Review articleVocalizations during withdrawal from opiates and cocaine: possible expressions of affective distress
Introduction
The term “anxiety” refers to distress and uneasiness in common parlance and, in psychiatric definitions of anxiety disorders, the excessive and recurrent nature is highlighted such as in panic, phobias, obsessive-compulsive, post-traumatic distress and generalized anxiety disorders (Barlow and Wincze, 1998). The focus on anxiety in drug abuse is chiefly related to its postulated role in instigating relapse to intensive alcohol, opiate and stimulant abuse following periods of abstinence Kosten et al., 1986, Markou et al., 1998, Satel et al., 1991. In an influential scheme of the addiction cycle, Gawin and Kleber (1986) have pointed to signs and symptoms of anxiety and craving in the phase of withdrawal from cocaine that is most significant in promoting relapse.
Most drugs of abuse may induce transient positive states such as feelings of well-being or euphoria that contrast profoundly with dysphoric states during withdrawal from the drug. The Opponent Process Theory has been used in order to account for these contrasting effects of drugs at different stages of the self-administration cycle Ettenberg et al., 1999, Solomon, 1980. While initially euphoric effects may reinforce drug taking positively, alleviation of a persistent negative affective state and physiological distress during withdrawal appears to negatively reinforce continued drug taking. Operationally, such renewed drug taking is defined as being negatively reinforced, that is discontinuation or removal of aversive anxiety-like and depressive-like symptoms as well as other physiological symptoms of distress are the key consequences for continued drug self-administration Ahmed et al., 2002, Jaffe, 1985, Markou and Koob, 1991. Although there is no universal consensus for defining dependence adequately, quantifiable withdrawal symptoms following discontinuation of drug taking can be accepted as sufficient evidence (Jaffe, 1992), and they represent the cardinal criteria for diagnosing substance dependence according to the Diagnostic and Statistical Manual of Mental Disorders (4th edition; American Psychiatric Association, 1994). While discontinued use of drugs such as alcohol and opiates produces clear signs of withdrawal including tremors, nausea, tachycardia, seizures and fever, as well as affective and psychosomatic disturbances such as craving, anxiety and depression, psychomotor stimulants do not produce such clear signs of dependence Farrell, 1994, Lago and Kosten, 1994. Still, 12–60 h after discontinuing a binge of psychomotor stimulant use, symptoms comprising motivational fatigue, decreased psychological well-being—often referred to as anhedonia, and dysphoria concurrently develop with intense emotional memories about the cocaine euphoria (Gawin, 1991). These symptoms of affective distress, in conjunction with severe craving, have been viewed as significant determinants for relapse to cocaine binges.
The most likely time for resuming drug use, including stimulants, opiates and alcohol, corresponds to the point at which anxiety is reportedly at its highest peak after cessation of drug taking (Gawin, 1991). A challenge for preclinical research remains the need to more adequately characterize the affective or emotional component of withdrawal. Classic experimental models in animals have relied on disruption or suppression of ongoing behavioral performance or exaggeration of reflexive responses for the study of drugs with anxiolytic potential Brady, 1956, Davis and Gallager, 1988, Geller and Seifter, 1960. Inferences about the cause for disrupted or exaggerated behavior remain, however, tentative and indirect due to the multiple causes for these types of behavioral changes. Similarly, the term “anxiety” in clinical populations is merely a hypothetical construct used to describe more than one possible disruption of the behavioral repertoire. Preclinical studies of affective distress have begun to delineate the underlying mesocorticolimbic circuits that offer targets for pharmacotherapeutic interventions Burgdorf et al., 2001, Miczek et al., 1991, Miczek et al., 1995, Stutzmann et al., 1998, Vivian and Miczek, 1999.
The current review will initially discuss long-established indices of drug withdrawal, foremost based on observational assessments and, additionally, on measures of disrupted conditioned behavior during withdrawal from psychomotor stimulants and opiates. The final section will focus on a methodological approach that promises to capture the affective dimension of drug withdrawal states, namely distress vocalizations.
