Pindolol increases extracellular 5-HT while inhibiting serotonergic neuronal activity

Paz-Valiñas

Naunyn-Schmiedeberg's Archives of Pharmacology

et al. 2002

We used intracerebral microdialysis to study the role of raphe and presynaptic serotonin (5-HT) autoreceptors in the effect of the selective 5-HT reuptake inhibitor, paroxetine, on 5-HT release from ventral hippocampus of anaesthetised rats. In addition, we have tested the ability of pindolol, a non-selective beta-adrenergic/5-HT(1A) receptor antagonist, to alter the response of hippocampal 5-HT to paroxetine. Doses of paroxetine with maximal effects were near to three-fold less effective when administered systemically than after local infusion at increasing extracellular 5-HT in ventral hippocampus. Moreover, systemic paroxetine treatment resulted in a marked decrease of the extracellular 5-HT in the hippocampus when 5-HT reuptake was blocked with paroxetine 3 microM applied locally, thereby evidencing that systemic treatment induced a decrease of 5-HT release in the neuronal terminal. A similar drop was observed when paroxetine 3 microM was perfused into the median raphe, a region that contains the cell bodies of the neurons innervating the ventral hippocampus. Racemic (+/-)-pindolol (10 mg/kg, s.c.) completely blocked the paroxetine-induced decrease in 5-HT release from rat hippocampus. In addition, the infusion into median raphe of (-)-pindolol, the isoform with highest antagonist activity, at concentrations of 10 microM and 100 microM was able to partially block the decrease of hippocampal 5-HT release after systemic paroxetine. However, perfusion of (-)-pindolol into the hippocampus was without effect on local 5-HT release. These data suggest that pindolol acts preferentially through the blockade of somatodendritic 5-HT(1A) autoreceptors to restore the decline in 5-HT outflow in rat forebrain following systemic administration of selective 5-HT reuptake inhibitors.

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Somatodendritic action of pindolol to attenuate the paroxetine-induced decrease in serotonin release from the rat ventral hippocampus: a microdialysis study

Paz-Valiñas

Naunyn-Schmiedeberg's Archives of Pharmacology

et al. 2002

Neuropsychopharmacology

“…24, NO. 2 Tonic Inhibition of Firing Activity by 5-HT 149 onstrated that (-)pindolol increases extracellular 5-HT in the cat brain (Fornal et al 1999) and that this drug does not antagonize postsynaptic 5-HT 1A receptors in the rat hippocampus . These observations indicate the decrease in the firing activity could be produced by the (-)pindolol-induced increase in the extracellular 5-HT.…”

Section: K Kasamo Et Almentioning

confidence: 99%

Endogenous 5-HT Tonically Inhibits Spontaneous Firing Activity of Dorsal Hippocampus CA1 Pyramidal Neurons Through Stimulation of 5-HT1A Receptors in Quiet Awake Rats In Vivo Electrophysiological Evidence

Kasamo

2001

The present study was performed to examine an overall effect of endogenous serotonin (5-HT) on the spontaneous firing activity of the dorsal hippocampus CA1 pyramidal neurons in quiet awake rats. A selective 5-HT 1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY-100635: 0.03-0.2 mg/kg, s.c.) It has been shown that there are at least 14 serotonin (5-HT; 5-hydroxytryptamine) receptor subtypes over seven distinct receptor subfamilies. Among these seven receptor subfamilies, only the 5-HT 1 subfamily is inhibitory whereas the others are excitatory (see Hoyer et al. 1994; Glennon and Dukat 1995 for reviews). Several in situ hybridization studies have demonstrated that ten of these 14 receptor subtypes are detectable over the CA1 region of the rat hippocampus (see Andrade 1998 for review).In accordance with the distribution and exuberance of 5-HT receptors expressed in this area, several in vitro electrophysiological studies have demonstrated multiple actions of 5-HT on the excitability of the CA1 pyramidal neurons. These are the direct inhibitory and exci- 142 K. Kasamo et al. N EUROPSYCHOPHARMACOLOGY 2001 -VOL . 24 , NO . 2 tatory actions through stimulating 5-HT 1A and 5-HT 4 receptors on the pyramidal neurons, respectively. In addition, via inhibitory interneurons, 5-HT indirectly decreases and increases the excitability through stimulating 5-HT 2 and 5-HT 3 , and 5-HT 1A receptors, respectively (see Hoyer et al. 1994; Aghajanian 1995; Andrade 1998 for reviews). Given these extremely diverse actions of 5-HT demonstrated in vitro , endogenous 5-HT should produce multiple actions simultaneously on the excitability of the CA1 pyramidal neurons in vivo. These in vitro data have been obtained with the preparations isolated from various potentially confounding factors, such as the effects of activation of other receptor systems. Contrary, in vivo cells in the brain are exposed continuously to the various neurotransmitter, neuromodulator and hormonal stimuli. In any cell, these stimuli are integrated spatially and temporally. Furthermore, the intracellular signaling cascades are extensively interconnected. Moreover, even in vivo , the use of anesthesia drastically reduces the 5-HT tone (Jacobs 1985; as well as the spontaneous firing activity of the hippocampus pyramidal neurons (Blier et al. 1993). The reduction in the firing activity indicates that the use of anesthesia per se markedly decreases the excitability of hippocampal pyramidal neurons. Thus, an overall action of endogenous 5-HT on the firing activity of the pyramidal neurons in awake rats is unpredictable solely basing on the data obtained from in vivo studies with anesthetized animals and from in vitro experiments. Therefore, using awake animals is essential to scrutinize the influence of endogenous 5-HT. To our knowledge, such studies examining the net effect of endogenous 5-HT on cellular activity in the brain of awake rats have not been performed so far.Thus, the present study was carried out to...

Neuropsychopharmacology

“…Thus, such a drug combination may have rapid therapeutic effects that may be detectable during the short-lasting drug withdrawal. Second, the combination of a SSRI with pindolol [antagonist at 5-HT 1A , 5-HT 1B , and ␤ -adrenergic receptors (Assie and Koek 1996;Bourin et al 1998;Gobert and Millan 1999;Hoyer and Schoeffter 1991;Newman-Tancredi et al 1998); also reported to act as a partial agonist at 5-HT 1A and ␣ -adrenergic receptors (Clifford et al 1998;Fornal et al 1999aFornal et al , 1999bFornal et al , 1999cGobert and Millan 1999; Palmier 1994a, 1994b)] accelerates the onset of antidepressant action of SSRIs in humans (Bordet et al 1998;Zanardi et al 1997Zanardi et al , 1998, or augments the antidepressant response to SSRIs in terms of both magnitude and duration of the response (Maes et al 1999;Perez et al 1997;Tome and Isaac 1998; for review, see McAskill et al 1998; however, see Berman et al 1997 however, see Berman et al , 1999Tome et al 1997aTome et al , 1997b. In the present study, instead of pindolol, which has multiple receptor actions, the relatively selective 5-HT 1A receptor antagonist p-MPPI was used.…”

mentioning

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

157

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...