repeat behaviors that result in the delivery of cocaine, heroin, and ethanol, although
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some drug classes (e.g., hallucinogens and cannabinoids) represent notable exceptions to this general rule of thumb, as noted above. Intuitive appeal for drug abuse also has fostered the popularity of other pre-clinical assays such as place conditioning, in which preference for an environment that had been previously paired with a drug of abuse is measured.
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Reinstatement is an adaptation of intravenous drug self-administration that is considered by some to be a pre-clinical model of relapse. Reinstatement involves removal of intravenous drug delivery by substituting vehicle until lever pressing occurs at very low levels (i.e., extinction). Once extinguished, a variety of stimuli will cause resumption of lever pressing at relatively high levels (i.e., reinstatement) even though the contingency for lever pressing continues to be intravenous vehicle delivery. Stimuli that reinstate lever pressing include non-contingent administration of the drug that had been self-administered as well as presentation of foot shock or another noxious stimulus often referred to as a stressor. Resumption of lever pressing after a period of extinction resembles relapse after a period of abstinence. However, some aspects of reinstatement differ markedly from those of relapse (Katz and Higgins, 2003). Nonetheless, reinstatement accounts for a significant amount of ongoing drug self-administration research.
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The simple face validity of drug self-administration stands in contrast to drug discrimination: what are discriminative stimulus effects? Drug discrimination is often considered to be highly correlative with subjective effects (Schuster et al., 1981; Schuster and Johanson, 1988). However, that interpretation can be misleading. The subjective effects of drugs are private events that define the human experience of drug use. Unlike external events that can be independently described among human observers, the verbal description of the internal events associated with drug use are based solely on the conditioning history and experience of the individual. An individual who reports euphoria after receiving a dose of cocaine potentially has a very different subjective experience from the individual who reports aversion after receiving the same dose of cocaine. Despite these markedly different subjective experiences, both individuals can be trained to reliably perform the same operant behavior after receiving a dose of cocaine and the same distinct operant behavior when receiving vehicle. Both individuals discriminate cocaine, as evidenced by unitary responses, but their subjective description of the cocaine experience is markedly different. Likewise, individuals with a history of opioid and stimulant use will rate the subjective effects of methamphetamine and hydromorphone as being identical on measures of “drug-liking”, yet the drugs do not share discriminative stimulus effects in the same individuals (e.g., Lamb and Henningfield, 1994).
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Stimuli originating outside the organism are transduced by one of the five sensory modalities (e.g., sight, sound, smell, taste, or touch) and the CNS processes that information. A wavelength of light labeled “blue” by humans can be discriminated in the same way that a drug can be discriminated. Behavioral performance associated with discrimination of the blue light generalizes to wavelengths of light that approximate the blue light. As the wavelength diverges from the blue-light training stimulus, animals begin to respond as though they have not been presented with the blue light. In addition to external stimuli transduced by the five sensory modalities, the CNS processes stimuli originating from inside the organism including drugs acting at receptors to alter neurotransmission within the CNS.
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The control that a drug exerts over choice behavior, and the transfer of that control to pharmacologically related drugs, is similar to the control that a given wavelength of light or frequency of tone exerts over choice behavior. However, wavelengths and frequency are discriminated on a unidimensional continuum, whereas drug discrimination is considered to be more complex, comprising multidimensional, qualitatively distinct stimuli (Schuster et al., 1981). All drugs of abuse have discriminative stimulus effects and indeed any CNS-acting drug has the potential to be discriminated. By now hopefully the reader is convinced that drug discrimination has excellent predictive validity for CNS receptor mechanisms in whole animals. Yet drug discrimination lacks face validity for drug abuse or any other human disease or condition, which is arguably a major factor preventing drug discrimination from gaining the same widespread appeal as drug self-administration.
