Drug Discrimination in Neurobiology

doi:10.1016/S0091-3057(99)00047-7

Pharmacology Biochemistry and Behavior

Volume 64, Issue 2, October 1999, Pages 337-345

https://doi.org/10.1016/S0091-3057(99)00047-7 Get rights and content

Abstract

Areas of neurobiological interest are identified towards which drug discrimination (DD) studies have made important contributions. DD allows ligand actions to be analyzed at the whole organism level, with a neurobiological specificity that is exquisite and often unrivalled. DD analyses have thus been made of a vast array of CNS agents acting on receptors, enzymes, or ion channels, including most drugs of abuse. DD uniquely offers access to the study of subjective drug effects in animals, using a methodology that also is transposable to humans and has generated unprecedented models of pathology (e.g., chronic pain, opiate addiction). Parametric studies of such independent variables as training dose and reinforcement provide refined insights into the dynamic psychophysiological mechanisms of both drug effects and behavior. Three different mechanisms have been identified by which discriminative, and perhaps other behaviors, can come about. DD also is superbly sensitive to small, partial activation of molecular substrates; this has enabled DD analyses to pioneer the unravelling of molecular mechanisms of drug action (attributing, f.ex., LSD's particular subjective effects to an unusual, partial activation of 5-HT, and perhaps other receptors). DD has both oriented and served as a tool to conduct drug discovery research (e.g., pirenperone-risperidone, loperamide). The DD response arguably constitutes a quantal, rather than graded, variable, and as such allows a comprehension of molecular, pharmacological, and behavioral mechanisms that would have been otherwise inaccessible. Perhaps most important are the following further contributions. One is the notion that particular, different levels of receptor activation are associated with qualities of neurobiological actions that also differ and are unique, this notion arguably constituting the most significant addition to affinity and intrinsic activity since the earliest theoretical conceptions of molecular pharmacology. Another contribution consists of studies that render redundant the notion of tolerance and identify fundamental mechanisms of signal transduction; these mechanisms account for apparent tolerance, dependence, addiction, and sensitization, and appear to operate ubiquitously in a bewildering array of biological systems.

Section snippets

The dd paradigm

In a typical DD experiment, animals are trained to discriminate the injection of a particular dose (the training dose) of a particular drug (the training drug; D) from the injection of saline (S). For example (19), food-deprived rats can be trained to press one of two levers for food in daily 15-min sessions; arrangements are made so that, at some time before the sessions, the animals are injected with either D or S. After D injection, the animal is required to press one lever (the drug lever,

Neurobiological specificity

Early DD studies utilizing opiate training drugs revealed the paradigm to demonstrate exquisite molecular specificity. Thus, rats trained to discriminate fentanyl or morphine from saline showed orderly dose-dependent generalization with lower doses of the training drug and with other compounds that were known to act as agonists at opiate receptors 13, 14, 140. This generalization was antagonized by naloxone and other putative opiate antagonists. The generalization also displayed the

An in vivo technique of neuropharmacology

The specificity and the further features, discussed below, of the DD paradigm, have made of DD a now widely used technique of behavioral pharmacology, assaying at a whole organism level of analysis various ligands that act at such molecular substrates as ion channels, enzymes and, in particular, the seemingly unlimited diversity of neurotransmitter receptor types and subtypes. Among the ligands that have been studied as such are the CNS stimulants cocaine and amphetamine 39, 84, inhibitors of

Subjective effects and drug abuse

Although in the previous section we have found DD to be a particularly valuable technique of neuropharmacological research, the drug-produced discriminative stimulus, in the first instance, constitutes a special physiological phenomenon. The definitive identification of this phenomenon will likely require many more years of more sophisticated research, but early studies of opiates 13, 14, 24 have provided initial evidence that drug-produced discriminative effects ar homologous to the

Modelling pathology

As indicated above, the DD paradigm makes subjective drug effects accessible for empirical, experimental research. This unique feature also confers on the DD paradigm an equally unique capability to model certain pathologies in terms of the subjective experience with which they are associated.

