The Experts below are selected from a list of 321 Experts worldwide ranked by ideXlab platform

Jonathan A Stamford - One of the best experts on this subject based on the ideXlab platform.

  • time window of Autoreceptor mediated inhibition of limbic and striatal dopamine release
    Synapse, 2002
    Co-Authors: Paul E M Phillips, Pamela J Hancock, Jonathan A Stamford
    Abstract:

    Forebrain dopamine release is under the local control of D2 family (D2 and D3) Autoreceptors. In this study, Autoreceptor-mediated modulation of forebrain dopamine release was investigated using amperometry in brain slices following local electrical stimulation. 350 microm-thick slices of nucleus accumbens or dorsolateral neostriatum were prepared from male Wistar rats (150-200 g) and superfused with artificial cerebrospinal fluid at 32 degrees C. Dopamine release was evoked by electrical pulses (0.1 ms, 10 mA) across bipolar tungsten stimulating electrodes and measured at carbon fibre microelectrodes using fixed potential amperometry (+300 mV vs. Ag/AgCl). Peak dopamine release on stimulation (single pulse) was 0.75 microM (neostriatum) and 1.37 microM (nucleus accumbens). Metoclopramide (1 microM) had no significant effect on DA efflux from a single pulse in either region. Using paired pulse stimuli, dopamine release on the second pulse varied according to the interval between the two pulses. At very long intervals (>20 sec), dopamine release was similar to that for the first pulse. At shorter intervals, dopamine efflux was attenuated. Metoclopramide had no effect on second pulse dopamine release when the pulse was applied at short ( 5.0 sec) intervals after the first. At intermediate intervals, metoclopramide significantly increased second pulse dopamine release. The peak dopamine Autoreceptor effect occurred at approximately 550 ms in neostriatum and approximately 700 ms in nucleus accumbens. The onset time is due both to diffusion of dopamine from the release sites to the Autoreceptors and receptor-effector mechanisms. These findings may have implications for the local control of forebrain dopamine function in physiological and pathological states.

  • multiple 5 ht1 Autoreceptor subtypes govern serotonin release in dorsal and median raphe nuclei
    Neuropharmacology, 2001
    Co-Authors: Sarah E Hopwood, Jonathan A Stamford
    Abstract:

    The present study investigated the possibility of multiple 5-HT1 Autoreceptor subtypes in the rostral raphe nuclei. Slices (350 μm) of rat dorsal or median raphe nucleus (DRN/MRN) were taken from male Wistar rats and superfused with artificial cerebrospinal fluid at 32°C. Fast cyclic voltammetry at carbon fibre microelectrodes was used to monitor serotonin (5-HT) release following local electrical stimulation. In both DRN and MRN, 5-HT release on short trains was reduced by the selective 5-HT1A agonist 8-OH-DPAT (1 μM), an effect blocked by the selective 5-HT1A antagonist WAY 100635 (0.1 μM) but not by SB 216641 (0.05 and 0.2 μM) or BRL 15572 (0.5 μM), selective antagonists at the 5-HT1B and 5-HT1D receptors respectively. The selective 5-HT1B agonist CP 93129 (0.3 μM) also reduced 5-HT release in both nuclei. Its effect was blocked by SB 216641 but not by WAY 100635 or BRL 15572. The 5-HT1D/1B agonist sumatriptan (0.5 μM) decreased 5-HT release in both DRN and MRN. In DRN, the effect of sumatriptan was blocked by BRL 15572 but not by WAY 100635 or SB 216641. In MRN, the effect of sumatriptan was not blocked by any of the above antagonists. BRL 15572 increased 5-HT release on long stimulations in DRN and MRN while WAY 100635 had no effect. SB 216641 increased 5-HT release in MRN but not DRN. WAY 100635 potentiated the effect of SB 216641 in DRN but not MRN. The data suggest that 5-HT release in DRN is controlled by 5-HT1A, 5-HT1B and 5-HT1D Autoreceptors. 5-HT release in MRN is controlled by 5-HT1A and 5-HT1B Autoreceptors and another, as yet unidentified mechanism.