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5. Use of drug self-administration versus drug discrimination in the study of neurobiology Drug self-administration is not only a useful screen for abuse liability, but also has utility for examining the neurobiology of reinforced behavior generally. Drugs of abuse target the same mesocorticolimbic dopamine pathways that also mediate other types of reinforced behavior such as eating and sex. Microinjection of drugs and optogenetic manipulations are examples of approaches that can be used to manipulate and examine brain areas underlying drug selfadministration. Drugs can be self-administered directly into discrete brain regions through indwelling cannula. Drug self-administration research has grown in parallel with the explosion of neuroscience research in the last few decades.
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In contrast to the reasonably well-defined brain circuits implicated in drug-reinforced behavior, brain regions mediating discriminative stimulus effects are largely undefined. Different pharmacological classes have separable discriminative stimulus effects and receptors mediating the diversity of drugs that can be discriminated are located throughout the brain. Multiple brain regions are expected to mediate discriminative stimulus effects and, in fact, localization of a discriminative stimulus effect to a single, discrete brain region or pathway seems unlikely. Moreover, brain regions involved in discrimination are expected to vary from one drug class to another. For example, brain regions mediating discriminative stimulus effects of antidepressants acting at pre-synaptic serotonin and/or norepinephrine transporters are predicted to differ from those mediating the discriminative stimulus effects of heroin and other μ opioid agonists. These are testable hypotheses amenable to the same types of brain manipulation routinely employed in drug self-administration research. Despite the potential involvement of numerous different brain areas in mediating discrimination of various drug classes, widespread appeal for exploring such relationships is lacking. Mice are being increasingly used for intravenous drug self-administration, especially with improvements in techniques for maintaining catheter patency. Mice enable transgenic approaches not currently available in other animal species. Mice are also increasingly used for drug discrimination research, although the results of these drug discrimination experiments in transgenic mice are sometimes difficult to interpret. Mice lacking β2 subunits Drug Alcohol Depend. Author manuscript; available in PMC 2016 May 25.
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of nicotinic acetylcholine receptors were unable to discriminate nicotine from saline (Shoaib et al., 2002), suggesting a critical role for these receptor types in the discriminative stimulus effects of nicotine. However, drug discrimination is often successfully established in transgenic mice, even when deleting receptor types that have been shown to mediate discriminative stimulus effects through pharmacological approaches. For example, dopamine D2 receptor knockout mice can discriminate cocaine, even though D2 receptors mediate the discriminative stimulus effects of cocaine (Chausmer et al., 2002). Thus, deleting a receptor that otherwise mediates the discriminative stimulus effects of a drug does not necessarily prevent discrimination of that drug, indicating that other actions of a drug, potentially at additional receptor types, can produce discriminative stimulus effects. Discrepancies between transgenic and pharmacological approaches are certainly not unique to drug discrimination, however, inasmuch as self-administration of drugs correlates strongly with binding affinity of those drugs at the dopamine transporter (Ritz et al., 1987), yet drug selfadministration is apparently unperturbed in mice lacking dopamine transporters (Rocha et al., 1998).
