Fluoxetine Combined with a Serotonin-1A Receptor Antagonist Reversed Reward Deficits Observed During Nicotine and Amphetamine Withdrawal in Rats Amanda A
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Fluoxetine Combined with a Serotonin-1A Receptor Antagonist Reversed Reward Deficits Observed during Nicotine and Amphetamine Withdrawal in Rats Amanda A. Harrison1, Ph.D., Yves T. B. Liem2, Pharm.D., and Athina Markou, Ph.D. The symptom of “diminished interest or pleasure” in treatment had opposite effects in control rats where rewarding stimuli is an affective symptom of nicotine and reductions in reward were produced, suggesting that amphetamine withdrawal, and a core symptom of animal models should be based primarily on studying depression. An operational measure of this symptom is specific deficits that are pathognomic of a psychiatric elevation of brain reward thresholds during drug disorder. The reversal of the affective aspects of drug withdrawal. We report here that acute co-administration of withdrawal by a treatment that enhances serotonin fluoxetine, a selective serotonin reuptake inhibitor, and neurotransmission indicates that decreased serotonergic p-MPPI, a serotonin-1A receptor antagonist, alleviated the function may mediate the reward decrements characterizing diminished interest in brain stimulation reward observed nicotine and amphetamine withdrawal, and that these during withdrawal from nicotine or amphetamine in rats symptoms may be homologous to a core symptom of non- (i.e., increased reward). By contrast, the same drug drug–induced depressions. combination treatment did not reduce the somatic signs of [Neuropsychopharmacology 25:55–71, 2001] nicotine withdrawal indicating symptom-specific © 2001 American College of Neuropsychopharmacology neurobiological abnormalities. Surprisingly, the same Published by Elsevier Science Inc. KEY WORDS: Drug withdrawal; Depression; Serotonin; Cessation of chronic nicotine or amphetamine adminis- Nicotine; Amphetamine; Intracranial self-stimulation; tration precipitates withdrawal syndromes character- Reward; Motivation; Fluoxetine; 5-HT1A antagonist; ized by affective symptoms, including “diminished in- Somatic signs; Body weight terest or pleasure” in rewarding stimuli (i.e., anhedonia) (American Psychiatric Association 1994; Covey et al. 1998; Glassman 1993; Hughes 1992). Inter- From the Scripps Research Institute, Department of Neurophar- estingly, the symptom of “diminished interest or plea- macology, La Jolla, CA. sure” is not only a symptom of drug withdrawal, but Address correspondence to: Athina Markou, Ph.D., Department of Neuropharmacology, CVN-7, The Scripps Research Institute, also a core symptom of depression and a negative 10550 North Torrey Pines Road, La Jolla, CA 92037. Tel.: (858) 784- symptom of schizophrenia (American Psychiatric Asso- 7244; Fax: (858) 784-7405; E-mail: [email protected] ciation 1994; Markou et al. 1998). Brain reward thresh- Received June 23, 2000; revised October 25, 2000; accepted Octo- ber 26, 2000. old elevation is an operational measure of this symp- 1Present address: School of Psychology, University of Leeds, tom because it reflects diminished sensitivity to Leeds, England, UK rewarding electrical stimuli. In rats, withdrawal from 2Present address: Department of Psychopharmacology, Faculty of Pharmacy, Utrecht University, Sorbonnelaan 16, 3508 TB Utrecht, drugs of abuse belonging to diverse pharmacological 3508 TB Utrecht, The Netherlands. classes, such as nicotine (Epping-Jordan et al. 1998; NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 1 © 2001 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/01/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(00)00237-2 56 A.A. Harrison et al. NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 1 Watkins et al. 2000b), amphetamine (Kokkinidis and Za- Kung et al. 1994a, 1994b, 1995) was selected based on charko 1980a, 1980b; Kokkinidis et al. 1980, 1986; Leith the following considerations. First, the threshold eleva- and Barrett 1976, 1980; Lin et al. 1999, 2000; Paterson et tions associated with nicotine (Epping-Jordan et al. al. 2000; Wise and Munn 1995), cocaine (Baldo et al. 1998) and amphetamine (Lin et al. 1999, 2000; Paterson 1999; Kokkinidis and McCarter 1990; Markou and Koob et al. 2000) withdrawal, and the increases in somatic 1991, 1992a; Markou et al. 1992) morphine (Schulteis et signs seen during nicotine withdrawal (Epping-Jordan al. 1994) and ethanol (Schulteis et al. 1995) elevated et al. 1998) are relatively short lasting phenomena (3–5 brain stimulation reward thresholds. days) that do not allow the detection of the effects of In addition to the affective aspects of drug with- pharmacological treatments that may require chronic drawal reflected in threshold elevations, nicotine, opi- administration for producing their