  • multiple 5 ht1 Autoreceptor subtypes govern serotonin release in dorsal and median raphe nuclei
    Neuropharmacology, 2001
    Co-Authors: Sarah E Hopwood, Jonathan A Stamford
    Abstract:

    The present study investigated the possibility of multiple 5-HT(1) Autoreceptor subtypes in the rostral raphe nuclei. Slices (350 microm) of rat dorsal or median raphe nucleus (DRN/MRN) were taken from male Wistar rats and superfused with artificial cerebrospinal fluid at 32 degrees C. Fast cyclic voltammetry at carbon fibre microelectrodes was used to monitor serotonin (5-HT) release following local electrical stimulation. In both DRN and MRN, 5-HT release on short trains was reduced by the selective 5-HT(1A) agonist 8-OH-DPAT (1 microM), an effect blocked by the selective 5-HT(1A) antagonist WAY 100635 (0.1 microM) but not by SB 216641 (0.05 and 0.2 microM) or BRL 15572 (0.5 microM), selective antagonists at the 5-HT(1B) and 5-HT(1D) receptors respectively. The selective 5-HT(1B) agonist CP 93129 (0.3 microM) also reduced 5-HT release in both nuclei. Its effect was blocked by SB 216641 but not by WAY 100635 or BRL 15572. The 5-HT(1D/1B) agonist sumatriptan (0.5 microM) decreased 5-HT release in both DRN and MRN. In DRN, the effect of sumatriptan was blocked by BRL 15572 but not by WAY 100635 or SB 216641. In MRN, the effect of sumatriptan was not blocked by any of the above antagonists. BRL 15572 increased 5-HT release on long stimulations in DRN and MRN while WAY 100635 had no effect. SB 216641 increased 5-HT release in MRN but not DRN. WAY 100635 potentiated the effect of SB 216641 in DRN but not MRN. The data suggest that 5-HT release in DRN is controlled by 5-HT(1A), 5-HT(1B) and 5-HT(1D) Autoreceptors. 5-HT release in MRN is controlled by 5-HT(1A) and 5-HT(1B) Autoreceptors and another, as yet unidentified mechanism.

Sara R. Jones - One of the best experts on this subject based on the ideXlab platform.

  • dopamine d3 Autoreceptor inhibition enhances cocaine potency at the dopamine transporter
    Journal of Neurochemistry, 2016
    Co-Authors: Molly M Mcginnis, Cody A Siciliano, Sara R. Jones
    Abstract:

    Cocaine is a commonly abused central nervous system stimulant that enhances dopamine (DA) neurotransmission through its ability to block dopamine transporters (DATs). Recent evidence suggests there may be an interaction between DATs and D2/D3 Autoreceptors that modulates cocaine's effects. The purpose of this study was to explore how D2/D3 Autoreceptors modulate the ability of cocaine to inhibit DA uptake through DATs on pre-synaptic DA terminals. Using fast-scan cyclic voltammetry in brain slices containing the nucleus accumbens core from male and female C57BL/6J mice, we first sought to examine the effects of global Autoreceptor blockade using the non-selective D2/D3 Autoreceptor antagonist, raclopride. We found that the ability of cocaine to inhibit DA uptake was increased by raclopride and that this effect was consistent across sexes. Furthermore, using D2 (L-741,626) or D3 (SB-277011-A) Autoreceptor selective antagonists, we discovered that blockade of D3, but not D2, Autoreceptors was responsible for the increased cocaine potency. Alterations in cocaine potency were attributable to alterations in uptake inhibition, rather than cocaine effects on vesicular DA release, suggesting that these results may be a product of a functional D3/DAT interaction apart from the canonical inhibitory actions of D3 Autoreceptors on DA release. In addition, application of D2 (sumanirole) and D3 (PD 128907) Autoreceptor-specific agonists had inverse effects, whereby D2 Autoreceptor activation decreased cocaine potency and D3 Autoreceptor activation had no effect. Together, these data show that DA Autoreceptors dynamically regulate cocaine potency at the DAT, which is important for understanding cocaine's rewarding and addictive properties. We propose a model whereby presynaptic dopamine Autoreceptors dynamically modulate cocaine potency through two separate mechanisms. We demonstrate that D2 agonists decrease cocaine potency, whereas D3 antagonists increase cocaine potency, likely through an allosteric mechanism outside of their canonical actions on dopamine release. These findings give important and novel insight into the contribution of D2/D3 Autoreceptors to dopamine transporter function.