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One of the consequences of the drug self-administration boom is an increasing lack of appreciation of the complexities of operant conditioning behavior and misinterpretation of self-administration data. Whether or not responding for a drug occurs in greater amounts than for saline (i.e., a drug is self-administered) is a simple enough question. However, there is difficulty interpreting a change in the amount of drug self-administered as a consequence of some manipulation, such as administration of a second drug or an environmental change. Simply put, a sufficient quantity of anything will decrease operant responding for any reinforcer including a drug reinforcer. A reduction in self-administration is often misinterpreted as a decrease in reinforcing effects without first eliminating simpler interpretations (i.e., general suppression of all operant behavior) that can only be rejected by gathering additional, control data. Operant responding for non-drug reinforcers such as food are often used as a control, yet responding for food often occurs at different rates and patterns than responding for drug. Drug-induced changes in operant behavior can vary dramatically as a function of rates and patterns of behavior independent of the reinforcer that maintains behavior (Kelleher and Morse, 1968). The self-administration dose–response function, i.e., the number of lever presses or infusions earned per unit dose expressed as a function of the unit dose, is non-monotonic or characterized by an inverted U shape when the schedule requirement is held constant. Variations such as progressive ratio schedules (Roberts et al., 1989) or procedures involving a choice between drug and another reinforcer such as food (Paronis et al., 2002) have been developed to avoid an inverted U shape dose– response function. However, the entire dose–response function or some portion thereof is often needed to interpret a change in self-administration behavior. Unfortunately, inattention to such complexities has led to frequent misinterpretation of drug self-administration data. There are pitfalls associated with interpretation of drug discrimination data as well. There can be loss of a well-trained animal’s ability to discriminate properly in the presence of some drug types or relatively large doses of drug. Moreover, attenuation of the discriminative stimulus effects of a drug by another can sometimes be due to a perceptual masking phenomenon, rather than to functional or competitive antagonism at the receptor
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level. However, the prevalence of these and other pitfalls is modest given the more restricted use of drug discrimination as compared with self-administration. In summary, the apparent plateau and tendency toward a decline in drug discrimination research is due to a number of factors. The downsizing of pre-clinical neuropharmacological research in private industry has taken its toll. Fewer academic laboratories seem to be conducting drug discrimination research as compared with self-administration research. Hopefully this commentary has touched upon the most important factors underlying this disparity. Drug discrimination has many applications, some tried-and-true and others more novel and unique. Most importantly, drug discrimination continues to be among the best if not the best option for classification and characterization of the mechanism of action of CNS acting drugs in whole animals.
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Fig. 1.
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Data are drawn from a database maintained by Stolerman and colleagues with support from NIDA 1982–2012. Original journal articles, book chapters, whole books, and publically accessible abstracts and research reports are included. The drug discrimination (DD) data were derived primarily from searches of PubMed and PsychInfo. The drug selfadministration (DSA) data were derived from PubMed and manually adjusted to remove citations that did not qualify for inclusion (e.g., non-operant conditioning-based alcohol preference tests).
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Drug Alcohol Depend. Author manuscript; available in PMC 2016 May 25. Published in final edited form as: Drug Alcohol Depend. 2015 June 1; 151: 284–288.
The rise (and fall?) of drug discrimination research☆ Lance R. McMahon Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, United States
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Drug discrimination has unsurpassed utility among preclinical assays for examining the extent to which CNS-acting drugs share neuropharmacological mechanisms in whole animals. Drugs of abuse were routinely used in the earliest days of drug discrimination. However, over the years the scope of drug discrimination research has extended well beyond drugs of abuse. Any CNS-mediated event that can be repeated consistently, not necessarily drug-induced, has the potential to be trained as a discriminative stimulus. This commentary briefly touches upon the history of drug discrimination research, highlights some useful and novel applications, and discusses its current status in relation to drug self-administration. This commentary is written in part to address the markedly different trajectories of drug discrimination and drug self-administration research, evidenced by a larger number of published scientific papers reporting self-administration data as compared with drug discrimination data. Antecedents and consequences of this disparity are discussed.
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1. History and applications
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Drug discrimination emerged as an experimental approach in the late 1960s and early 1970s. In the earliest experiments conducted by Cathleen Morrison, Herbert Barry, and Francis Colpaert, it was demonstrated that rats could make a “correct” choice depending on the presence versus the absence of the effect of a dose of a drug (Morrison and Stephenson, 1969; Barry, 1974; Colpaert et al., 1975a,b,c). During training animals are presented with a choice between two alternative and mutually exclusive responses (e.g., pressing a left or right lever). The correct response results in delivery of a reinforcer such as food. The correct response is determined by administration of drug or saline beforehand. After administration of a dose of a drug (i.e., the training dose and training drug) the animal can only obtain reinforcers by responding on one of the two levers (e.g., right lever) and the same lever is always paired with the same dose of the same drug. The other lever (e.g., left lever) is always the correct lever following vehicle administration. Incorrect responses do not result in delivery of the reinforcer. Training proceeds until animals reliably make the correct choice, as evidenced by responding on the drug-associated lever after drug administration and the vehicle-lever after vehicle administration. Tests are the same as training sessions except that any dose of any drug can be administered. Moreover, during tests responding on
☆This material is not peer-reviewed by the Journal, but is reviewed prior to publication by the members of the CPDD Publications Committee and invited members of the College. News and Views is edited by the Chair of the CPDD Publications Committee: Gregory M. Miller, Ph.D., Harvard Medical School, New England Primate Research Center, Pine Hill Drive, Southborough, MA 01772, USA.
