Discriminative Stimulus Properties Of Drugs Research Articles

Drug Discrimination: Historical Origins, Important Concepts, and Principles.

Research on the stimulus properties of drugs began with studies on state dependent learning during the first half of the twentieth century. From that research, an entirely new approach evolved called drug discrimination. Animals (including humans) could discriminate the presence or absence of a drug; once learned, the drug could serve as a discriminative stimulus, signaling the availability or nonavailability of reinforcement. Early drug discrimination research involved the use of a T-maze task, which evolved in the 1970s into a two-lever operant drug discrimination task that is still used today. A number of important concepts and principles of drug discrimination are discussed. (1) The discriminative stimulus properties of drugs are believed in large part to reflect the subjective effects of drugs. While it has been impossible to directly measure subjective effects in nonhuman animals, drug discrimination studies in human subjects have generally supported the belief that discriminative stimulus properties of drugs in nonhuman animals correlate highly with subjective effects of drugs in humans. In addition to the ability of the drug discrimination procedure to measure the subjective effects of drugs, it has a number of other strengths that help make it a valuable preclinical assay. (2) Drug discrimination can be used for classification of drugs based on shared discriminative stimulus properties. (3) The phenomena of tolerance and cross-tolerance can be studied with drug discrimination. (4) Discriminative stimulus properties of drugs typically have been found to be stereospecific, if a drug is comprised of enantiomers. (5) Discriminative stimulus properties of drugs reflect specific CNS activity at neurotransmitter receptors. (6) Both human and nonhuman subjects display individual differences in their sensitivity to discriminative stimuli and drugs. (7) The drug discrimination procedure has been used extensively as a preclinical assay in drug development. This chapter is the first in the volume The Behavioural Neuroscience of Drug Discrimination, which includes chapters concerning the discriminative stimulus properties of various classes of psychoactive drugs as well as sections on the applications and approaches for using this procedure.

The Discriminative Stimulus Properties of Drugs Used to Treat Depression and Anxiety.

Drug discrimination is a powerful tool for evaluating the stimulus effects of psychoactive drugs and for linking these effects to pharmacological mechanisms. This chapter reviews the primary findings from drug discrimination studies of antidepressant and anxiolytic drugs, including novel pharmacological mechanisms. The stimulus properties revealed from these animal studies largely correspond to the receptor affinities of antidepressant and anxiolytic drugs, indicating that subjective effects may correspond to either therapeutic or side effects of these medications. We discuss drug discrimination findings concerning adjunctive medications and novel pharmacologic strategies in antidepressant and anxiolytic research. Future directions for drug discrimination work include an urgent need to explore the subjective effects of medications in animal models, to better understand shifts in stimulus sensitivity during prolonged treatments, and to further characterize stimulus effects in female subjects. We conclude that drug discrimination is an informative preclinical procedure that reveals the interoceptive effects of pharmacological mechanisms as they relate to behaviors that are not captured in other preclinical models.

Application of the conditioned taste aversion paradigm to assess discriminative stimulus properties of psychostimulants in rats

BackgroundThe conditioned taste aversion (CTA) paradigm is one of the reliable methods to evaluate the discriminative stimulus properties of drugs and is characterized by a short conditioning period and no need for special equipment. This method, however, has not yet been fully investigated for psychostimulants such as cocaine and methamphetamine. MethodsIn the present study, rats were trained to discriminate between cocaine and a vehicle using CTA and substitution tests with various psychostimulants were conducted to evaluate the usefulness of the method for assessing the discriminative stimulus properties of this pharmacological class. Male rats received an intraperitoneal (i.p.) injection of cocaine (10mg/kg) 10min prior to access saccharin for 20-min, and immediately after the saccharin access they received an i.p. dose of LiCl (1.8mEq; n=8, Group CL) or the vehicle (n=8, Group CW) on the day of conditioning; on the other days (2 or 3 days between the cocaine conditioning days), they were injected with saline prior to access to saccharin without the LiCl or vehicle injection after the access. ResultsBy the fifteenth cocaine conditioning trial, all animals acquired discrimination. In the substitution test, cocaine dose dependently decreased saccharin consumption. The psychostimulants, methamphetamine, methylphenidate, bupropion and sibutramine, substituted for cocaine, whereas the opioid μ agonist morphine and the cannabinoid agonist, Δ9-tetrahydrocannabinol, did not substitute for cocaine. Mazindol did not substitute for cocaine although it has CNS stimulant activities. ConclusionThese results suggest that discriminative stimulus properties of psychostimulants can be evaluated using the CTA paradigm.