Section snippets
Preclinical assessment of withdrawal from psychomotor stimulants
Stimulant use originates during intermittent episodes of controlled drug taking that are scrupulously regulated by the user. Dependence is established following the transition to prolonged periods of uncontrollable drug taking that occur during recurrent binges that may last in excess of 24 h (Gawin, 1989). The prevailing consequences of this intense form of stimulant use are characterized by substantial disturbances in mood and behavior amid periods of abstinence. Unlike opiates and alcohol,
Preclinical assessment of opiate withdrawal
A major hypothesis attributes a key role to the experience of anxiety during withdrawal from opiates in the relapse to opiate seeking and taking (Goldstein, 1972). Behavioral, somatic and autonomic signs of opiate withdrawal can be identified across many organisms, ranging from invertebrates to humans, and are characterized by a distinctive onset, time-course and intensity. Typically, physiological and behavioral signs of withdrawal from opiates include responses that are opposite to those of
Distress vocalizations
During intense excitement, humans emit high-pitched sounds Ploog, 1988, Williams and Stevens, 1972 and high-frequency vocalizations appear to be related to highly frightening as well as attraction behavior in other mammals Bentley et al., 2000, Jürgens, 1983, Tembrock, 1975. In addition to communicating affective expressions, vocalizations may also serve semantic, pragmatic and physiologic functions, which may complement the expression of emotion (Scherer and Zei, 1988).
In myomorphic rodents,
Future perspectives
High-pitched vocalizations, particularly certain types of ultrasonic vocalizations in rodents, represent responses that communicate affective and anxiety-like expressions. In addition to their communicative role in maternal separation distress, sexual satiety, defensive, submissive and nociceptive responses, certain types of rodent ultrasonic vocalizations are also prominent features of withdrawal from diverse classes of substances such as opiates, alcohol, benzodiazepines and psychomotor
References (163)
- et al.
Integrated defense reaction elicited by excitatory amino acid microinjection in the midbrain periaqueductal region of the unrestrained cat
Brain Res.
(1988) - et al.
Tolerance and withdrawal to chronic morphine treatment in the week-old rat pup
Eur. J. Pharmacol.
(1992) - et al.
Effects of withdrawal from an escalating dose schedule of d-amphetamine on sexual behavior in the male rat
Pharmacol. Biochem. Behav.
(1999) - et al.
Drug effects on animal performance and the stress syndrome
J. Pharm. Sci.
(1966) - et al.
Stimulatory effects on the reproductive axis in female songbirds by conspecific and heterospecific male song
Horm. Behav.
(2000) Pharmacological and behavioral characteristics of 22 kHz alarm calls in rats
Neurosci. Biobehav. Rev.
(2001)- et al.
Ultrasonic vocalization in rats produced by cholinergic stimulation of the brain
Neurosci. Lett.
(1990) - et al.
Performance influence on the development of tolerance to amphetamine
Pharmacol. Biochem. Behav.
(1973) - et al.
Cholinergic neurons of the pontomesencephalic tegmentum release acetylcholine in the basal nuclear complex of freely moving rats
Neuroscience
(1990) - et al.
Afferent and efferent connections of the laterodorsal tegmental nucleus in the rat
Brain Res. Bull.
(1990)
Ondansetron inhibits a behavioural consequence of withdrawing from drugs of abuse
Pharmacol. Biochem. Behav.
An electrophysiological charecterization of the projection from the central nucleus of the amygdala to the periaqueductal gray of the rat: the role of opioid receptors
Brain Res.
Continuous slow release of low levels of diazepam produces tolerance to its depressant and anxiolytic effects on the startle reflex
Eur. J. Pharmacol.
Shock-induced ultrasonic vocalization in young adult rats: a model for testing putative anti-anxiety drugs
Eur. J. Pharmacol.
Evidence for opponent-process actions of intravenous cocaine
Pharmacol. Biochem. Behav.
The anxiogenic action of benzodiazepine antagonists
Neuropharmacology
Schedule-controlled behavior in the morphine-dependent rat
Pharmacol. Biochem. Behav.