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either of the two levers results in delivery of a reinforcer or lever-pressing is not reinforced, i.e., tests are conducted under conditions of extinction.
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Drug discrimination has a high degree of selectivity for the primary mechanism by which a training drug produces its neuropharmacological effects in whole animals. For example, when animals that are trained to discriminate the μ opioid agonist fentanyl receive another μ opioid agonist, they respond as though they received fentanyl. In contrast, animals trained to discriminate fentanyl typically do not respond as though they received fentanyl when instead they receive a drug that is not a μ opioid agonist, though there are exceptions. Instead fentanyl-trained animals will respond on the non-drug (e.g., vehicle) associated lever (Colpaert et al., 1975a). The pharmacological selectivity of drug discrimination has been demonstrated for a number of drug classes including abused drugs such as cannabinoids (Balster and Prescott, 1992) and different classes of GABAA receptor-mediated sedative/ hypnotics (Colpaert et al., 1976) as well as non-abused drugs such as the serotonin releasing agent fenfluramine (White and Appel, 1981). Such pharmacological selectivity is highly useful for examining and classifying in vivo pharmacological mechanism(s) of CNS-acting drugs in the whole animal.
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Many CNS-acting drugs, including some abused drugs, bind to multiple receptor sites and have a complex pharmacology. Drug discrimination has been highly useful as a tool for examining the relative importance of multiple receptor sites of action to the in vivo effects of drugs. For example, the stimulants cocaine, amphetamine, and 3,4methylenedioxymethamphetamine (MDMA) bind to membrane-bound, pre-synaptic monoamine transporter proteins to promote the release and/or block the reuptake of monoamine neurotransmitters (Rothman et al., 2001). Drug discrimination has been used to identify not only the relative importance of monoamines, but also the relative contribution of monoamine receptor types to the in vivo effects of stimulants. Drug discrimination assays have been used to dissect the mechanisms of action of other abused drugs with complex pharmacology, including but not limited to alcohol (Grant and Colombo, 1993), gamma hydroxybutyric acid (Carter et al., 2003), and GABAA receptor modulators (Ator and Griffiths, 1983).
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Research programs in academia and private industry have exploited drug discrimination to provide critical early information on the extent to which chemical modeling and in vitro pharmacological profiles translate into whole-animal pharmacology. Richard Glennon and Roger Nichols incorporated drug discrimination in their respective academic research programs into hallucinogenic drugs and the relative contribution of serotonin 5-HT2A and other receptor subtypes to in vivo effects (Glennon and Rosecrans, 1982; Marona-Lewicka and Nichols, 1995). The laboratories of Glennon and Nichols also used drug discrimination to examine relationships between chemical structure, binding at monoamine transporters, and in vivo effects of various stimulants and appetite-suppressants (Schechter and Glennon, 1985; Oberlender and Nichols, 1988). Pre-clinical neuropharmacological research divisions of pharmaceutical companies have similarly relied upon drug discrimination. For example, Synthelabo Recherché Laboratories used drug discrimination to compare and contrast the pharmacology of benzodiazepine-related drugs (Sanger and Zivkovic, 1986). Janssen Pharmaceuticals, primarily through the pioneering efforts of Frances Colpaert, used drug
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discrimination to study a variety of drug classes including opioids, stimulants, hallucinogens, and alpha-adrenergic receptor ligands (Colpaert, 1984). Later at Pierre Fabre, Colpaert and colleagues used drug discrimination to identify serotonin 5-HT1A agonists as part of a program to develop novel analgesics (Kleven and Koek, 1998; Kleven et al., 1997).