  • protein kinase c beta regulates the d2 like dopamine Autoreceptor
    Neuropharmacology, 2015
    Co-Authors: Kathryn D Luderman, Sara R. Jones, Rong Chen, Mark J Ferris, Margaret E. Gnegy
    Abstract:

    The focus of this study was the regulation of the D2-like dopamine Autoreceptor (D2 Autoreceptor) by protein kinase Cβ, a member of the protein kinase C (PKC) family. Together with the dopamine transporter, the D2 Autoreceptor regulates the level of extracellular dopamine and thus dopaminergic signaling. PKC regulates neuronal signaling via several mechanisms, including desensitizing Autoreceptors to increase the release of several different neurotransmitters. Here, using both PKCβ−/− mice and specific PKCβ inhibitors, we demonstrated that a lack of PKCβ activity enhanced the D2 Autoreceptor-stimulated decrease in dopamine release following both chemical and electrical stimulations. Inhibition of PKCβ increased surface localization of D2R in mouse striatal synaptosomes, which could underlie the greater sensitivity to quinpirole following inhibition of PKCβ. PKCβ−/− mice displayed greater sensitivity to the quinpirole-induced suppression of locomotor activity, demonstrating that the regulation of the D2 Autoreceptor by PKCβ is physiologically significant. Overall, we have found that PKCβ downregulates the D2 Autoreceptor, providing an additional layer of regulation for dopaminergic signaling. We propose that in the absence of PKCβ activity, surface D2 Autoreceptor localization and thus D2 Autoreceptor signaling is increased, leading to less dopamine in the extracellular space and attenuated dopaminergic signaling.

  • Amphetamine Self-Administration Attenuates Dopamine D2 Autoreceptor Function
    Neuropsychopharmacology, 2014
    Co-Authors: Erin S. Calipari, Deborah J. Luessen, Sara R. Jones, Khalil Eldeeb, Xin Feng, Allyn C Howlett, Rong Chen
    Abstract:

    Dopamine D2 Autoreceptors located on the midbrain dopaminergic neurons modulate dopamine (DA) neuron firing, DA release, and DA synthesis through a negative-feedback mechanism. Dysfunctional D2 Autoreceptors following repeated drug exposure could lead to aberrant DA activity in the ventral tegmental area (VTA) and projection areas such as nucleus accumbens (NAcc), promoting drug-seeking and -taking behavior. Therefore, it is important to understand molecular mechanisms underlying drug-induced changes in D2 Autoreceptors. Here, we reported that 5 days of amphetamine (AMPH) self-administration reduced the ability of D2 Autoreceptors to inhibit DA release in the NAcc as determined by voltammetry. Using the antibody-capture [^35S]GTP γ S scintillation proximity assay, we demonstrated for the first time that midbrain D2/D3 receptors were preferentially coupled to G α i2, whereas striatal D2/D3 receptors were coupled equally to G α i2 and G α o for signaling. Importantly, AMPH abolished the interaction between G α i2 and D2/D3 receptors in the midbrain while leaving striatal D2/D3 receptors unchanged. The disruption of the coupling between D2/D3 receptors and G α i2 by AMPH is at least partially explained by the enhanced RGS2 (regulator of G-protein signaling 2) activity resulting from an increased RGS2 trafficking to the membrane. AMPH had no effects on the midbrain expression and trafficking of other RGS proteins such as RGS4 and RGS8. Our data suggest that midbrain D2/D3 receptors are more susceptible to AMPH-induced alterations. Reduced D2 Autoreceptor function could lead to enhanced DA signaling and ultimately addiction-related behavior. RGS2 may be a potential non-dopaminergic target for pharmacological intervention of dysfunctional DA transmission and drug addiction.

  • loss of Autoreceptor functions in mice lacking the dopamine transporter
    Nature Neuroscience, 1999
    Co-Authors: Sara R. Jones, Donald C Cooper, Francis J White, Raul R Gainetdinov, Marc G Caron, Mark R Wightman
    Abstract:

    Autoreceptors provide an important inhibitory feedback mechanism for dopamine neurons by altering neuronal functions in response to changes in extracellular levels of dopamine. Elevated dopamine may be a component of several neuropsychiatric disorders. However, evidence concerning the state of Autoreceptors in such conditions has remained elusive. The function of dopamine Autoreceptors was assessed in mice lacking the dopamine transporter (DAT). Genetic deletion of the DAT gene in mice results in a persistent elevation in levels of extracellular dopamine. Direct assessment of impulse-, synthesis- and release-regulating Autoreceptors in these mice reveals a nearly complete loss of function. These findings may provide insight into the neurochemical consequences of hyperdopaminergia.

