Hippocampal 5-HT synthesis and release in vivo is decreased by infusion of 8-OHDPAT into the nucleus raphe dorsalis

doi:10.1016/0304-3940(89)90698-8

Neuroscience Letters

Volume 100, Issues 1–3, 22 May 1989, Pages 276-280

https://doi.org/10.1016/0304-3940(89)90698-8 Get rights and content

Abstract

Infusion of the serotonin-1A (5-HT_1A) agonist, 8-hydroxy-2-di(n-propylamino)tetralin (8-OHDPAT) (0.5, 1.0 and 2.0 μg) into the dorsal raphe, decreased extracellular 5-HT as measured by dialysis in the ventral hippocampus and also decreased 5-HT synthesis in both the hippocampus and the rest of the brain as measured by 5-hydroxytryptophan (5-HTP) accumulation following decarboxylase inhibition by NSD 1015.

References (10)

P.H. Hutson et al.
Neurochemical and behavioural evidence for mediation of the hyperphagic action of 8-OHDPAT by 5-HT cell body autoreceptors
Eur. J. Pharmacol.
(1986)
D. Weissmann-Nanopoulos et al.
Evidence for the localisation of 5-HT_1A binding sites on serotonin containing neurons in the raphe dorsalis and raphe centralis nuclei of the rat brain
Neurochem. Int.
(1985)
D. Verge et al.
Presynaptic 5-HT autoreceptors on serotonergic cell bodies and/or dendrites but not terminals are of the 5-HT_1A subtype
Eur. J. Pharmacol.
(1985)
B.H.C. Westerink et al.
Scope and limitations of in vivo brain dialysis: a comparison of its application to various neurotransmitter systems
Life Sci.
(1987)
S. Hjorth et al.
8-Hydroxy-2-di(n-propylamino)tetralin, 8-OHDPAT, a potent and selective simplified ergot congener with central 5-HT receptor stimulating activity
J. Neural Transm.
(1982)

There are more references available in the full text version of this article.

Cited by (190)