2. Using drug discrimination to study the state of an organism
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Unique applications of drug discrimination have involved the study of physical dependence and withdrawal. Holtzmann was among the first of a handful of investigators to demonstrate that the μ opioid antagonist naltrexone could be readily discriminated by animals rendered dependent on morphine (Gellert and Holtzman, 1979). The discriminative stimulus effects of naltrexone in morphine-dependent animals were correlated in time with physical signs of withdrawal. Antagonist-discrimination procedures in drug-dependent animals have been extended to include withdrawal from benzodiazepines (Gerak and France, 1999) and cannabinoid agonists such as Δ9-tetrahydrocannabinol (Stewart and McMahon, 2010). Emmett-Oglesby, Lal, and colleagues used a different approach in studies of dependence and withdrawal: animals were trained to discriminate the GABAA receptor antagonist pentylenetetrazole, which produces convulsions at relatively large doses and anxiety-like behaviors at smaller doses. Abrupt discontinuation of chronic treatment from a variety of drugs including ethanol, GABAA receptor modulators, and nicotine was demonstrated to share discriminative stimulus effects with pentylenetetrazole; these results were interpreted as reflecting anxiety that occurs during drug withdrawal (Emmett-Oglesby et al., 1990).
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Other relatively novel applications have eliminated drugs entirely from discrimination training conditions. Rats have been trained to discriminate between food satiation and food deprivation by Jewett and colleagues. This approach has been used to examine various peptides and neurotransmitters involved in feeding and to identify drugs that potentially modify appetite (Jewett et al., 2009). An early review of drug discrimination suggested possible applications to a variety of other internally mediated events that could be studied in conjunction with drugs such as pain, inflammation, and hypertension (Lal, 1977). Experimental support for the discrimination of pain was provided by a study demonstrating that rats could discriminate aspirin more readily in the presence of chronic pain (Weissman, 1976). However, the full potential of discriminating such internally mediated events has not been realized, perhaps due to the challenges associated with maintaining stability of such stimuli.
3. Drug discrimination as an alternative or adjunct to self-administration in Author Manuscript
abuse liability assessment Self-administration and drug discrimination are complimentary approaches for examining abuse liability and underlying pharmacological mechanisms. Known drugs of abuse can serve as training drugs and then tests can be conducted with novel drugs. Alternatively, a novel drug can be trained and then evaluated by testing known drugs of abuse. In either case, overlapping discriminative stimulus effects suggests that there is the potential for overlapping abuse liability. An example of the use of both approaches involves studies with synthetic analogs of cathinones that are abused in various formulations including products Drug Alcohol Depend. Author manuscript; available in PMC 2016 May 25.
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marketed and sold as “bath salts”. Known drugs of abuse such as MDMA and methamphetamine were demonstrated to substitute when the synthetic cathinone 3,4methylenedioxypyrovalerone (MDPV) was trained (Fantegrossi et al., 2013), whereas MDPV was demonstrated to substitute when either cocaine or amphetamine were used as training drugs (Gatch et al., 2013). Because discriminations of known drugs of abuse can be maintained for several years or more depending on the species, and dose–response functions for drugs can be obtained in a few weeks, drug discrimination can provide rapid feedback on possible abuse liability.
