Occupancy of Agonist Drugs at the 5-HT1A Receptor

Bantick, R Alexander; Rabiner, Eugenii A.; Hirani, Ella; Vries, M. Hugo de; Hume, Susan P.; Grasby, Paul M.

doi:10.1038/sj.npp.1300390

Cited by 45 publications

(40 citation statements)

References 81 publications

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“…A single dose of 10 or 40 mg of buspirone occupies ϳ5% 5-HT 1A receptors in healthy human subjects (Rabiner et al, 2000;Passchier et al, 2001). A similar low fraction (Ͻ10%) of occupancy in humans has been observed with other selective and nonselective 5-HT 1A agonists such as tandospirone, flesinoxan, and EMD 128 130 after single or multiple clinical doses capable of activating central 5-HT 1A receptor functions (Nakayama et al, 2002;Rabiner et al, 2002;Bantick et al, 2004). Results of the current study are consistent with these literature observations, suggesting that high levels of 5-HT 1A receptor occupancy are not required to elicit an anxiolytic effect either preclinically in rats and clinically in humans.…”

Section: Discussionmentioning

confidence: 63%

6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine_1AReceptor Occupancy in Rats

Wong

Dockens²,

Pajor³

et al. 2007

Drug Metab Dispos

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ABSTRACT:The pharmacokinetics and in vivo potency of 6-hydroxybuspirone (6-OH-buspirone), a major metabolite of buspirone, were investigated. The plasma clearance (47.3 ؎ 3.5 ml/min/kg), volume of distribution (2.6 ؎ 0.3 l/kg), and half-life (1.2 ؎ 0.2 h) of 6-OHbuspirone in rats were similar to those for buspirone. Bioavailability was higher for 6-OH-buspirone (19%) compared with that for buspirone (1.4%). After intravenous infusions to steady-state levels in plasma, 6-OH-buspirone and buspirone increased 5-hydroxytryptamine (HT) 1A Buspirone ( Fig. 1) is a potent and selective 5-HT 1A receptor partial agonist that has been prescribed for the treatment of generalized anxiety disorders (Sramek et al., 2002;Blier and Ward, 2003;Goodman, 2004). Although the onset of action of buspirone is relatively slow and the efficacy is only obtained after chronic treatment, therapy with buspirone is not associated with undesirable side effects such as sedation, cognitive impairment, withdrawal symptoms, and potential abuse liability that can occur with benzodiazepine treatment (Eison and Temple, 1986;Tunnicliff, 1991;Argyropoulos and Nutt, 1999). Buspirone has also been suggested to have a role in the treatment of depressive disorders (Thase et al., 1998;Blier and Ward, 2003).Current hypotheses on the clinical mechanisms of action of buspirone focus on its agonist activities on 5-HT 1A receptors (Schreiber and De Vry, 1993;Blier and Ward, 2003). Belonging to the superfamily of G-protein-coupled receptors, 5-HT 1A receptors share a high identity (89%) of their transmembrane-spanning amino acid sequences in humans and rats (Albert et al., 1990). They are abundant as presynaptic (somatodendritic) autoreceptors on serotonergic neurons, primarily in the midbrain dorsal raphe nucleus; activation of the 5-HT 1A autoreceptors inhibits the neuronal activity and results in a reduction of 5-HT release in terminal synapses of the serotonergic neurons (Blier and Ward, 2003). 5-HT 1A receptors are also present as postsynaptic receptors in the forebrain limbic structures; activation of these receptors inhibits activities of postsynaptic neurons innervated by serotonergic axonal terminals. It has been hypothesized that prolonged activation of 5-HT 1A autoreceptors in the dorsal raphe with 5-HT 1A agonists, such as buspirone and its analogs, results in desensitization of the receptors and consequently increases releases of 5-HT in the limbic regions (Blier and Ward, 2003). The enhanced serotonergic functions are believed to be responsible for anxiolytic and antidepressant effects of these agents. Although behavioral/clinical effects of buspirone and other 5-HT 1A agonists are believed to be mediated through occupying and acting on 5-HT 1A receptors, the level of 5-HT 1A receptor occupancy required for the effects has not been well investigated. In two human positron emission tomography studies, little or no occupancy of 5-HT 1A receptors has been observed after administration of clinically efficacious doses of buspirone (Rabiner et al., 200...

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Section: Discussionmentioning

confidence: 63%

6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine_1AReceptor Occupancy in Rats

Wong

Dockens²,

Pajor³

et al. 2007

Drug Metab Dispos

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“…Antagonists such as diprenorphine or naloxone bind homogeneously to both, but agonists such as morphine or methadone bind with high affinity only to G-protein-coupled receptors (e.g., Bantick et al, 2004). Given that our studies show exogenous agonists at behaviorally active doses do not result in detectable occupancy, it is interesting to note that endogenous peptides, whose in vitro intrinsic efficacies are comparable with morphine, seem to be able to block in vivo binding of radiolabeled diprenorphine.…”

Section: Sensitivity Of [mentioning

confidence: 79%

Low Sensitivity of the Positron Emission Tomography Ligand [¹¹C]Diprenorphine to Agonist Opiates