Serotonin modulation of hippocampal functions: From anatomy to neurotherapeutics
2021, Progress in Brain Research
Citation Excerpt :
5-HT1A receptors are expressed by 5-HT neurons in the raphe nuclei (autoreceptors) and by hippocampal cells (see above). Injection of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) at 0.5 and 2.5 μg into the DRN caused a dose-related fall in hippocampal 5-HT output compared to saline-injected controls (Hutson et al., 1989; Sharp and Hjorth, 1990). Accordingly, the putative 5-HT1A receptor agonists gepirone (5 mg/kg, s.c.), ipsapirone (5 mg/kg, s.c.) and buspirone (5 mg/kg, s.c.) significantly reduced levels of 5-HT in hippocampal perfusates (Sharp and Hjorth, 1990).
The hippocampal region receives a dense serotoninergic innervation originating from both medial and dorsal raphe nuclei. This innervation regulates hippocampal activity through the activation of distinct receptor families that are expressed in excitatory and inhibitory neurons, terminals of several afferent neurotransmitter systems, and glial cells. Preclinical and clinical studies indicate that hippocampal dysfunctions are involved in learning and memory deficits, dementia, Alzheimer's disease, epilepsy and mood disorders such as anxiety, depression and post-traumatic syndrome disorder, whereas the hippocampus participates also in the therapeutic mechanisms of numerous medicines. Not surprisingly, several drugs acting via 5-HT mechanisms are efficacious to some extent in some diseases and the link between 5-HT and the hippocampus although clear remains difficult to untangle. For this reason, we review reported data concerning the distribution and the functional roles of the 5-HT receptors in the hippocampal region in health and disease. The impact of the 5-HT systems on the hippocampal function is such that the research of new 5-HT mechanisms and drugs is still very active. It concerns notably drugs acting at the 5-HT_1A,_2A,_2C,_4,6 receptor subtypes, in addition to the already existing drugs including the selective serotonin reuptake inhibitors.
Chronic fluoxetine rescues changes in plasma membrane density of 5-HT1A autoreceptors and serotonin transporters in the olfactory bulbectomy rodent model of depression
2017, Neuroscience
Citation Excerpt :
The 5-HT1A auto-receptor is another key regulator of serotonergic neurotransmission. Activation of somatodendritic 5-HT1A auto-receptors by locally released 5-HT inhibits firing of 5-HT neurons, thereby reducing 5-HT actions throughout the brain (Blier and de Montigny, 1987; Sprouse and Aghajanian, 1987; Hutson et al., 1989; Sharp et al., 1989; Adell et al., 2002). In animal studies of antidepressant treatment with selective serotonin reuptake inhibitors, the firing rate of 5-HT neurons is reduced at initiation of treatment and recovers over weeks, corresponding with the time course of 5-HT1A auto-receptor desensitization and/or internalization (Li et al., 1996; Le Poul et al., 1997; Czachura and Rasmussen, 2000; Aznavour et al., 2006; Riad et al., 2008).
Reduced serotonin (5-HT) neurotransmission is postulated to underlie the pathogenesis of depression. The serotonin transporter (SERT) and 5-HT1A auto-receptors act in concert to ensure homeostasis of serotonin (5-HT) neurotransmission and regulation of their cell surface expression represent efficient mechanisms to maintain this homeostasis. Thus, we investigated the changes in the subcellular distribution of SERT and 5-HT1A receptors (5-HT1AR) in the rat olfactory bulbectomy model of depression using immuno-gold labeling and electron microscopy, and examined the effect of chronic treatment with the antidepressant, fluoxetine, a serotonin reuptake inhibitor, on the subcellular distribution of SERT and 5-HT1AR. The density of plasma membrane labeling of 5-HT1A auto-receptors on dendrites of dorsal raphe neurons was increased after bulbectomy, but the 5-HT1A hetero-receptor membrane labeling on dendrites of CA3 hippocampal neurons was not. The density of membrane labeling of SERTs was increased both in dendrites of dorsal raphe neuron and axon terminals in the hippocampus after bulbectomy. However, the proportion of 5-HT1AR and SERT membrane labeling relative to total labeling was unchanged, suggesting an increase in protein levels. The increases in 5-HT1AR and SERTs membrane labeling induced by bulbectomy were reversed by chronic fluoxetine treatment, and these changes were associated with a reduction in the relative proportion of membrane versus total labeling, consistent with a protein shift between subcellular compartments. Our findings support the hypothesis that changes in efficacy of serotonergic neurotransmission in this model of depression depends on both activity and density of cell surface-expressed SERT and 5-HT1A auto-receptors.
Nucleus incertus contributes to an anxiogenic effect of buspirone in rats: Involvement of 5-HT<inf>1A</inf> receptors
2016, Neuropharmacology
The nucleus incertus (NI), a brainstem structure with diverse anatomical connections, is implicated in anxiety, arousal, hippocampal theta modulation, and stress responses. It expresses a variety of neurotransmitters, neuropeptides and receptors such as 5-HT_1A, D₂ and CRF₁ receptors. We hypothesized that the NI may play a role in the neuropharmacology of buspirone, a clinical anxiolytic which is a 5-HT_1A receptor partial agonist and a D₂ receptor antagonist. Several preclinical studies have reported a biphasic anxiety-modulating effect of buspirone but the precise mechanism and structures underlying this effect are not well-understood. The present study implicates the NI in the anxiogenic effects of a high dose of buspirone. Systemic buspirone (3 mg/kg) induced anxiogenic effects in elevated plus maze, light-dark box and open field exploration paradigms in rats and strongly activated the NI, as reflected by c-Fos expression. This anxiogenic effect was reproduced by direct infusion of buspirone (5 μg) into the NI, but was abolished in NI-CRF-saporin-lesioned rats, indicating that the NI is present in neural circuits driving anxiogenic behaviour. Pharmacological studies with NAD 299, a selective 5-HT_1A antagonist, or quinpirole, a D₂/D₃ agonist, were conducted to examine the receptor system in the NI involved in this anxiogenic effect. Opposing the 5-HT_1A agonism but not the D₂ antagonism of buspirone in the NI attenuated the anxiogenic effects of systemic buspirone. In conclusion, 5-HT_1A receptors in the NI contribute to the anxiogenic effect of an acute high dose of buspirone in rats and may be functionally relevant to physiological anxiety.
Regulation of dorsal raphe nucleus function by serotonin autoreceptors: A behavioral perspective
2011, Journal of Chemical Neuroanatomy
