Increase in extracellular serotonin produced by uptake inhibitors is enhanced after chronic treatment with fluoxetine

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126

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...

Section: Discussionmentioning

confidence: 99%

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

Harrison

Liem

Markou

2001

158

126

“…This reduces the efficacy of the above negative feedback and increases extracellular 5-HT (Bel and Artigas 1993;Invernizzi et al 1994;Rutter et al 1994;Arborelius et al 1996). Other studies, however, have failed to observe such effects even using large doses of SSRIs (Hjorth and Auerbach 1994a;Bosker et al 1995;Invernizzi et al 1995).…”

mentioning

confidence: 99%

“…The prolonged administration of SSRIs has been reported to desensitize raphe 5-HT 1A autoreceptors, as assessed by single unit recordings and brain microdialysis (Blier and de Montigny 1994;Invernizzi et al 1994;Arborelius et al 1995;Le Poul et al 1995). This reduces the efficacy of the above negative feedback and increases extracellular 5-HT (Bel and Artigas 1993;Invernizzi et al 1994;Rutter et al 1994;Arborelius et al 1996). Other studies, however, have failed to observe such effects even using large doses of SSRIs (Hjorth and Auerbach 1994a;Bosker et al 1995;Invernizzi et al 1995).…”

mentioning

confidence: 99%

Desensitization of 5-HT1A Autoreceptors by a Low Chronic Fluoxetine Dose Effect of the Concurrent Administration of WAY-100635

Hervás

2001

100

Using microdialysis, receptor autoradiography and in situ hybridization, we examined the effects of fluoxetine alone or with WAY-100635 on: (a) extracellular 5-HT in frontal cortex; and (b) density and sensitivity of 5-HT 1A autoreceptors in rat brain. WAY-100635 (0.3 mg/kg, s.c.) doubled the increase in extracellular 5-HT produced by fluoxetine (3 mg/kg, i.p.) (SSRI) Selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRIs) are extensively used in the treatment of major depression. The increase in forebrain extracellular 5-HT elicited by SSRIs is limited by a negative feed-back involving raphe autoreceptors . The prevention of this inhibitory mechanism with 5-HT 1A receptor antagonists augments the neurochemical and behavioral effects of SSRIs (Gartside et al. 1995;Artigas et al. 1996;Hashimoto et al. 1997;Mitchell and Redfern 1997;Grignaschi et al. 1998;Trillat et al. 1998). At the clinical level, the ␤ -adrenoceptor/ 5-HT 1A receptor antagonist pindolol accelerates the antidepressant effects of SSRIs in open-label and placebocontrolled trials Blier and Bergeron 1995;Pérez et al. 1997;Zanardi et al. 1997Zanardi et al. , 1998Bordet et al. 1998). However, its effectiveness to potentiate antidepressant response in chronically ill or treatmentresistant patients is still controversial (Maes et al. 1996(Maes et al. , 1999Berman et al. 1997;Moreno et al. 1997;Pérez et al. 1999). Based on this rationale, selective 5-HT 1A receptor antagonists (for use with SSRIs; add-on strategy) and dual action compounds (5-HT reuptake inhibitor ϩ 5-HT 1A antagonist) are being developed for use in the treatment of major depression. The prolonged administration of SSRIs has been reported to desensitize raphe 5-HT 1A autoreceptors, as assessed by single unit recordings and brain microdialysis (Blier and de Montigny 1994;Invernizzi et al. 1994;Arborelius et al. 1995;Le Poul et al. 1995). This reduces the efficacy of the above negative feedback and increases extracellular 5-HT (Bel and Artigas 1993;Invernizzi et al. 1994;Rutter et al. 1994;Arborelius et al. 1996). Other studies, however, have failed to observe such effects even using large doses of SSRIs (Hjorth and Auerbach 1994a;Bosker et al. 1995;Invernizzi et al. 1995).To our knowledge, there are no published reports on the effects of prolonged treatments with combinations of SSRIs and 5-HT 1A receptor antagonists on these experimental paradigms, except in abstract form (Dawson et al. 1998). As with pindolol, future selective 5-HT 1A receptor antagonists would be administered for a limited period of time. Should prolonged blockade of 5-HT 1A receptor result in receptor sensitization, the withdrawal of the antagonist would increase the efficacy of the above negative feed-back and reduce the ability of the SSRI to increase extracellular 5-HT, thus increasing the possibility of a clinical relapse. Since this is crucial for the success of this therapeutic strategy, we examined the effects of two-week treatments with fluoxetine, WAY-100635 and their combination...

