Robust presynaptic serotonin 5-HT<sub>1B</sub> receptor inhibition of the striatonigral output and its sensitization by chronic fluoxetine treatment

Ding, Shengyuan; Li, Li; Zhou, Fu-Ming

doi:10.1152/jn.00831.2014

Cited by 16 publications

(12 citation statements)

References 72 publications

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“…In addition to ChIs, striatal 5-HT1B heteroreceptor regulates transmission in glutamatergic nerve terminals innervating the nucleus accumbens (36) and in SPNs innervating either the midbrain (37,38) or the pallidum (39), whereas 5-HT1B autoreceptor is found in striatal terminals of serotonergic neurons (40). Interestingly, mice bearing a constitutive deletion of 5-HT1B display aggressive behavior and reduced anxiety relative to WT, but do not display anhedonia (28,31).…”

Section: Discussionmentioning

confidence: 99%

Opposing roles for serotonin in cholinergic neurons of the ventral and dorsal striatum

Virk

Sagi

Medrihan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Little is known about the molecular similarities and differences between neurons in the ventral (vSt) and dorsal striatum (dSt) and their physiological implications. In the vSt, serotonin [5-Hydroxytryptamine (5-HT)] modulates mood control and pleasure response, whereas in the dSt, 5-HT regulates motor behavior. Here we show that, in mice, 5-HT depolarizes cholinergic interneurons (ChIs) of the dSt whereas hyperpolarizing ChIs from the vSt by acting on different 5-HT receptor isoforms. In the vSt, 5-HT1A (a postsynaptic receptor) and 5-HT1B (a presynaptic receptor) are highly expressed, and synergistically inhibit the excitability of ChIs. The inhibitory modulation by 5-HT1B, but not that by 5-HT1A, is mediated by p11, a protein associated with major depressive disorder. Specific deletion of 5-HT1B from cholinergic neurons results in impaired inhibition of ACh release in the vSt and in anhedonic-like behavior.5-HT1A | 5-HT1B | cholinergic interneurons | ventral striatum | TRAP C holinergic interneurons (ChIs) represent only 1-2% of all striatal neurons (1). Despite their low abundance, ChIs play a major role in striatal function, by modulating both inputs to and outputs from spiny projection neurons (SPNs) (2). In the ventral striatum (vSt), ChIs are thought to play a major role in mediating reward, motivation, food intake, and hedonic behavior, whereas ChIs of the dorsal striatum (dSt) are implicated in motor behavior and action selection (3-5). Despite their functional differences, only a few morphological differences between vSt and dSt ChIs have been demonstrated, but no molecular differences between these two populations have been reported (6).Serotonin [5-Hydroxytryptamine (5-HT)] signaling in the striatum has long been implicated in modulating locomotion as well as in mood control (7-9). Striatal 5-HT levels are high, and multiple 5-HT receptors (5-HTRs) are thought to mediate the function of 5-HT in these circuits (7, 10). In dSt ChIs, several 5-HTRs (5-HT7, 5-HT6, and 5-HT2) have been reported to induce membrane depolarization (11,12), but the role of 5-HT signaling in vSt ChIs and its implication for mood regulation are poorly understood. To elucidate the role of 5-HT in vSt ChIs, we used electrophysiological recordings, optogenetics, and cell type-specific gene expression analysis. We demonstrate that 5-HT1A and 5-HT1B synergistically inhibit the function of vSt ChIs. The effect of activation of 5-HT1B, but not that of 5-HT1A, is mediated by p11. Furthermore, deletion of 5-HT1B from cholinergic neurons resulted in a loss of pleasure response (anhedonia), a core symptom of major depressive disorder. ResultsOpposite Effects of 5-HT on Cell Excitability Between vSt ChIs and dSt ChIs. To investigate the effect of 5-HT on ChIs from the vSt and dSt, we carried out electrophysiological recordings from visually identified neurons in acute brain slices. To identify ChIs, we used translating ribosome affinity purification (TRAP) mice expressing a GFP-tagged ribosomal protein, L10a, under the choline acetyltrans...