Hume¹,

Lingford‐Hughes²,

Nataf³

et al. 2007

J Pharmacol Exp Ther

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Previously, we reported minimal opioid receptor occupancy following a clinical dose of the -opioid agonist, methadone, measured in vivo using positron emission tomography (PET) with [11 C]diprenorphine and subsequently used rats to obtain experimental data in support of a high receptor reserve hypothesis (Melichar et al., 2005). Here, we report on further preclinical studies investigating opioid receptor occupancy with oxycodone (-and -receptor agonist), morphine (-receptor agonist), and buprenorphine (partial agonist at the -receptor and antagonist at the ␦-and -receptors), each given at antinociceptive doses. In vivo binding of [ 11 C]diprenorphine was not significantly reduced after treatment with the full agonists but was reduced by ϳ90% by buprenorphine. In addition, given that [ 11 C]diprenorphine is a non-subtype-specific PET tracer, there was no regional variation that might feasibly be interpreted as due to differences in opioid subtype distribution. The data support minimal competition between the high-efficacy agonists and the non-subtype-selective antagonist radioligand and highlight the limitations of [ 11 C]diprenorphine PET to monitor in vivo occupancy. Alternative means may be needed to address clinical issues regarding opioid receptor occupancy that are required to optimize treatment strategies.Positron emission tomography (PET) with the radioligand, [ 11 C]diprenorphine has been used for over a decade to assess or measure opioid receptor function in human brain. Specific binding of this ligand in vivo can be blocked by the opioid receptor antagonist, naloxone (13 g/kg naloxone resulted in ϳ50% reduction in binding; Melichar et al., 2003) and is locally reduced in conditions expected to result in an increased concentration of endogenous agonist; for example, pain (for review, see Sprenger et al., 2005). We had therefore used PET with [ 11 C]diprenorphine to quantify opioid receptor occupancy in methadone-maintained opiate-dependent patients. Our aim was to address clinical issues in treatment of opioid dependence such as agonist dose-to-outcome, with a view to optimizing treatment strategies but, in the end, found no statistically significant reduction in specific binding compared with control (Melichar et al., 2005). A likely explanation was that clinically relevant doses (18 -90 mg daily) of methadone result in low levels of occupancy of opioid receptors. Other factors considered were receptor trafficking, agonist concentration at the site of action, and, since the predominant form of the opioid receptor in vivo is a low agonist affinity state, the limited ability of agonists to block highaffinity binding of an antagonist radiotracer.

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“…Written informed consent was obtained in accordance with the procedures set by the Human Subjects Protection Committee, University of California, Los Angeles. None of the subjects had a history of other neurological, medical, or psychiatric condition and all were free from medication with possible effect on 5-HT 1A receptors (28 , a word list learning task, was also used as a memory-specific test for demonstration of cognitive changes in the MCI group (11). To diagnose MCI, we followed the American Academy of Neurology guidelines for amnestic MCI (i.e., memory impairment without other cognitive impairments) (30).…”

Section: Methodsmentioning

confidence: 99%

Serotonin 1A receptors in the living brain of Alzheimer's disease patients

Kepe

Barrio

Huang

et al. 2006

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

217

154

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[F-18]MPPF ͉ brain 5-HT1A receptors ͉ neuronal loss ͉ positron emission tomography E xtensive brain cell loss in vulnerable cortical neuronal populations is one of the most striking hallmarks of Alzheimer's disease (AD). Neuronal loss appears to be correlated with the presence of abundant intraneuronal neurofibrillary tangles (NFTs) and is also an excellent parameter to correlate with the degree of dementia (1). Among the vulnerable neurons affected in the earliest stages of the disease are large pyramidal neurons in the CA1 and subicular regions of hippocampus, a part of the medial temporal lobe (MTL) system supporting declarative memory (2). The pattern of neuronal loss in AD is distinctively different from the cell loss observed in normal aging and is highest in entorhinal cortex and hippocampus CA1 region (1, 3). Although these large pyramidal neurons are glutamatergic in nature, they receive inhibitory serotonergic input from the dorsal raphe nucleus via the serotonin 1A (5-HT 1A ) receptors located on their axonal hillock (4). The correlation between the loss of glutamatergic pyramidal neurons in CA1 field of hippocampus and the decrease in 5-HT 1A receptor densities in the same areas was demonstrated earlier by using in vitro 4- [F-18] and can be partially attributed to the neuronal loss in epileptic foci (6). Availability of methods for 5-HT 1A receptor density quantification with PET therefore offers an excellent opportunity for in vivo assessment of neuronal damage in 5-HT 1A receptor-rich areas in AD, particularly in hippocampus. In this work, changes in 5-HT 1A receptor densities in the living brain of AD patients (ADs) and mild cognitive impairment patients (MCIs) were also correlated with global and regional measures of glucose metabolic activity, with the extent and spatial distribution of the NFT͞␤-amyloid senile plaque deposition and with behavioral measures [e.g., Mini Mental State Exam (MMSE) and Buschke scores]. In vitro autoradiography in ADs and normal subject brain specimens was used in support of the observations in living subjects.

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Occupancy of Agonist Drugs at the 5-HT1A Receptor

Cited by 45 publications

References 81 publications

6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine_1AReceptor Occupancy in Rats

6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine_1AReceptor Occupancy in Rats

Low Sensitivity of the Positron Emission Tomography Ligand [¹¹C]Diprenorphine to Agonist Opiates

Serotonin 1A receptors in the living brain of Alzheimer's disease patients

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Occupancy of Agonist Drugs at the 5-HT1A Receptor

Cited by 45 publications

References 81 publications

6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine1AReceptor Occupancy in Rats

6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine1AReceptor Occupancy in Rats

Low Sensitivity of the Positron Emission Tomography Ligand [11C]Diprenorphine to Agonist Opiates

Serotonin 1A receptors in the living brain of Alzheimer's disease patients

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Product

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6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine_1AReceptor Occupancy in Rats

6-Hydroxybuspirone Is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5-Hydroxytryptamine_1AReceptor Occupancy in Rats

Low Sensitivity of the Positron Emission Tomography Ligand [¹¹C]Diprenorphine to Agonist Opiates