Of all human pathology, pain arguably represents the one instance where the suffering is most comprehensively defined by subjective perception. Indeed, pain in essence is a subjective experience (113), and

Psychophysiology of subjective perception

The DD paradigm thus appears to offer an experimental access to the subjective experience, or perception, of stimuli that are produced by drugs or that arise from other, physiologically defined, but invariably internal conditions 19, 26. In this capacity, DD studies have begun to provide insights into the psychophysiology of subjective perception. Among the factors (53) that have been found to determine the subjective perception are training dose [for review, see (58)] and discriminability (41)

Mechanisms of behavior

In the DD paradigm one typically manipulates, as an independent variable, some (training) drug acting on a particular molecular substrate (e.g., the opiate fentanyl); and one physically measures as the dependent variable, some behavior such as food-rewarded lever pressing (19). The DD paradigm thus also is a paradigm of behavioral pharmacology and in that capacity allows one to address the question as to how behaviors can come about. More specifically, the paradigm allows, at least in

The third dimension of molecular pharmacology

Early studies (20) found the DD paradigm to be superbly sensitive to the effects of opiate receptor ligands possessing only weak or partial efficacy. Experimental 39, 48, 52 and theoretical analyses 51, 55, 101 of the partial generalization and of the other, complex, effects that partial receptor agonists produce in the DD paradigm have discovered an exceptionally interesting and important phenomenon. In essence, the phenomenon signifies that a particular magnitude of receptor activation is

Molecular and cellular mechanisms of drug action

The notion, derived from studies of opiates, that a particular magnitude of receptor activation may generate a particular, unique, quality of subjective experience, has made us analyze LSD's molecular actions in this light. It appeared 40, 45 that agents then known as 5-HT antagonists, partially antagonized LSD's DS effects, but also produced partial generalization, the sum of these partial antagonist and agonist effects amounting to about 100%. A parsimonious account of these findings is that

Drug discovery

Because the DD paradigm enables one to unravel molecular, cellular, and psychophysiological mechanisms of drug action, it comes as no surprise that DD has been deployed as a tool in drug discovery research. But even more than a tool, DD has had a unique role in the conceptualization of novel drug treatments. The concept that LSD's particular, hallucinogenic effects may derive from a partial activation of 5-HT receptors, and the finding that none of the then available ligands was silent enough

Tolerance and signal transduction

One early and most remarkable finding has been that tolerance does not develop to opiate drug discrimination 17, 31. Although many other investigators have unanimously claimed that tolerance does develop (164), and while the matter has long remained controversial, a recent detailed analysis of the data (58) found no evidence to substantiate the development of tolerance.

If, as we argued, tolerance does not develop to opiate DD, and given that opiate DD emanates with exquisite specificity from

Drug discrimination: a paradigm of neurbiology

From this brief, cursory overview it would seem that DD over the past several decades has been, and in the future will continue to be, a particularly powerful paradigm of neurobiological research. More than simply constituting another technique of behavioral pharmacology or of neuropharmacology, DD studies have truly made pioneering contributions to such fundamental areas as partial receptor activation and signal transduction. By the very nature of its subject matter, the DD paradigm makes

Acknowledgements

This article is dedicated to the memory of Dr. Carlos J. E. Niemegeers.

References (166)

C.L Amrick et al.
N-Methyl-d-aspartate produces discriminative stimuli in rats
Life Sci.
(1987)
R.L Balster
Abuse potential evaluation of inhalants
Drug Alcohol Depend.
(1987)
R.J Barrett et al.
Drug discrimination in ratsEvidence for amphetamine-like cue state following chronic haloperidol
Pharmacol. Biochem. Behav.
(1983)
M Bartoletti et al.
Time-dependent generalization of morphine stimulus properties to meperidineAntagonism by naloxone
Pharmacol Biochem. Behav.
(1989)
D.A Bennett et al.
Discriminative stimulus properties of the vasodilator, hydralazineDifferential generalization with alpha-one and alpha-two adrenoreceptor drugs
Prog. Neuropsychopharmacol. Biol. Psychiatry
(1982)
F.C Colpaert et al.
Apomorphine as a discriminative stimulus, and its antagonism by haloperidol
Eur. J. Pharmacol.
(1975)
F.C Colpaert et al.
Discriminative stimulus properties of benzodiazepines, barbiturates and pharmacologically related drugs; Relation to some intrinsic and anticonvulsant effects
Eur. J. Pharmacol.
(1976)
F.C Colpaert et al.
Discriminative stimulus properties of fentanyl and morphineTolerance and dependence
Pharmacol. Biochem. Behav.
(1976)
F.C Colpaert et al.
Blockade of apomorphine's discriminative stimulus propertiesRelation to neuroleptic activity in neuropharmacological and biochemical assays
Pharmacol. Biochem. Behav.
(1976)
F.C Colpaert et al.
Fentanyl and apomorphineAsymmetrical generalization of discriminative stimulus properties
Neuropharmacology
(1976)

J.L Altman et al.

Drugs as discriminable events in humans

Ariëns, E. J.: The mode of action of biologically active compounds. In: Molecular pharmacology, vol. 1. New York:...

R.J Barrett et al.