Sidney B. Auerbach - One of the best experts on this subject based on the ideXlab platform.

  • Autoreceptor antagonists enhance the effect of the reuptake inhibitor citalopram on extracellular 5 ht this effect persists after repeated citalopram treatment
    Neuropharmacology, 1997
    Co-Authors: C Gundlah, S Hjorth, Sidney B. Auerbach
    Abstract:

    Abstract The effect of repeated administration of the reuptake inhibitor citalopram (10 mg/kg s.c., b.i.d. for 14 days) or saline on extracellular 5-hydroxytryptamine (5-HT) and Autoreceptor sensitivity was assessed using microdialysis in the frontal cortex (FCx) and dorsal hippocampus (DH) of unanesthetized rats. Acute citalopram (5 mg/kg s.c.) challenge produced significant increases in DH and FCx 5-HT. The nonselective 5-HT1A/1B receptor antagonist (−)-penbutolol (8 mg/kg s.c.), administered 2 hr after citalopram challenge, significantly enhanced 5-HT in FCx and DH of both the chronic citalopram and saline pretreatment groups. Administration of the selective 5-HT1A receptor antagonist WAY 100635 (0.3 mg/kg s.c.) after citalopram challenge significantly enhanced 5-HT in FCx but not DH of both pretreatment groups. This suggests that there may be differences between DH and FCx in regulation of 5-HT release. Nevertheless, these results provide evidence that 5-HT Autoreceptors are still active in restraining 5-HT release even after repeated administration of an antidepressant drug. © 1997 Elsevier Science Ltd.

  • Effect of chronic administration of the selective serotonin (5-HT) uptake inhibitor citalopram on extracellular 5-HT and apparent Autoreceptor sensitivity in rat forebrain in vivo
    Naunyn-Schmiedeberg's Archives of Pharmacology, 1995
    Co-Authors: Sidney B. Auerbach, Stephan Hjorth
    Abstract:

    Rats were administered the selective serotonin (5-HT) uptake blocker citalopram or saline for 14 days to determine if prolonged treatment would lead to changes in extracellular 5-HT or Autoreceptor sensitivity. One day after drug withdrawal, dialysis probes were implanted in the frontal cortex and dorsal hippocampus. Dialysis experiments were carried out using chloral hydrate anesthetized rats. The experimental protocol comprised the administration of three consecutive drug challenges: (1) After stable baseline levels were obtained, citalopram was infused through the dialysis probes to locally block uptake in the forebrain. (2) Subsequently, a 5-HT_1B receptor agonist (RU24969 or CP93,129) was infused through the probe to test for changes in terminal Autoreceptor sensitivity. (3) Last, citalopram was administered systemically to test the effect of indirect activation of somatodendritic Autoreceptors. Under these conditions, with uptake already blocked locally in the forebrain, systemic citalopram produces a decrease in extracellular 5-HT, an effect that can be inhibited by pretreatment with antagonists of 5-HT_1A receptors. The results indicate that during local infusion of citalopram extracellular 5-HT was significantly higher in the dorsal hippocampus of the chronic citalopram as compared to saline treatment group. This difference persisted throughout the full time course of the experiment. However, the decreases in 5-HT levels produced by local infusion of a 5-HT_1B receptor agonist or after systemic citalopram administration were not significantly different between the chronic citalopram and saline treated groups. There were no significant differences between chronic citalopram and saline treated animals in frontal cortex. These results suggest that prolonged inhibition of 5-HT uptake may produce a selective change in the regulation of release from median raphe 5-HT neurons, but this change could not be clearly linked to a change in nerve terminal or somatodendritic Autoreceptor sensitivity.