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In non-humans as in humans, some drug classes are not robustly self-administered. Hallucinogens such as lysergic acid diethylamide and 1-(2,5-dimethoxy-4-methylphenyl)-2aminopropane (DOM) are not typically self-administered by non-human species. Drug discrimination has provided an excellent alternative for classifying these and other drugs on the basis of hallucinogenic activity mediated by 5-HT2A receptors. Likewise, cannabinoid agonists are not robustly self-administered in non-humans, although exceptions have been noted, especially in squirrel monkeys (Tanda et al., 2000). Discrimination of Δ9tetrahydrocannabinol has provided an alternative to self-administration for assessing pharmacological actions of Δ9-tetrahydrocannabinol that could mediate both the abuse liability and subjective effects of cannabinoids (Balster and Prescott, 1992). Moreover, drug discrimination has been a valuable resource for assessing the in vivo pharmacology of drugs with unique physicochemical properties. Volatile gasses such as toluene are abused via inhalation and there is no convenient alternative route of administration for pre-clinical studies. Shelton and colleagues have devised methods to precisely control the amount of volatile gas administered to rodents and have used this technology to examine the discriminative stimulus effects of toluene and other volatile gasses (Richardson and Shelton, 2015).
4. Disparity in drug discrimination vs. self-administration publication trends: antecedents and consequences A PUBMED search with the keywords “drug self-administration” yields a much larger number of publications (maximum 1847 in 2013) as compared with the keywords “drug discriminative stimulus” (maximum 117 in 1999). Trends over time have also differed. Hits per year for the keywords “drug self-administration” exhibit a steady increase over time, with 2014 being an exception. Conversely, hits per year for the keywords “drug discriminative stimulus” have been stable or declining for at least 10 years. The disparity is illustrated further in Fig. 1. What are the potential factors and consequences of these trends?
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The popularity of drug self-administration is due in part to a high degree of face validity for drug use and abuse. Without too much trouble one can readily see the similarity between humans engaging in various drug-taking behaviors and animals completing an operant response (e.g., lever press) to obtain drug. Conceptualizing drugs of abuse as reinforcers like food and sex has intuitive appeal. The predictive validity of drug self-administration for drug abuse liability is also better than most other pre-clinical assays. Both humans and nonhumans repeat behaviors that result in the delivery of cocaine, heroin, and ethanol, although
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some drug classes (e.g., hallucinogens and cannabinoids) represent notable exceptions to this general rule of thumb, as noted above. Intuitive appeal for drug abuse also has fostered the popularity of other pre-clinical assays such as place conditioning, in which preference for an environment that had been previously paired with a drug of abuse is measured.
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Reinstatement is an adaptation of intravenous drug self-administration that is considered by some to be a pre-clinical model of relapse. Reinstatement involves removal of intravenous drug delivery by substituting vehicle until lever pressing occurs at very low levels (i.e., extinction). Once extinguished, a variety of stimuli will cause resumption of lever pressing at relatively high levels (i.e., reinstatement) even though the contingency for lever pressing continues to be intravenous vehicle delivery. Stimuli that reinstate lever pressing include non-contingent administration of the drug that had been self-administered as well as presentation of foot shock or another noxious stimulus often referred to as a stressor. Resumption of lever pressing after a period of extinction resembles relapse after a period of abstinence. However, some aspects of reinstatement differ markedly from those of relapse (Katz and Higgins, 2003). Nonetheless, reinstatement accounts for a significant amount of ongoing drug self-administration research.
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The simple face validity of drug self-administration stands in contrast to drug discrimination: what are discriminative stimulus effects? Drug discrimination is often considered to be highly correlative with subjective effects (Schuster et al., 1981; Schuster and Johanson, 1988). However, that interpretation can be misleading. The subjective effects of drugs are private events that define the human experience of drug use. Unlike external events that can be independently described among human observers, the verbal description of the internal events associated with drug use are based solely on the conditioning history and experience of the individual. An individual who reports euphoria after receiving a dose of cocaine potentially has a very different subjective experience from the individual who reports aversion after receiving the same dose of cocaine. Despite these markedly different subjective experiences, both individuals can be trained to reliably perform the same operant behavior after receiving a dose of cocaine and the same distinct operant behavior when receiving vehicle. Both individuals discriminate cocaine, as evidenced by unitary responses, but their subjective description of the cocaine experience is markedly different. Likewise, individuals with a history of opioid and stimulant use will rate the subjective effects of methamphetamine and hydromorphone as being identical on measures of “drug-liking”, yet the drugs do not share discriminative stimulus effects in the same individuals (e.g., Lamb and Henningfield, 1994).