Tolerance, withdrawal and supersensitivity to dopamine mediated cues in a drug-drug discrimination

Psychopharmacology (Berlin)

(1992)

H.I Barry et al.

Discriminable stimuli produced by alcohol and other CNS depressants

A.J Bertalmio et al.

Differentiation between mu and kappa receptor mediated effects in opioid drug discriminationApparent pA2 analysis

J. Pharmacol. Exp. Ther.

(1987)

W.K Bickel et al.

Opioid drug discrimination in humansStability, specificity and relation to self-reported drug effect

J. Pharmacol. Ther.

(1989)

V.L Coffin et al.

Behavioral pharmacology of adenosine analogs

F.C Colpaert et al.

Investigations on drug produced and subjectively experienced discriminative stimuli. 1. The fentanyl cue, a tool to investigate subjectively experienced narcotic drug actions

Life Sci.

Methylnaltrexone crosses the blood-brain barrier and attenuates centrally-mediated behavioral effects of morphine and oxycodone in mice
2021, Neuropharmacology
Citation Excerpt :
Perhaps the most compelling behavioral evidence of MNTX acting centrally involved results from oxycodone discrimination tests. It is well-established that the discriminative stimulus properties of drugs are mediated by the CNS (Colpaert, 1999). In the present study, MNTX antagonized oxycodone's discriminative stimulus effects in a dose- and time-dependent manner.
Antagonism of peripheral opioid receptors by methylnaltrexone (MNTX) was recently proposed as a potential mechanism to attenuate the development of opioid analgesic tolerance based on experiments conducted in mice. However, reports indicate that MNTX is demethylated to naltrexone (NTX) in mice, and NTX may subsequently cross the blood-brain barrier to antagonize centrally-mediated opioid effects. The goal of this study was to determine whether MNTX alters centrally-mediated behaviors elicited by the opioid analgesics, morphine and oxycodone, and to quantify concentrations of MNTX and NTX in blood and brain following their administration in mice.
Combinations of MNTX and morphine were tested under acute and chronic conditions in thermal nociceptive assays. Effects of MNTX and NTX pretreatment were assessed in an oxycodone discrimination operant procedure. Blood and brain concentrations of these antagonists were quantified after their administration using liquid chromatography-mass spectrometry.
MNTX dose-dependently attenuated acute and chronic morphine antinociception. MNTX and NTX dose-dependently antagonized the discriminative stimulus effects of oxycodone. MNTX and NTX were detected in both blood and brain after administration of MNTX, confirming its demethylation and demonstrating that MNTX itself can cross the blood-brain barrier.
These results provide converging behavioral and analytical evidence that MNTX administration in mice attenuates centrally-mediated effects produced by opioid analgesics and results in functional concentrations of MNTX and NTX in blood and brain. Collectively, these findings indicate that MNTX cannot be administered systemically in mice for making inferences that its effects are peripherally restricted.
Substances of abuse
2020, Information Resources in Toxicology, Volume 1: Background, Resources, and Tools
The nonmedical use of legal prescription drugs by healthy subjects has increased tremendously during the last decades, particularly in young people. The health concerns regarding potential addiction to these prescription drugs have created an increased awareness for both the pharma industry and governmental agencies worldwide toward more profound investigation of the abuse potential of all medicinal drug candidates in development (irrespective of their therapeutic indication) whenever they exert an activity in the brain.
The drug licensing authorities have therefore released distinct guidances on the investigation of the abuse potential of drug candidates and on the evaluation and labeling of abuse deterrent opioids.
Driven by these guidelines, the pharma industry is being coerced into taking increased responsibility to identify in more detail the abuse potential of new CNS-active drug candidates in development, primarily to protect the patient who will use this medication as prescribed, but also to prohibit, in every conceivable way, the possibility of abuse practices within the healthy population.
As such, an extensive Abuse Liability Assessment must be submitted to the regulatory agencies, consisting of preclinical investigations of the physical dependence and of the rewarding and reinforcing properties of new CNS-active drug candidates, but also including consequences at the clinical, regulatory, and final product form level and the subsequent scheduling as controlled substances (DEA).
This chapter provides resources on regulatory guidances worldwide and preclinical designs to study the abuse potential of novel drug candidates.
Evaluating the abuse potential of psychedelic drugs as part of the safety pharmacology assessment for medical use in humans
2018, Neuropharmacology
Psychedelics comprise drugs come from various pharmacological classes including 5-HT_2A agonists, indirect 5-HT agonists, e.g., MDMA, NMDA antagonists and κ-opioid receptor agonists. There is resurgence in developing psychedelics to treat psychiatric disorders with high unmet clinical need. Many, but not all, psychedelics are schedule 1 controlled drugs (CDs), i.e., no approved medical use. For existing psychedelics in development, regulatory approval will require a move from schedule 1 to a CD schedule for drugs with medical use, i.e., schedules 2–5. Although abuse of the psychedelics is well documented, a systematic preclinical and clinical evaluation of the risks they pose in a medical-use setting does not exist. We describe the non-clinical tests required for a regulatory evaluation of abuse/dependence risks, i.e., drug-discrimination, intravenous self-administration and physical dependence liability. A synopsis of the existing data for the various types of psychedelics is provided and we describe our findings with psychedelic drugs in these models. FDA recently issued its guidance on abuse/dependence evaluation of drug-candidates (CDER/FDA, 2017). We critically review the guidance, discuss the impact this document will have on non-clinical abuse/dependence testing, and offer advice on how non-clinical abuse/dependence experiments can be designed to meet not only the expectations of FDA, but also other regulatory agencies. Finally, we offer views on how these non-clinical tests can be refined to provide more meaningful information to aid the assessment of the risks posed by CNS drug-candidates for abuse and physical dependence.