  • systemic uptake inhibition decreases serotonin release via somatodendritic Autoreceptor activation
    Synapse, 1995
    Co-Authors: John J Rutter, Chrisana Gundlah, Sidney B. Auerbach
    Abstract:

    In vivo microdialysis was used to examine the effects of peripheral uptake inhibition on extracellular serotonin (5-HT). Previous results from this lab indicated that systemic fluoxetine caused a decrease in 5-HT when terminal uptake was inhibited by local infusion of the uptake blocker. We hypothesized that the decrease in 5-HT levels in the terminal region was due to an increase in 5-HT in the vicinity of the inhibitory somatodendritic Autoreceptors in the dorsal raphe nucleus (DRN). To test this prediction, rats were implanted with probes in both the basal diencephalon (a nerve terminal region) and the DRN (the cell body region). Fluoxetine (10 mg/kg i.p.) increased extracellular 5-HT, in a depolarization-dependent manner, by approximately 140% in both areas. In a separate experiment, fluoxetine was infused into the diencephalon overnight to block nerve terminal uptake sites. This pretreatment caused an eight- to 10-fold increase in 5-HT levels. Subsequent systemic fluoxetine, sertraline, or paroxetine, produced a 50% decrease in extracellular 5-HT in the diencephalon, presumably due to activation of the 5-HT1A somatodendritic Autoreceptors. Consistent with this hypothesis, systemic administration of the 5-HT1 antagonists spiperone, penbutolol, or WAY100135 reversed the fluoxetine-induced decrease in 5-HT to approximately 85% of the pre-fluoxetine baseline levels. Likewise, pretreatment with penbutolol, but not selective s-adrenergic antagonists, blocked the fluoxetine-induced decrease in release. These findings suggest that the ability of acute systemic 5-HT uptake inhibition to elevate nerve terminal 5-HT is limited by Autoreceptor activation following elevation of 5-HT in the DRN. © 1995 Wiley-Liss, Inc.

Francesc Artigas - One of the best experts on this subject based on the ideXlab platform.

  • preferential in vivo action of f15599 a novel 5 ht1a receptor agonist at postsynaptic 5 ht1a receptors
    British Journal of Pharmacology, 2010
    Co-Authors: Laia Lladopelfort, Francesc Artigas, Mariebernadette Assie, Adrian Newmantancredi, Pau Celada
    Abstract:

    Background and purpose:  F15599, a novel 5-hydroxytryptamine (5-HT)1A receptor agonist with 1000-fold selectivity for 5-HT compared with other monoamine receptors, shows antidepressant and procognitive activity at very low doses in animal models. We examined the in vivo activity of F15599 at somatodendritic Autoreceptors and postsynaptic 5-HT1A heteroreceptors. Experimental approach:  In vivo single unit and local field potential recordings and microdialysis in the rat. Key results:  F15599 increased the discharge rate of pyramidal neurones in medial prefrontal cortex (mPFC) from 0.2 µg·kg−1 i.v and reduced that of dorsal raphe 5-hydroxytryptaminergic neurones at doses >10-fold higher (minimal effective dose 8.2 µg·kg−1 i.v.). Both effects were reversed by the 5-HT1A antagonist (±)WAY100635. F15599 did not alter low frequency oscillations (∼1 Hz) in mPFC. In microdialysis studies, F15599 increased dopamine output in mPFC (an effect dependent on the activation of postsynaptic 5-HT1A receptors) with an ED50 of 30 µg·kg−1 i.p., whereas it reduced hippocampal 5-HT release (an effect dependent exclusively on 5-HT1A Autoreceptor activation) with an ED50 of 240 µg·kg−1 i.p. Likewise, application of F15599 by reverse dialysis in mPFC increased dopamine output in a concentration-dependent manner. All neurochemical responses to F15599 were prevented by administration of (±)WAY100635. Conclusions and implications:  These results indicate that systemic administration of F15599 preferentially activates postsynaptic 5-HT1A receptors in PFC rather than somatodendritic 5-HT1A Autoreceptors. This regional selectivity distinguishes F15599 from previously developed 5-HT1A receptor agonists, which preferentially activate somatodendritic 5-HT1A Autoreceptors, suggesting that F15599 may be particularly useful in the treatment of depression and of cognitive deficits in schizophrenia.

