Fluoxetine Combined with a Serotonin-1A Receptor Antagonist Reversed Reward Deficits Observed during Nicotine and Amphetamine Withdrawal in Rats

Abstract

Cessation of chronic nicotine or amphetamine administration precipitates withdrawal syndromes characterized by affective symptoms, including "diminished interest or pleasure" in rewarding stimuli (i.e., anhedonia) (American Psychiatric Association 1994;Covey et al. 1998;Glassman 1993;Hughes 1992). Interestingly, the symptom of "diminished interest or pleasure" is not only a symptom of drug withdrawal, but also a core symptom of depression and a negative symptom of schizophrenia (American Psychiatric Association 1994;Markou et al. 1998). Brain reward threshold elevation is an operational measure of this symptom because it reflects diminished sensitivity to rewarding electrical stimuli. In rats, withdrawal from drugs of abuse belonging to diverse pharmacological classes, such as nicotine (Epping-Jordan et al. 1998 Watkins et al. 2000b), amphetamine Zacharko 1980a, 1980b;Kokkinidis et al. 1980Kokkinidis et al. , 1986 Barrett 1976, 1980;Lin et al. 1999Lin et al. , 2000Paterson et al. 2000;Wise and Munn 1995), cocaine (Baldo et al. 1999;Kokkinidis and McCarter 1990; Koob 1991, 1992a;Markou et al. 1992) morphine (Schulteis et al. 1994) and ethanol (Schulteis et al. 1995) elevated brain stimulation reward thresholds.In addition to the affective aspects of drug withdrawal reflected in threshold elevations, nicotine, opiate, or ethanol withdrawal also lead to alterations in a set of behaviors termed somatic signs. In the case of nicotine, these somatic signs are primarily gasps, writhes, eye blinks, and ptosis (Epping-Jordan et al. 1998;Hildebrand et al. 1997Hildebrand et al. , 1999Malin et al. 1992). It is unlikely that these somatic signs in the rat reflect the affective component of drug withdrawal. Nevertheless, the study of both threshold elevations and somatic signs permits the investigation of the effects of manipulations on the various aspects of withdrawal.Based on evidence demonstrating the efficacy of serotonergic antidepressant treatments, reduced cerebrospinal fluid levels of serotonin metabolites, endocrine measures reflecting reduced serotonergic neurotransmission and the exacerbation of depressive symptomatology seen after serotonin (5-HT) depletion in depressed individuals, it is hypothesized that reduced serotonergic neurotransmission underlies at least some aspects or some subtypes of non-drug-induced depressions (for reviews, see Caldecott-Hazard et al. 1991; CaldecottHazard and Schneider 1992;Heninger et al. 1996;Markou et al. 1998;Meltzer and Lowy 1988;Willner 1985). The purpose of the present study was to test the hypothesis that reduced serotonergic neurotransmission mediates some of the affective aspects, not only of non-drug-induced depressions, but also of druginduced depressions. Thus, the present study tested the hypothesis that enhancement of serotonergic neurotransmission through acute administration of the selective serotonin reuptake inhibitor (SSRI) fluoxetine (Wong et al. 1995) in combination with a relatively selective 5-HT 1A receptor antagonist would alleviate the symptom of "dimin...

Influence of fluoxetine on positive and negative affect in a clinic-based smoking cessation trial

“…Findings from animal studies indicate that fluoxetine heightens responsivity to rewards, and suggest dopaminergic (DA) and serotonergic (5-HT) mechanisms of action. In animal studies, nicotine abstinence leads to a decrement in reward functioning that is reversed or prevented by fluoxetine (Harrison et al 2001), a finding analogous to fluoxetine's enhancement of positive affect in the present study. Fluoxetine's positive mood enhancing effects might plausibly come about via 5-HT/DA interaction.…”

“…Fluoxetine administration directly enhances 5-HT activity, which has been shown to facilitate dopamine release in the nucleus accumbens (Benloucif and Galloway 1991;De Deuwaerdere et al 1996), and increase sensitivity to reward (Sasaki-Adams and Kelley 2001). Conversely, decreased 5-HT release inhibits DA activity (Ichikawa et al 1995), a mechanism that has been linked with acquisition of anhedonia (Harrison et al 2001;Zagen et al 2001). Plausibly, therefore, reduction in positive affect during nicotine deprivation may be engendered by decreased 5-HT activity with consequent inhibition of DA release.…”

“…Third, administration of fluoxetine and serotonin 1A receptor antagonist, p-MPPI, in rats prevents a rise in brain reward threshold during nicotine deprivation (i.e. reverses diminished responding to rewarding stimuli; Harrison et al 2001). To the extent that diminished positive affect is associated with diminished reinforcing value of approach behavior to rewards (Depue and Collins 1999), fluoxetine might buffer the losses in positive affect associated with quitting smoking.…”

Withdrawal from Chronic Phencyclidine Treatment Induces Long-Lasting Depression in Brain Reward Function

“…An operational measure of this deficit in animals is the elevation in brain reward threshold observed during drug withdrawal that reflects diminished interest of the subjects in the rewarding electrical stimuli (Geyer and Markou, 1995). A deficit in brain reward function has been reported during withdrawal from amphetamine (eg Leith and Barrett, 1976;Kokkinidis and Zacharko, 1980;Kokkinidis et al, 1986;Lin et al, 1999;Paterson et al, 2000), cocaine Koob, 1991, 1992a;Baldo et al, 1999), opiates (Schulteis et al, 1994), ethanol (Schulteis et al, 1995), and nicotine (Epping-Jordan et al, 1998;Harrison et al, 2001). The aim of the present study was to characterize in rats the effects on brain stimulation reward of withdrawal from different PCP treatments.…”

“…As hypothesized previously Harrison et al, 2001;Markou and Kenny, 2002), elevations in brain reward thresholds associated with withdrawal from drugs of abuse may be homologous, or at least analogous, to the symptom of 'diminished interest or pleasure' (ie anhedonia) characterizing nondrug-induced depressions (American Psychiatric Association, 1994). Further it has been hypothesized that the negative symptoms of schizophrenia, such as anhedonia and avolition (ie lack of motivation; American Psychiatric Association, 1994) may be neurobiologically similar to depressive symptomatology, such as anhedonia and dysphoria, seen in both drug-and nondrug-induced depressions (Markou and Kenny, 2002).…”