“…Two-week treatments with SSRIs increase the basal 5-HT output in frontal cortex or facilitate the effect of a challenge dose of the antidepressant (Bel and Artigas 1993;Invernizzi et al 1994;Rutter et al 1994;Moret and Briley 1996). This effect is thought to derive from the desensitization of 5-HT 1A autoreceptors after chronic blockade of the 5-HT reuptake (Blier and de Montigny 1994;Invernizzi et al 1994).…”

Section: Discussionmentioning

confidence: 99%

“…These observations further support the existence of a complex interplay of the 5-HT and NA systems during the simultaneous blockade of the reuptake of both amines. Because duloxetine is more selective than milnacipran for the 5-HT reuptake, a higher activation of somatodendritic 5-HT 1A receptors can be expected after duloxetine administration, which would facilitate the effects of the concurrent administration of a 5-HT 1A receptor antagonist on the 5-HT output.Two-week treatments with SSRIs increase the basal 5-HT output in frontal cortex or facilitate the effect of a challenge dose of the antidepressant (Bel and Artigas 1993;Invernizzi et al 1994;Rutter et al 1994;Moret and Briley 1996). This effect is thought to derive from the desensitization of 5-HT 1A autoreceptors after chronic blockade of the 5-HT reuptake (Blier and de Montigny 1994;Invernizzi et al 1994).…”

mentioning

confidence: 99%

Modulation of the Extracellular 5-Hydroxytryptamine Brain Concentrations by the Serotonin and Noradrenaline Reuptake Inhibitor, Milnacipran Microdialysis Studies in Rats

Bel

Artigas

1999

We examined the effects of the administration of milnacipran, a dual inhibitor of serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline uptake on the 5-HT output in rat brain. Local milnacipran administration increased the 5-HT output in frontal cortex and the midbrain raphe nuclei 7-and 10-fold by a Ca 2 ϩ -and tetrodotoxin-dependent mechanism. However, the subcutaneous administration of milnacipran (1-60 mg/kg SC) elevated the 5-HT output much less in these areas (200-230% of baseline at 60 mg/kg). In hypothalamus, 10 mg/kg SC raised 5-HT levels to 170%. The 5-HT 1A antagonist WAY-100635 caused a small potentiation of the effects of milnacipran. The baseline 5-HT output was unaffected by 2-week treatments with milnacipran (30 and 60 mg/kg и day). The distinct regional profile and the lack of enhancement of its effects by WAY-100635 and prolonged treatment suggest that milnacipran does not exert itsThe administration of selective 5-HT reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and clomipramine markedly increases the extracellular concentration of 5-HT in the raphe nuclei of the midbrain (Adell and Artigas 1991; Bel and Artigas 1992;Invernizzi et al. 1992;Celada and Artigas 1993;Gartside et al. 1995;Malagié et al. 1995). In all instances, these elevations are superior to those produced in frontal cortex or, when examined, in hippocampus. The excess 5-HT in the extracellular space of the midbrain raphe activates 5-HT 1A autoreceptors in the soma and dendrites of serotonergic neurones and reduces the neuronal activity and release of 5-HT by nerve terminals in forebrain (see for review).Selective serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline reuptake inhibitors (SNRIs) are a new class of antidepressant drugs. These agents inhibit in vitro the neuronal uptake of 5-HT and noradrenaline without exhibiting significant activity at the dopamine transporter or aminergic receptors (see Artigas 1995; Briley 1998 for review). Consequently, they are devoid of the unwanted side effects of classic antidepressant Received January 17, 1999; revised May 21, 1999; accepted June 18, 1999. 746 N. Bel and F. Artigas N EUROPSYCHOPHARMACOLOGY 1999 -VOL . 21 , NO . 6 drugs, mainly derived from their affinity for ␣ -adrenergic, cholinergic, and histamine receptors (Richelson 1978;Richelson and Nelson 1984). Milnacipran is one such drug that blocks in vitro and in vivo the reuptake of 5-HT and noradrenaline, although it displays a slightly higher affinity for the latter (Moret et al. 1985;Stenger et al. 1987).Despite the potential advantages of SNRIs, the information on their in vivo effects on serotonergic transmission is scarce (e.g., Engleman et al. 1995;. In particular, a comparison of their effects in the somatodendritic region in the raphe nuclei and in forebrain has not been performed. Data obtained with the microdialysis technique suggest that the dual blockade of the 5-HT and noradrenaline transporters elevates the extracellular 5-HT concentration in rat brain, with a regional profile d...