  • preferential potentiation of the effects of serotonin uptake inhibitors by 5 ht1a receptor antagonists in the dorsal raphe pathway role of somatodendritic Autoreceptors
    Journal of Neurochemistry, 2002
    Co-Authors: Luz Romero, Francesc Artigas
    Abstract:

    5-HT 1A Autoreceptor antagonists enhance the effects of antidepressants by preventing a negative feedback of serotonin (5-HT) at somatodendritic level. The maximal elevations of extracellular concentration of 5-HT (5-HT ext ) induced by the 5-HT uptake inhibitor paroxetine in forebrain were potentiated by the 5-HT 1A antagonist WAY-100635 (1 mg/kg s.c.) in a regionally dependent manner (striatum > frontal cortex > dorsal hippocampus). Paroxetine (3 mg/kg s.c.) decreased forebrain 5-HT ext during local blockade of uptake. This reduction was greater in striatum and frontal cortex than in dorsal hippocampus and was counteracted by the local and systemic administration of WAY-100635. The perfusion of 50 μmol/L citalopram in the dorsal or median raphe nucleus reduced 5-HT ext in frontal cortex or dorsal hippocampus to 40 and 65% of baseline, respectively. The reduction of cortical 5-HT ext induced by perfusion of citalopram in midbrain raphe was fully reversed by WAY-100635 (1 mg/kg s.c.). Together, these data suggest that dorsal raphe neurons projecting to striatum and frontal cortex are more sensitive to self-inhibition mediated by 5-HT 1A Autoreceptors than median raphe neurons projecting to the hippocampus. Therefore, potentiation by 5-HT 1A antagonists occurs preferentially in forebrain areas innervated by serotonergic neurons of the dorsal raphe nucleus.

  • the 5 ht1a antagonist way 100635 selectively potentiates the presynaptic effects of serotonergic antidepressants in rat brain
    Neuroscience Letters, 1996
    Co-Authors: Luz Romero, Ildefonso Hervas, Francesc Artigas
    Abstract:

    The increases in extracellular serotonin (5-hydroxytryptamine; 5-HT) produced by some antidepressent drugs in forebrain are attenuated by the activation of somatodendritic 5-HT1A Autoreceptors by the excess 5-HT induced by these agents in the midbrain raphe. Using microdialysis, we have examined the effects of the selective 5-HT1A antagonist WAY-100635 in rats pretreated with the selective 5-HT reuptake inhibitors (SSRIs) citalopram, fluoxetine, fluvoxamine, the tricyclic antidepressants clomipramine and desipramine and the monoamine oxidase inhibitor phenelzine. WAY-100635 markedly potentiated the increases in 5-HT produced by the SSRIs, clomipramine and phenelzine but it did not alter that produced by desipramine. These results indicate that the effects of serotonergic antidepressant drugs (but not those of desipramine, which mainly blocks noradrenaline reuptake) can be potentiated by 5-HT1A Autoreceptor blockade.

John F Neumaier - One of the best experts on this subject based on the ideXlab platform.

  • 5 ht1b Autoreceptor regulation of serotonin transporter activity in synaptosomes
    Synapse, 2012
    Co-Authors: Catherine E Hagan, Ross A Mcdevitt, Yusha Liu, Amy R Furay, John F Neumaier
    Abstract:

    Serotonin-1B (5-HT(1B) ) Autoreceptors are located in serotonin (5-HT) terminals, along with serotonin transporters (SERT), and play a critical role in autoregulation of serotonergic neurotransmission and are implicated in disorders of serotonergic function, particularly emotional regulation. SERT modulates serotonergic neurotransmission by high-affinity reuptake of 5-HT. Alterations in SERT activity are associated with increased risk for depression and anxiety. Several neurotransmitter receptors are known to regulate SERT K(m) and V(max) , and previous work suggests that 5-HT(1B) Autoreceptors may regulate 5-HT reuptake, in addition to modulating 5-HT release and synthesis. We used rotating disk electrode voltammetry to investigate 5-HT(1B) Autoreceptor regulation of SERT-mediated 5-HT uptake into synaptosomes. The selective 5-HT(1B) antagonist SB224289 decreased SERT activity in synaptosomes prepared from wild-type but not 5-HT(1B) knockout mice, whereas SERT uptake was enhanced after pretreatment with the selective 5-HT(1B) agonist CP94253. Furthermore, SERT activity varies as a function of 5-HT(1B) receptor expression-specifically, genetic deletion of 5-HT(1B) decreased SERT function, while viral-mediated overexpression of 5-HT(1B) Autoreceptors in rat raphe neurons increased SERT activity in rat hippocampal synaptosomes. Considered collectively, these results provide evidence that 5-HT(1B) Autoreceptors regulate SERT activity. Because SERT clearance rate varies as a function of 5-HT(1B) Autoreceptor expression levels and is modulated by both activation and inhibition of 5-HT(1B) Autoreceptors, this dynamic interaction may be an important mechanism of serotonin autoregulation with therapeutic implications.