Drug discrimination: 30 years of progress

EditorialThe publication of this Special Issue of Psychopharmacol-ogy on the Stimulus Properties of Drugs marks the 30-yearanniversary in 2008 of the founding of the Society forStimulus Properties of Drugs (SSPD). As previouslydescribed by the society’s first three presidents (see Overtonet al. 1999), the decision to create an organization ofresearchers interested in the discriminative stimulus prop-erties of drugs occurred at a meeting in 1978 of theFederation of American Societies for Experimental Biology(FASEB). The first official meeting of SSPD was held a fewmonths later on June 3, 1978 in conjunction with themeeting of the Committee for Problems on Drug Depen-dence (CPDD) in Baltimore, MD, USA. SSPD has metannually since then and SSPD’s 30th anniversary meetingwas held on November 14, 2008 as a satellite meeting at themeeting of the Society for Neuroscience in Washington, D.C.In addition to the annual national meetings of thesociety, a number of international meetings have been heldsince 1978 with the most recent being in 2005 as a satellitemeeting of the European Behavioral Pharmacology Societyin Barcelona, Spain. There also have been a number ofbooks (often based on these symposia) on the stimulusproperties of drugs published over the years (Colpaert andBalster 1988, Colpaert and Slangen 1982, Glennon et al.1991, Lal 1977, Thompson and Pickens 1971) as well as acollection of articles in Volume 64 (No. 2) of Pharmacol-ogy, Biochemistry and Behavior in 1999.What are the stimulus properties of drugs?A very basic definition of a stimulus is something thataffects an organism by causing a response. In experimentalpsychology, stimuli have traditionally been such things astones, lights, etc., and typically, a laboratory situationwould be set up to assess changes in responding thatoccurred when changes in the stimulus were produced. Astimulus is generally defined by its characteristics, orproperties, and again, in a traditional sense, stimulusproperties would consist of such things as the frequencyof a tone or the intensity of a light. Clearly, drugs also canserve as stimuli and the properties of drug stimuli aremediated by the drug’s biological actions on the centralnervous system (e.g., functioning as an agonist or anantagonist at a specific neurotransmitter receptor). Much ofthe early research on the stimulus properties of drugs usedthe state-dependent paradigm (Overton 1974), but in the1970s the drug discrimination paradigm was developed (seereview by Colpaert 1999). As Colpaert (1999) describes(and the articles in this Special Issue mirror), the drugdiscrimination paradigm has largely replaced the state-dependent paradigm in the study of the stimulus propertiesof drugs. As Balster (1988)states,“One of the majorconceptual advances in behavioral pharmacology was theappreciation that drug effects could subserve stimulusproperties in stimulus–response learning theory.” Balsteralso points out that the first major recognition that drugscould function as stimuli and produce responses in organ-isms was in a collection of articles from the proceedings of a

Gender differences in response to lorazepam in a human drug discrimination study

Gender differences in the discriminative stimulus properties of drugs of abuse have sometimes been reported, although we have previously found no differences in subjective or discriminative responses in human subjects acquiring an alcohol discrimination. The aim of the present work was to determine if there were gender differences in the effects of lorazepam, a benzodiazepine-receptor agonist which substituted for the alcohol stimulus in trained social drinkers. Volunteers who had already acquired an alcohol (0.2g/kg) placebo discrimination were administered (double-blind) either placebo (nine females, nine males) or lorazepam 2mg (six females, six males). They then sampled a series of five drinks and rated each one for likeness to the training stimulus (the generalization response). In addition they completed rating scales for subjective effects and the Digit Symbol Substitution Test (DSST). Lorazepam substituted for the alcohol stimulus equally in both sexes and increased associated scores for lightheadedness. Females however, showed a much greater DSST performance impairment following lorazepam, compared with males. This effect was independent of body weight differences and sedation. These results are discussed in the light of current knowledge of gender differences in response to drugs of abuse and suggest that the stimulus and cognitive effects of benzodiazepine-receptor agonists are modulated by different brain mechanisms.