This article is part of the Special Issue entitled ‘Psychedelics: New Doors, Altered Perceptions’.
Nociceptin/orphanin FQ receptors modulate the discriminative stimulus effects of oxycodone in C57BL/6 mice
2018, Drug and Alcohol Dependence
Citation Excerpt :
The subjective effects of a drug are a predictor of its likelihood to be misused and can be modeled in animals using drug discrimination methodology. Drug discrimination affords remarkable in vivo pharmacological specificity, has aided in understanding the neurological mechanisms mediating a wide variety of behaviorally active substances (Colpaert, 1999), and is one of the principal preclinical approaches relevant to assessing abuse liability (Balster, 1991). Despite its widespread use for medicinal and recreational purposes, oxycodone has received little attention in this procedure.
Nociceptin/orphanin FQ (NOP) receptor ligands have shown efficacy as putative analgesics and can modulate the abuse-related effects of opioids, suggesting therapeutic applications. The discriminative stimulus effects of a drug are related to their subjective effects, a predictor of abuse potential. To determine whether activation of NOP receptors could alter the subjective effects of an abused opioid analgesic, a novel oxycodone discrimination was established in mice, characterized with positive and negative controls, and its expression evaluated with a NOP receptor agonist.
Adult male C57BL/6 mice were trained to discriminate 1.3 mg/kg oxycodone from vehicle in a two-lever operant procedure. The discrimination was characterized with naloxone challenge, and generalization tests with the μ-opioid receptor agonists, heroin and morphine, and the κ-opioid receptor selective agonist, U50488. Subsequently, effects of the NOP agonist Ro64-6198 were evaluated with and without oxycodone.
Oxycodone generalization occurred in a dose-dependent manner and was reversed by naloxone pretreatment. Heroin and morphine, but not U50488, substituted for oxycodone. Co-treatment of 1 mg/kg Ro64-6198 with the oxycodone training dose reduced % oxycodone lever responding (%OLR) and restored response rates to vehicle control levels. J-113397, a NOP antagonist, reversed these effects. Co-administration of 1 mg/kg Ro64-6198 with a range of oxycodone doses resulted in rightward dose-effect curve shifts in %OLR and response rates compared to oxycodone alone.
These results provide additional evidence that NOP receptor activation can modulate the subjective effects of opioid analgesics and represent the first characterization of oxycodone’s discriminative stimulus effects in mice.
Mu-opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) receptor activation both contribute to the discriminative stimulus properties of cebranopadol in the rat
2018, Neuropharmacology
The novel potent analgesic cebranopadol is an agonist at nociceptin/orphanin FQ peptide (NOP) and classical opioid receptors, with the highest in-vitro activity at NOP and mu-opioid peptide (MOP) receptors, and somewhat lower activity at kappa-opioid peptide (KOP) and delta-opioid peptide (DOP) receptors. We addressed the question of which of these pharmacological activities contribute to the stimulus properties of cebranopadol using a rat drug discrimination procedure. First, cebranopadol was tested in generalization tests against a morphine cue, including receptor-specific antagonism. Second, cebranopadol was established as a cue, and MOP, NOP, KOP and DOP receptor-selective agonists were tested in generalization tests. Third, cebranopadol in combination with receptor-selective antagonists was tested against the cebranopadol cue. Cebranopadol generalized to the morphine cue. Full generalization was only seen at clearly supra-analgesic doses. The effect of cebranopadol was reduced by naloxone, but was enhanced by the NOP receptor antagonist J-113397. In cebranopadol-trained rats, cebranopadol as well as morphine produced generalization. A NOP receptor agonist did not, while a DOP receptor agonist and a KOP receptor agonist weakly generalized to the cebranopadol cue. Conversely, generalization of cebranopadol was reduced by naloxone and J-113397, but not by a DOP or a KOP receptor antagonist. These results suggest a contribution of MOP receptor activity and a relative lack of contribution of DOP and KOP receptor activity to cebranopadol's stimulus properties. The findings regarding the contribution of NOP receptor activity were equivocal, but interestingly, the morphine-like stimulus property of cebranopadol appears to be reduced by its intrinsic NOP receptor activity.
Interoceptive Stimulus Effects of Drugs of Abuse
2018, Neural Mechanisms of Addiction
There has been an increasing interest in the role of interoception in drug addiction. Work in this area has largely come from two different directions. The first direction being from altered neural activity in individuals with substance use disorders that impairs emotional processing. Thus, physiological changes caused by drugs or drug-associated stimuli are interpreted in ways that evoke drug cravings, thereby driving enhanced drug seeking. The second direction being from the study of operant and Pavlovian conditioning processes. Here, drug effects are conceptualized as interoceptive stimuli that acquire control over behavior. Such learned alterations involving drug stimuli come to guide drug-related behaviors that affect risk and abuse liability. This chapter delves into the point at which these approaches appear to be converging, and discusses where we are in our understanding today and how this research may inform improved therapeutic techniques.