Citation Excerpt :
Additionally, behavioral pharmacology can be used to study autoreceptor function indirectly by measuring behaviors influenced by autoreceptor function, although it can be difficult to parse the effects of autoreceptors versus heteroreceptors in some cases. A straightforward way of selectively activating 5-HT1A autoreceptors is by infusing 5-HT1A ligands directly into the DRN, which results in decreased spike rate of serotonergic DRN neurons (Blier et al., 1989) and reduced 5-HT release in terminal regions (Bonvento et al., 1992; Hjorth and Sharp, 1991; Hutson et al., 1989). A second, less selective, method of pharmacologically manipulating 5-HT1A autoreceptors is by systemically injecting agonists/antagonists at low doses, which preferentially activate autoreceptors (Blier et al., 1993; Hjorth and Magnusson, 1988; Kennett et al., 1987; Sprouse and Aghajanian, 1988).
Neurotransmission by serotonin (5-HT) is tightly regulated by several autoreceptors that fine-tune serotonergic neurotransmission through negative feedback inhibition at the cell bodies (predominantly 5-HT_1A) or at the axon terminals (predominantly 5-HT_1B); however, more subtle roles for 5-HT_1D and 5-HT_2B autoreceptors have also been detected. This review provides an overview of 5-HT autoreceptors, focusing on their contribution in animal behavioral models of stress and emotion. Experiments targeting 5-HT autoreceptors in awake, behaving animals have generally shown that increasing autoreceptor feedback is anxiolytic and rewarding, while enhanced 5-HT function is aversive and anxiogenic; however, the role of serotonergic activity in behavioral models of helplessness is more complex. The prevailing model suggests that 5-HT autoreceptors become desensitized in response to stress exposure and antidepressant administration, two seemingly opposite manipulations. Thus there are still unresolved questions regarding the role of these receptors—and serotonin in general—in normal and pathological states.
Role of the 5-HT<inf>1A</inf> somatodendritic autoreceptor in the dorsal raphe nucleus on salt satiety signaling in rats
2009, Experimental Neurology
We investigated the possible role of 5-HT_1A somatodendritic autoreceptors in the dorsal raphe nucleus (DRN) on salt intake response during basal conditions and following natriorexigenic challenge aroused by sodium depletion in rats. Acute systemic administration (76–1520 nmol/kg s.c.) of 8-OH-DPAT, a selective 5-HT_1A somatodendritic autoreceptor agonist, induced a clear and dose-dependent preference for salt intake through free choice between water and 0.3 M NaCl simultaneously offered under basal conditions. Acute intra-DRN microinjection (7.5 nmol/rat) of 8-OH-DPAT significantly mimicked the acute systemic protocol in sodium-replete rats. Interestingly, microinjection of 8-OH-DPAT into the DRN raised an additional long-lasting increase of 0.3 M NaCl intake in sodium-depleted rats despite a high volume ingested 30 min after central injection. Conversely, chronic systemic treatment (1520 nmol/kg s.c.) with 8-OH-DPAT for 2 and 3 weeks or repeated intra-DRN microinjection (7.5 nmol/rat) evoked a significant long-term decrease in 0.3 M NaCl intake in sodium-depleted rats given only water and a sodium-deficient diet over the course of 24 h after furosemide injection. These results show a clear-cut involvement of the DRN 5-HT_1A somatodendritic autoreceptors in sodium satiety signaling under basal conditions and during the consummatory phase of salt intake in sodium-depleted rats.
Both acute and chronic buspirone treatments have different effects on regional 5-HT synthesis in Flinders Sensitive Line rats (a rat model of depression) than in control rats
2009, Neurochemistry International
The main objective of this investigation was to evaluate the effects of buspirone, a 5-HT_1A agonist with some partial agonist properties and also an antidepressant, on regional 5-HT synthesis in Flinders Sensitive Line (FSL) rats (“depressed”), and to compare the effects to the Flinders Resistant Line (FRL) control rats (not “depressed”). In addition results were compared to those previously reported in normal Sprague–Dawley (SPD) rats (normal control). Serotonin synthesis in both FSL and FRL rats was measured following acute and chronic treatments with buspirone. Both of these strains were derived from the SPD rats. No direct comparison was done between the FSL saline and FRL saline groups, or the FSL buspirone and FRL buspirone groups, because the objective of the studies was to evaluate effects of buspirone in these two strains. The results show that acute treatment with buspirone elevates 5-HT synthesis throughout the brain in the FRL rats. In the FSL rats, there were reductions in some brain regions (e.g., dorsal and median raphe, amygdala, anterior olfactory nucleus, substantia nigra reticulate), while in other regions, there were increases in the synthesis observed (e.g., frontal, parietal, visual and somatosensory cortices, ventral hippocampus). In 20 out of the 30 brain regions investigated in the FSL rats, there was no significant change in the synthesis following acute buspirone treatment. During the chronic treatment, buspirone produced a significant reduction of 5-HT synthesis in 15 out of 30 brain regions in the FRL rats. In the FSL rats, buspirone produced a significant elevation of the synthesis in 10 out of 30 brain regions. In both the FSL and FRL rats, buspirone produced rather different effects than those reported previously for SPD (normal) rats. The acute effect in the FSL rats was somewhat similar to the effect reported previously for the SPD rats, while in the FRL rats, the acute buspirone treatment produced an effect observed previously in treatments with 5-HT_1A antagonists suggesting an action of buspirone as partial agonist in FRL rats. The data suggest that with respect to 5-HT synthesis, FRL rats differ from SPD rats (a natural control; normal rats) and, as such, indicate that when the effects related to the serotonergic system (e.g., influence of serotonergic drugs) are studied in the FSL rats and compared to those in the FRL rats, any conclusions drawn may not reflect differences relative to a normal rat.

View all citing articles on Scopus

^∗: Present address: Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, Essex, CM20 2QR, U.K.

View full text

Hippocampal 5-HT synthesis and release in vivo is decreased by infusion of 8-OHDPAT into the nucleus raphe dorsalis

Abstract

Eur. J. Pharmacol.

Neurochem. Int.

Eur. J. Pharmacol.

Life Sci.

8-Hydroxy-2-di(n-propylamino)tetralin, 8-OHDPAT, a potent and selective simplified ergot congener with central 5-HT receptor stimulating activity

J. Neural Transm.