Reinforcement frequency, but not gender, determines sensitivity,to discriminative discriminative stimulus effects of. morphine

We demonstrated previously that several parameters of a morphine discrimination were significantly different in female versus male rats, using a fixed ratio (FR)-10 schedule of food reinforcement; however, this schedule produced a significant bias in reinforcement frequency between saline and morphine sessions in males but not in females. To determine whether this schedule-drug-sex interaction caused the sex difference in discriminability of morphine, female and male rats were trained to discriminate 3.0 mg/kg morphine from saline using a variable interval (VI) 15-s/VI 15-s (Phase I), a VI 7.5-s/VI 15-s (Phase II), and a VI 15-s/VI 15-s (Phase III) schedule of food reinforcement on morphine/saline levers, respectively. After a minimum of 40 training sessions in each phase, mean reinforcement rates in morphine sessions were highest, and the ED50 values for morphine discrimination were lowest, in Phase II. Thus, as predicted, the morphine dose-effect curves shifted to the left from Phase I to Phase II, and back to the right from Phase II to III, presumably due to the bias in reinforcement rate between saline and morphine sessions that was induced by manipulating the VI schedule on the morphine lever. However, there were no sex differences in the morphine versus saline reinforcement rate or in discrimination ED50 in any phase, suggesting that the sex difference observed in our initial study was probably due to the bias in reinforcement frequency (towards the saline condition) that occurred only in males under the FR-10 schedule. This study demonstrates the importance of considering group differences in schedule-drug interactions when comparing discriminative stimulus properties of drugs between groups.

Effects of food deprivation and satiation on sensitivity to the discriminative-stimulus effects of pentobarbital in pigeons and morphine in rats

Food deprivation can produce a substantial increase in the self-administration of drugs of abuse, suggesting that food deprivation increases their reinforcing properties. This finding has been replicated with a wide variety of reinforcing drugs. The present experiments examined the effects of food deprivation and satiation on the discriminative stimulus properties of drugs, to determine whether food deprivation affects the discriminative-stimulus effects of drugs in a similar manner. Using pigeons that were trained to discriminate 5mg/kg i.m. pentobarbital from saline, dose-effect curves were determined under both food-deprivation conditions (80% free-feeding body weight) and partial food-satiation conditions (25% and 50% of the amount of full satiation). It was found that generalization curves for both pentobarbital and saline were similar at all levels of food deprivation. In a second set of experiments, rats were trained to discriminate 10mg/kg i.p. morphine from saline, and the discriminative properties of morphine were then tested when the animals were either food-deprived or after a 15min supplemental feeding. The ED(50) value for the food-deprived condition was comparable to that the food-satiated condition (3.6 vs. 4.8mg/kg, respectively). Thus, in both pigeons and rats, there was little evidence that food deprivation increased sensitivity to the discriminative stimulus properties of drugs. Thus, food deprivation must increase drug self-administration by a mechanism other than by increasing the discriminative stimulus properties of self-administered drugs.

Behavioral and pharmacological influences on phencyclidine discrimination in the pigeon

Discriminative stimuli produced by drugs control behavior in the same way as exteroceptive discriminative stimuli control behavior, despite the difficulty in controlling the intensity of the discriminative stimulus properties of drugs throughout test sessions. In recent years, many investigators have correlated the potency of drugs as discriminative stimuli, with their affinity for specific pharmacological receptors. High correlations have been interpreted as evidence that the discriminative stimulus properties of drugs are mediated by these specific pharmacological receptors. However, the relationship between discriminative stimulus potency and receptor affinity can be confounded by other pharmacological effects of drugs, such as their ability to produce position responding, and by behavioral variables, such as the schedule of reinforcement under which the drug discrimination is established and measured.

Agonist and antagonist effects of prototype opiate drugs in fentanyl dose-dose discrimination.