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ArticlesDrug Discrimination in Neurobiology

Abstract

Section snippets

The dd paradigm

Neurobiological specificity

An in vivo technique of neuropharmacology

Subjective effects and drug abuse

Modelling pathology

Psychophysiology of subjective perception

Mechanisms of behavior

The third dimension of molecular pharmacology

Molecular and cellular mechanisms of drug action

Drug discovery

Tolerance and signal transduction

Drug discrimination: a paradigm of neurbiology

Acknowledgements

Life Sci.

Drug Alcohol Depend.

Pharmacol. Biochem. Behav.

Pharmacol Biochem. Behav.

Prog. Neuropsychopharmacol. Biol. Psychiatry

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Neuropharmacology

Eur. J. Pharmacol.

Life Sci.

Pharmacol. Biochem. Behav.

Neuropharmacology

Neuropharmacology

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Neuropharmacology

Neuropharmacology

Eur. J. Pharmacol.

Behav. Brain Res.

Neurosci. Biobehav. Rev.

Neuropharmacology

Pharmacol. Biochem. Behav.

Life Sci.

Pharmacol. Biochem. Behav.

Life Sci.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Drugs as discriminable events in humans

Tolerance, withdrawal and supersensitivity to dopamine mediated cues in a drug-drug discrimination

Psychopharmacology (Berlin)

Discriminable stimuli produced by alcohol and other CNS depressants

Differentiation between mu and kappa receptor mediated effects in opioid drug discriminationApparent pA2 analysis

J. Pharmacol. Exp. Ther.

Opioid drug discrimination in humansStability, specificity and relation to self-reported drug effect

J. Pharmacol. Ther.

Behavioral pharmacology of adenosine analogs

Investigations on drug produced and subjectively experienced discriminative stimuli. 1. The fentanyl cue, a tool to investigate subjectively experienced narcotic drug actions

Life Sci.

Investigations on drug produced and subjectively experienced discriminative stimuli. 2. Loperamide, an antidiarrheal devoid of narcotic cue producing actions

Life Sci.

Theoretical and methodological considerations on drug discrimination learning

Psychopharmacologia

On the ability of narcotic antagonists to produce the narcotic cue

J. Pharmacol. Exp. Ther.

The narcotic discriminative stimulus complexRelation to analgesic activity

J. Pharmacol. Pharmacol.

Discriminative stimulus properties of analgesic drugsNarcotic versus non-narcotic analgesics

Arch. Int. Pharmacodyn. Thér.

Experimental approach to the evaluation of drug abuse liability

Drug-produced cues and statesSome theoretical and methodological inferences

Narcotic cuing and analgesic activity of narcotic analgesicsAssociative and dissociative characteristics

Psychopharmacology (Berlin)

Neuroleptic interference with the cocaine cueInternal stimulus control of behaviour and psychosis

Psychopharmacology (Berlin)

Changes of sensitivity to the cuing properties of narcotic drugs as evidenced by generalization and cross-generalization experiments

Psychopharmacology (Berlin)

Factors regulating drug cue sensitivity. A long-term study on the cocaine cue

Articles
Drug Discrimination in Neurobiology