Distress vocalization in rat pups: a simple screening method for anxiolytic drugs
J. Pharmacol. Methods
Changes in sensitivity to operant effects of dopaminergic and cholinergic agents following morphine withdrawal in rats
Eur. J. Pharmacol.
Effect of morphine and naloxone on separation distress and approach attachment: evidence for opiate mediation of social affect
Pharmacol. Biochem. Behav.
Multiple regulators of ultrasonic vocalization in the infant rat
Psychoneuroendocrinology
Evidence for a periaqueductal gray–nucleus retroambiguus–spinal cord pathway in the rat
Neuroscience
Interaction of methadone and pentobarbital on chained fixed-interval performance in pigeons
Pharmacol. Biochem. Behav.
Attenuation of acute morphine withdrawal in the neonatal rat by the competitive NMDA receptor antagonist LY235959
Neuropsychopharmacology
The discriminative stimulus effects of pentylenetetrazol as a model of anxiety: recent developments
Neurosci. Biobehav. Rev.
Role of periaqueductal grey in vocal expression of emotion
Brain Res.
High-frequency ultrasonic vocalizations index conditioned pharmacological reward in rats
Physiol. Behav.
Post-amphetamine depression of self-stimulation responding from the substantia nigra: reversal by tricyclic antidepressants
Pharmacol. Biochem. Behav.
Drug addiction, dysregulation of reward, and allostasis
Neuropsychopharmacology
Opponent process model and psychostimulant addiction
Pharmacol. Biochem. Behav.
Anxiogenic behavior in rats during acute and protracted ethanol withdrawal: reversal by buspirone
Alcohol
Chronic cocaine differentially affects diazepam's anxiolytic and anticonvulsant actions: relationship to GABAA receptor subunit expression
Brain Res.
Neurobiological similarities in depression and drug dependence: a self-medication hypothesis
Neuropsychopharmacology
Diazepam and pentobarbital dependence in the rat
Life Sci.
Theoretical review: a review of methods to induce alcohol addiction in animals
Pharmacol. Biochem. Behav.
Evidence of possible opiate dependence during the behavioral depressant action of a single dose of morphine
Life Sci.
Neurobiological evidence for hedonic allostasis associated with escalating cocaine use
Nat. Neurosci.
Gamma-aminobutyric acid agonists and antagonists alter chloride flux across brain membranes
Mol. Pharmacol.
Diagnostic and Statistical Manual of Mental Disorders
Sexual behavior: ultrasonic post-ejaculatory song of the male rat
Science
The ultrasonic postejaculatory vocalization and the postejaculatory refractory period of the male rat
J. Comp. Physiol. Psychol.
Ultrasonic vocalizations in rat sexual behavior
Am. Zool.
DSM-IV and beyond: what is generalized anxiety disorder?
Acta Psychiatr. Scand.
Withdrawal following repeated exposure to d-amphetamine decreases responding for a sucrose solution as measured by a progressive ratio schedule of reinforcement
Psychopharmacology
Withdrawal from oral cocaine in rats: ultrasonic vocalizations and tactile startle
Psychopharmacology
Corticotropin-releasing factor antagonist attenuates the “anxiogenic-like” effect in the defensive burying paradigm but not in the elevated plus-maze following chronic cocaine in rats
Psychopharmacology
Infantile stimulation and ultrasonic signaling: a possible mediator of early handling phenomena
Dev. Psychobiol.
Development of physical dependence on morphine in respect to time and dosage and quantification of the precipitated withdrawal syndrome in rats
Psychopharmacologia
Assessment of drug effects on emotional behavior
Science
Schedule-controlled behavior in the morphine-dependent and post-dependent rat
Psychopharmacology
Cited by (99)
Behavioral analysis in laboratory rats: Challenges and usefulness of 50-kHz ultrasonic vocalizations
2023, Neuroscience and Biobehavioral ReviewsAppetitive 50 kHz calls in a pavlovian conditioned approach task in Cacna1c haploinsufficient rats
2022, Physiology and BehaviorUltrasonic vocalizations and individual differences in rats performing a Pavlovian conditioned approach task
2021, Behavioural Brain ResearchRat ultrasonic vocalizations as an index of memory
2021, Neuroscience Letters