The experiments characterized the effects of fentanyl, morphine, naloxone, cyclazocine, nalorphine, ketocyclazocine and N-allylnormetazocine in rats that were trained to discriminate 0.04 mg/kg from 0.02 mg/kg fentanyl (dose-dose discrimination). The data are compared to results obtained previously in rats discriminating 0.04 mg/kg fentanyl from saline (drug-saline discrimination). In the dose-dose discrimination fentanyl and morphine produced responding appropriate to 0.04 mg/kg fentanyl at doses which were 3.0- and 1.6-fold higher, respectively, than in drug-saline discrimination. Naloxone antagonized the stimulus effects of 0.04 mg/kg fentanyl at 9.8-fold lower doses than in drug-saline discrimination. The dose-effect curves of fentanyl and naloxone in rats discriminating 0.04 mg/kg from 0.02 mg/kg fentanyl, were steeper than in rats discriminating 0.04 mg/kg fentanyl from saline. While cyclazocine, nalorphine and N-allylnormetazocine acted as mixed and partial agonists/antagonists in drug-saline discrimination, those compounds acted as pure and complete antagonists of 0.04 mg/kg fentanyl in dose-dose discrimination. The rank order of compounds in antagonizing the stimulus effects of 0.04 mg/kg fentanyl in dose-dose discrimination was naloxone greater than N-allylnormetazocine greater than cyclazocine greater than nalorphine. It is suggested that a greater magnitude of opiate activity is required for producing generalization with the same 0.04 mg/kg dose of fentanyl in dose-dose as compared with drug-saline discrimination. Dose-dose discrimination may afford a more accurate method of the discriminative stimulus properties of drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

An experimental paradigm for studying the discriminative stimulus properties of drugs in humans

An experimental paradigm for studying the discriminative stimulus effects of drugs in human subjects is presented. The paradigm was tested by training subjects to discriminate 10 mg d-amphetamine from placebo. Subjects who successfully learned the discrimination were then tested with two lower doses of d-amphetamine and with 10 mg diazepam. The discriminative stimulus properties of d-amphetamine were dose-dependent, and in two of five subjects the d-amphetamine stimulus generalized to diazepam. The simplicity and versatility of the paradigm give it the potential for use in a wide variety of experimental and clinical situations.

Discriminative stimulus properties of drugs: a brief history and a selective review.

A brief history of the background of drug discrimination research is given, focusing on the concepts of “drug dissociation” or state‐dependent learning; an alternative explanation to the state dependency concept is to view the drug as a discriminative stimulus. In drug discrimination learning both a qualitative and a quantitative dimension is identified as governing the discrimination, examples of which are provided in the text. Examples of how drug discrimination techniques may assist in future research are outlined.

A procedure for rapidly evaluating the discriminative stimulus properties of drugs: Seymore Herling, R. Young Hampton, Albert J. Bertalmio, Gail Winger, and James H. Woods, Departments of Pharmacology and Psychology, University of Michigan, Ann Arbor MI 48109.

A procedure for rapidly evaluating the discriminative stimulus properties of drugs: Seymore Herling, R. Young Hampton, Albert J. Bertalmio, Gail Winger, and James H. Woods, Departments of Pharmacology and Psychology, University of Michigan, Ann Arbor MI 48109.

Discriminative Stimulus Properties of Drugs

Back to table of contents Previous article Next article ArticleNo AccessDiscriminative Stimulus Properties of DrugsDANIEL S.P. SCHUBERTDANIEL S.P. SCHUBERTSearch for more papers by this authorPublished Online:1 Apr 2006https://doi.org/10.1176/ajp.135.4.515AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail "Discriminative Stimulus Properties of Drugs." American Journal of Psychiatry, 135(4), p. 515 Access content To read the fulltext, please use one of the options below to sign in or purchase access. Personal login Institutional Login Sign in via OpenAthens Purchase Save for later Item saved, go to cart PPV Articles - American Journal of Psychiatry $35.00 Add to cart PPV Articles - American Journal of Psychiatry Checkout Please login/register if you wish to pair your device and check access availability. Not a subscriber? Subscribe Now / Learn More PsychiatryOnline subscription options offer access to the DSM-5 library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development. Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.). FiguresReferencesCited byDetailsCited ByNone Volume 135Issue 4 April 1978Pages 515-515 Metrics PDF download History Published online 1 April 2006 Published in print 1 April 1978

Theoretical and methodological considerations on drug discrimination learning.

A method is described which allows the assessment of discriminative stimulus properties of drugs, and the ability of amphetamine (0.16 mg/kg s.c.), chlordiazepoxide (5 mg/kg p.o.), desipramine (5 mg/kg s.c.), and haloperidol (0.02 mg/kg s.c.) to produce a discriminative stimulus complex (DSC) is evidenced. The method is found to yield clear-cut data that are specifically related to drug discrimination learning without being possibly confounded by state dependent effects. In addition, the experimental procedure is designed so as to provide an appropriate measurement of operant response modulating drug effects.