  • regulation of dorsal raphe nucleus function by serotonin Autoreceptors a behavioral perspective
    Journal of Chemical Neuroanatomy, 2011
    Co-Authors: Ross A Mcdevitt, John F Neumaier
    Abstract:

    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.

  • serotonin 1b Autoreceptors originating in the caudal dorsal raphe nucleus reduce expression of fear and depression like behavior
    Biological Psychiatry, 2011
    Co-Authors: Ross A Mcdevitt, Ryoko Hiroi, Scott M Mackenzie, Nick C Robin, Aaron Cohn, Jeansok J Kim, John F Neumaier
    Abstract:

    Background Serotonin 1B (5-HT 1B ) Autoreceptors regulate release of serotonin from terminals of dorsal raphe nucleus (DRN) projections. Expression of 5-HT 1B in the DRN inversely correlates with behavioral measures of emotion, and viral-mediated overexpression of 5-HT 1B receptors in the middle DRN inversely reduces measures of fear and anxiety in unstressed rats. Because the caudal subregion of the DRN is important in translating stress into emotional dysregulation, we explored behavioral functions of 5-HT 1B Autoreceptors in the caudal DRN. Methods We manipulated 5-HT 1B Autoreceptor function in rats using either viral-mediated gene transfer into the caudal DRN or systemic injections of the 5-HT 1B agonist 3-(1,2,5,6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP-94253). Rats were tested in forced swim test, open field test, and contextual fear conditioning. Results Overexpression of 5-HT 1B in the caudal DRN increased swimming in the forced swim test. It did not alter locomotion or thigmotaxis in the open field test but did reduce conditioned freezing. Freezing was reduced when 5-HT 1B overexpression was present only during testing but not training. The CP-94253 exerted an inverted U-shaped dose response curve on conditioned freezing, with most pronounced effects seen at 1 mg/kg. At this dose, CP-94253 administered before a fear retention test reduced freezing both during that session and in subsequent drug-free testing, but only when drug was paired with re-exposure to the fear context. Conclusions The 5-HT 1B Autoreceptors originating in the caudal DRN regulate behavioral expression of helplessness and fear. Because systemic pharmacologic treatment with a 5-HT 1B agonist facilitates reductions in fear, 5-HT 1B receptors may be a target for the treatment of certain anxiety disorders.

  • overexpression of 5 ht1b receptor in dorsal raphe nucleus using herpes simplex virus gene transfer increases anxiety behavior after inescapable stress
    The Journal of Neuroscience, 2002
    Co-Authors: Michael R Clark, Timothy J Sexton, Molly Mcclain, Daniel Root, Ruth Kohen, John F Neumaier
    Abstract:

    5-HT(1B) Autoreceptors have been implicated in animal models of stress and are regulated selectively by serotonin-selective reuptake inhibitors such as fluoxetine. These terminal Autoreceptors regulate serotonin release from dorsal raphe nucleus (DRN) projections throughout rat forebrain. However, it has not been previously possible to manipulate 5-HT(1B) Autoreceptor activity selectively without also changing 5-HT(1B) activity in other neurons mediating different behavioral responses. Therefore, we have developed a viral-mediated gene transfer strategy to express hemagglutinin-tagged 5-HT(1B) and manipulate these Autoreceptors in DRN. Green fluorescent protein (GFP) was coexpressed from a separate transcriptional unit on the same amplicon to assist in monitoring infection and expression. We confirmed the expression and biological activity of both transgenic proteins in vitro. When injected directly into DRN using stereotaxic procedure, HA-5-HT(1B) receptors were expressed in serotonergic neurons and translocated to the forebrain. The effect of DRN expression of HA-5-HT(1B) on stress-induced behaviors was compared with control rats that received GFP-only amplicons. There was no change in immobility in the forced swim test. However, HA-5-HT(1B) expression significantly reduced entrances into the central region of an open-field arena after water-restraint stress without altering overall locomotor activity, but not in the absence of stress exposure. HA-5-HT(1B) expression also reduced entries into the open arms of the elevated plus maze after water restraint. Because these tests are sensitive to increases in anxiety-like behavior, our results suggest that overactivity of 5-HT(1B) Autoreceptors in DRN neurons may be an important mediator of pathological responses to stressful events.