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Stimuli originating outside the organism are transduced by one of the five sensory modalities (e.g., sight, sound, smell, taste, or touch) and the CNS processes that information. A wavelength of light labeled “blue” by humans can be discriminated in the same way that a drug can be discriminated. Behavioral performance associated with discrimination of the blue light generalizes to wavelengths of light that approximate the blue light. As the wavelength diverges from the blue-light training stimulus, animals begin to respond as though they have not been presented with the blue light. In addition to external stimuli transduced by the five sensory modalities, the CNS processes stimuli originating from inside the organism including drugs acting at receptors to alter neurotransmission within the CNS.
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The control that a drug exerts over choice behavior, and the transfer of that control to pharmacologically related drugs, is similar to the control that a given wavelength of light or frequency of tone exerts over choice behavior. However, wavelengths and frequency are discriminated on a unidimensional continuum, whereas drug discrimination is considered to be more complex, comprising multidimensional, qualitatively distinct stimuli (Schuster et al., 1981). All drugs of abuse have discriminative stimulus effects and indeed any CNS-acting drug has the potential to be discriminated. By now hopefully the reader is convinced that drug discrimination has excellent predictive validity for CNS receptor mechanisms in whole animals. Yet drug discrimination lacks face validity for drug abuse or any other human disease or condition, which is arguably a major factor preventing drug discrimination from gaining the same widespread appeal as drug self-administration.
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5. Use of drug self-administration versus drug discrimination in the study of neurobiology Drug self-administration is not only a useful screen for abuse liability, but also has utility for examining the neurobiology of reinforced behavior generally. Drugs of abuse target the same mesocorticolimbic dopamine pathways that also mediate other types of reinforced behavior such as eating and sex. Microinjection of drugs and optogenetic manipulations are examples of approaches that can be used to manipulate and examine brain areas underlying drug selfadministration. Drugs can be self-administered directly into discrete brain regions through indwelling cannula. Drug self-administration research has grown in parallel with the explosion of neuroscience research in the last few decades.
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In contrast to the reasonably well-defined brain circuits implicated in drug-reinforced behavior, brain regions mediating discriminative stimulus effects are largely undefined. Different pharmacological classes have separable discriminative stimulus effects and receptors mediating the diversity of drugs that can be discriminated are located throughout the brain. Multiple brain regions are expected to mediate discriminative stimulus effects and, in fact, localization of a discriminative stimulus effect to a single, discrete brain region or pathway seems unlikely. Moreover, brain regions involved in discrimination are expected to vary from one drug class to another. For example, brain regions mediating discriminative stimulus effects of antidepressants acting at pre-synaptic serotonin and/or norepinephrine transporters are predicted to differ from those mediating the discriminative stimulus effects of heroin and other μ opioid agonists. These are testable hypotheses amenable to the same types of brain manipulation routinely employed in drug self-administration research. Despite the potential involvement of numerous different brain areas in mediating discrimination of various drug classes, widespread appeal for exploring such relationships is lacking. Mice are being increasingly used for intravenous drug self-administration, especially with improvements in techniques for maintaining catheter patency. Mice enable transgenic approaches not currently available in other animal species. Mice are also increasingly used for drug discrimination research, although the results of these drug discrimination experiments in transgenic mice are sometimes difficult to interpret. Mice lacking β2 subunits Drug Alcohol Depend. Author manuscript; available in PMC 2016 May 25.