effect. In vivo mi- ate, or ethanol withdrawal also lead to alterations in a crodialysis work demonstrated that the administration set of behaviors termed somatic signs. In the case of nic- of a SSRI together with a 5-HT1A receptor antagonist otine, these somatic signs are primarily gasps, writhes, acutely and rapidly elevates forebrain serotonin dialy- eye blinks, and ptosis (Epping-Jordan et al. 1998; Hilde- sate levels beyond levels seen after acute treatment brand et al. 1997, 1999; Malin et al. 1992). It is unlikely with the SSRI alone (Auerbach and Hjorth 1995; Bel and that these somatic signs in the rat reflect the affective Artigas 1993; Bengtsson and Milano 1996; Hjorth 1993, component of drug withdrawal. Nevertheless, the 1996; Invernizzi et al. 1994; Knobelman et al. 2000; Kre- study of both threshold elevations and somatic signs iss and Lucki 1994, 1995; for reviews, see Artigas et al. permits the investigation of the effects of manipulations 1996; Blier and de Montigny 1994). Thus, such a drug on the various aspects of withdrawal. combination may have rapid therapeutic effects that Based on evidence demonstrating the efficacy of se- may be detectable during the short-lasting drug with- rotonergic antidepressant treatments, reduced cerebrospi- drawal. Second, the combination of a SSRI with pin-  nal fluid levels of serotonin metabolites, endocrine mea- dolol [antagonist at 5-HT1A, 5-HT1B, and -adrenergic sures reflecting reduced serotonergic neurotransmission receptors (Assie and Koek 1996; Bourin et al. 1998; and the exacerbation of depressive symptomatology Gobert and Millan 1999; Hoyer and Schoeffter 1991; seen after serotonin (5-HT) depletion in depressed indi- Newman-Tancredi et al. 1998); also reported to act as a ␣ viduals, it is hypothesized that reduced serotonergic partial agonist at 5-HT1A and -adrenergic receptors neurotransmission underlies at least some aspects or (Clifford et al. 1998; Fornal et al. 1999a, 1999b, 1999c; some subtypes of non–drug-induced depressions (for Gobert and Millan 1999; Pauwels and Palmier 1994a, reviews, see Caldecott-Hazard et al. 1991; Caldecott- 1994b)] accelerates the onset of antidepressant action of Hazard and Schneider 1992; Heninger et al. 1996; SSRIs in humans (Bordet et al. 1998; Zanardi et al. 1997, Markou et al. 1998; Meltzer and Lowy 1988; Willner 1998), or augments the antidepressant response to 1985). The purpose of the present study was to test SSRIs in terms of both magnitude and duration of the the hypothesis that reduced serotonergic neurotrans- response (Maes et al. 1999; Perez et al. 1997; Tome and mission mediates some of the affective aspects, not Isaac 1998; for review, see McAskill et al. 1998; how- only of non-drug-induced depressions, but also of drug- ever, see Berman et al. 1997, 1999; Tome et al. 1997a, induced depressions. Thus, the present study tested the 1997b). In the present study, instead of pindolol, which hypothesis that enhancement of serotonergic neu- has multiple receptor actions, the relatively selective rotransmission through acute administration of the se- 5-HT1A receptor antagonist p-MPPI was used. The use lective serotonin reuptake inhibitor (SSRI) fluoxetine of p-MPPI allowed the investigation of the role of sero- (Wong et al. 1995) in combination with a relatively se- tonergic neurotransmission and antagonism at 5-HT1A lective 5-HT1A receptor antagonist would alleviate the receptors in drug withdrawal, without complicating symptom of “diminished interest or pleasure” observed data interpretation with neuroadaptive effects that may in rats during nicotine or amphetamine withdrawal. occur with chronic SSRI treatment. In summary, acute Such an experimental outcome would suggest that the treatment with a SSRI together with a 5-HT1A receptor affective aspects of drug withdrawal may be homolo- antagonist allowed us to rapidly elevate extracellular gous to the core symptom of depression of “diminished serotonin levels and delineate the potential role of sero- interest or pleasure” in rewarding stimuli. It was also tonin neurotransmission in the affective and somatic as- hypothesized that this serotonergic drug treatment pects of drug withdrawal. would not reverse the somatic signs of nicotine with- drawal that most likely do not reflect affective aspects of withdrawal. MATERIALS AND METHODS The combination treatment of a SSRI together with Subjects the relatively selective 5-HT1A receptor antagonist p-MPPI [4-(2Ј-methoxy-phenyl)-1-[2Ј-(n-(2Љ-pyridinyl)- Male Wistar rats (Charles River, Hollister, CA) (300–320 p-iodobenzamido]-ethyl-piperazine] (Allen et al. 1997; g at the start of the experiment) were housed in pairs in NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 1 Fluoxetine and a 5-HT1A Antagonist Reversed Withdrawal 57 a temperature and humidity controlled environment mal and typically ranged from