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Section: Discussionmentioning

confidence: 99%

Opposing roles for serotonin in cholinergic neurons of the ventral and dorsal striatum

Virk

Sagi

Medrihan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…This would reflect a particular phenomenon that an antidepressant has to overcome the negative tone of 5-HT1B on 5-HT transmission in order to produce a clinical effect. In other words, desensitization and inhibition of 5-HT1B function is mandatory for an antidepressant action [155]. In agreement with this, PET studies have showed that the 5-HT1B binding in brain is reduced in the dorsal brain stem (DBS) after effective treatment of MDD [156].…”

Section: -Ht1b and Depressionmentioning

confidence: 81%

“…Increased adverse side effects and lack of benefits in treating depression in AD were shown in antidepressants particularly sertraline and mirtazapine in a randomized, multicenter, double blind, placebo-controlled trial [236]. We suggest that the refractoriness of SSRIs in AD could be due to SSRI-induced molecular events in AD that might, early, activate or increase expression of 5-HT inhibitory receptors such as 5-HT1B and 5-HT1A instead of the desired desensitization of these receptors [155]. Consequently, activation of these receptors would results in lower intracellular 5-HT levels and subsequent decrease in the release of 5-HT in longer time scales.…”

Section: Modulations Of Sertmentioning

confidence: 88%

Association of Platelet Serotonin Levels in Alzheimer’s Disease with Clinical and Cerebrospinal Fluid Markers

Tajeddinn

Fereshtehnejad

Ahmed

et al. 2016

JAD

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“…In this scenario, the relevant 5-HT1B receptors would be expressed by striatonigral (direct pathway) neurons and be situated on their terminals in the substantia nigra to inhibit GABA release from these neurons (Ding et al, 2015; see Castanon et al, 2000, for discussion). Reduced GABA release would be expected to increase (disinhibit) dopamine input to striatal neurons (Castanon et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

The 5-HT1B serotonin receptor regulates methylphenidate-induced gene expression in the striatum: Differential effects on immediate-early genes

et al. 2017

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Drug combinations that include a psychostimulant such as methylphenidate (Ritalin) and a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine are indicated in several medical conditions. Co-exposure to these drugs also occurs with “cognitive enhancer” use by individuals treated with SSRIs. Methylphenidate, a dopamine reuptake inhibitor, by itself produces some addiction-related gene regulation in the striatum. We have demonstrated that co-administration of SSRIs potentiates these methylphenidate-induced molecular effects, thus producing a more “cocaine-like” profile. There is evidence that the 5-HT1B serotonin receptor subtype mediates some of the cocaine-induced gene regulation. We thus investigated whether the 5-HT1B receptor also modifies methylphenidate-induced gene regulation, by assessing effects of a selective 5-HT1B receptor agonist (CP94253) on immediate-early gene markers (Zif268, c-Fos, Homer1a) in adolescent male rats. Gene expression was measured by in situ hybridization histochemistry. Our results show that CP94253 (3, 10 mg/kg) produced a dose-dependent potentiation of methylphenidate (5 mg/kg)-induced expression of Zif268 and c-Fos. This potentiation was widespread in the striatum and was maximal in lateral (sensorimotor) sectors, thus mimicking the effects seen after cocaine alone, or co-administration of fluoxetine. However, in contrast to fluoxetine, this 5-HT1B agonist did not influence methylphenidate-induced expression of Homer1a. CP94253 also potentiated methylphenidate-induced locomotor activity. These findings indicate that stimulation of the 5-HT1B receptor can enhance methylphenidate (dopamine)-induced gene regulation. This receptor may thus participate in the potentiation induced by fluoxetine (serotonin) and may serve as a pharmacological target to attenuate methylphenidate+SSRI-induced “cocaine-like” effects.

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Robust presynaptic serotonin 5-HT_1B receptor inhibition of the striatonigral output and its sensitization by chronic fluoxetine treatment

Cited by 16 publications

References 72 publications

Opposing roles for serotonin in cholinergic neurons of the ventral and dorsal striatum

Opposing roles for serotonin in cholinergic neurons of the ventral and dorsal striatum

Association of Platelet Serotonin Levels in Alzheimer’s Disease with Clinical and Cerebrospinal Fluid Markers

The 5-HT1B serotonin receptor regulates methylphenidate-induced gene expression in the striatum: Differential effects on immediate-early genes

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Robust presynaptic serotonin 5-HT1B receptor inhibition of the striatonigral output and its sensitization by chronic fluoxetine treatment

Cited by 16 publications

References 72 publications

Opposing roles for serotonin in cholinergic neurons of the ventral and dorsal striatum

Opposing roles for serotonin in cholinergic neurons of the ventral and dorsal striatum

Association of Platelet Serotonin Levels in Alzheimer’s Disease with Clinical and Cerebrospinal Fluid Markers

The 5-HT1B serotonin receptor regulates methylphenidate-induced gene expression in the striatum: Differential effects on immediate-early genes

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Robust presynaptic serotonin 5-HT_1B receptor inhibition of the striatonigral output and its sensitization by chronic fluoxetine treatment