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of nicotinic acetylcholine receptors were unable to discriminate nicotine from saline (Shoaib et al., 2002), suggesting a critical role for these receptor types in the discriminative stimulus effects of nicotine. However, drug discrimination is often successfully established in transgenic mice, even when deleting receptor types that have been shown to mediate discriminative stimulus effects through pharmacological approaches. For example, dopamine D2 receptor knockout mice can discriminate cocaine, even though D2 receptors mediate the discriminative stimulus effects of cocaine (Chausmer et al., 2002). Thus, deleting a receptor that otherwise mediates the discriminative stimulus effects of a drug does not necessarily prevent discrimination of that drug, indicating that other actions of a drug, potentially at additional receptor types, can produce discriminative stimulus effects. Discrepancies between transgenic and pharmacological approaches are certainly not unique to drug discrimination, however, inasmuch as self-administration of drugs correlates strongly with binding affinity of those drugs at the dopamine transporter (Ritz et al., 1987), yet drug selfadministration is apparently unperturbed in mice lacking dopamine transporters (Rocha et al., 1998).
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One of the consequences of the drug self-administration boom is an increasing lack of appreciation of the complexities of operant conditioning behavior and misinterpretation of self-administration data. Whether or not responding for a drug occurs in greater amounts than for saline (i.e., a drug is self-administered) is a simple enough question. However, there is difficulty interpreting a change in the amount of drug self-administered as a consequence of some manipulation, such as administration of a second drug or an environmental change. Simply put, a sufficient quantity of anything will decrease operant responding for any reinforcer including a drug reinforcer. A reduction in self-administration is often misinterpreted as a decrease in reinforcing effects without first eliminating simpler interpretations (i.e., general suppression of all operant behavior) that can only be rejected by gathering additional, control data. Operant responding for non-drug reinforcers such as food are often used as a control, yet responding for food often occurs at different rates and patterns than responding for drug. Drug-induced changes in operant behavior can vary dramatically as a function of rates and patterns of behavior independent of the reinforcer that maintains behavior (Kelleher and Morse, 1968). The self-administration dose–response function, i.e., the number of lever presses or infusions earned per unit dose expressed as a function of the unit dose, is non-monotonic or characterized by an inverted U shape when the schedule requirement is held constant. Variations such as progressive ratio schedules (Roberts et al., 1989) or procedures involving a choice between drug and another reinforcer such as food (Paronis et al., 2002) have been developed to avoid an inverted U shape dose– response function. However, the entire dose–response function or some portion thereof is often needed to interpret a change in self-administration behavior. Unfortunately, inattention to such complexities has led to frequent misinterpretation of drug self-administration data. There are pitfalls associated with interpretation of drug discrimination data as well. There can be loss of a well-trained animal’s ability to discriminate properly in the presence of some drug types or relatively large doses of drug. Moreover, attenuation of the discriminative stimulus effects of a drug by another can sometimes be due to a perceptual masking phenomenon, rather than to functional or competitive antagonism at the receptor
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level. However, the prevalence of these and other pitfalls is modest given the more restricted use of drug discrimination as compared with self-administration. In summary, the apparent plateau and tendency toward a decline in drug discrimination research is due to a number of factors. The downsizing of pre-clinical neuropharmacological research in private industry has taken its toll. Fewer academic laboratories seem to be conducting drug discrimination research as compared with self-administration research. Hopefully this commentary has touched upon the most important factors underlying this disparity. Drug discrimination has many applications, some tried-and-true and others more novel and unique. Most importantly, drug discrimination continues to be among the best if not the best option for classification and characterization of the mechanism of action of CNS acting drugs in whole animals.
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Fig. 1.
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Data are drawn from a database maintained by Stolerman and colleagues with support from NIDA 1982–2012. Original journal articles, book chapters, whole books, and publically accessible abstracts and research reports are included. The drug discrimination (DD) data were derived primarily from searches of PubMed and PsychInfo. The drug selfadministration (DSA) data were derived from PubMed and manually adjusted to remove citations that did not qualify for inclusion (e.g., non-operant conditioning-based alcohol preference tests).
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