5-HT1A and 5-HT2A serotonin receptor turnover in adult rat offspring prenatally exposed to cocaine

Vicentic, Aleksandra; Cabrera‐Vera, Theresa M.; Pinto, Wilfred; Battaglia, George

doi:10.1016/s0006-8993(00)02668-8

Cited by 8 publications

(7 citation statements)

References 49 publications

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“…B max values estimated by the model were 245 nM and 47.0 nM for D 2 receptors in striatum and 5-HT 2A receptors in frontal cortex, respectively. This 5-HT 2A receptor density is in line with the values of 25–60 nM estimated from in vitro studies (36–39) (assuming 10% protein content (40)). Average D 2 receptor density from in vitro studies is 48 nM (40) with a highest estimated value of 75 nM (41).…”

Section: Discussionsupporting

confidence: 88%

Pharmacokinetic-Pharmacodynamic Modeling of the D2 and 5-HT2A Receptor Occupancy of Risperidone and Paliperidone in Rats

et al. 2012

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PurposeA pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe the time course of brain concentration and dopamine D2 and serotonin 5-HT2A receptor occupancy (RO) of the atypical antipsychotic drugs risperidone and paliperidone in rats.MethodsA population approach was utilized to describe the PK-PD of risperidone and paliperidone using plasma and brain concentrations and D2 and 5-HT2A RO data. A previously published physiology- and mechanism-based (PBPKPD) model describing brain concentrations and D2 receptor binding in the striatum was expanded to include metabolite kinetics, active efflux from brain, and binding to 5-HT2A receptors in the frontal cortex.ResultsA two-compartment model best fit to the plasma PK profile of risperidone and paliperidone. The expanded PBPKPD model described brain concentrations and D2 and 5-HT2A RO well. Inclusion of binding to 5-HT2A receptors was necessary to describe observed brain-to-plasma ratios accurately. Simulations showed that receptor affinity strongly influences brain-to-plasma ratio pattern.ConclusionBinding to both D2 and 5-HT2A receptors influences brain distribution of risperidone and paliperidone. This may stem from their high affinity for D2 and 5-HT2A receptors. Receptor affinities and brain-to-plasma ratios may need to be considered before choosing the best PK-PD model for centrally active drugs.

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Section: Discussionsupporting

confidence: 88%

Pharmacokinetic-Pharmacodynamic Modeling of the D2 and 5-HT2A Receptor Occupancy of Risperidone and Paliperidone in Rats

et al. 2012

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“…The slow axoplasmic transport [29] and limited half-life of cytoskeletal proteins [30,31] render local synthesis a more effective means to deliver these proteins to distal axons or growth cones [32,33]. We do not know the half-life of serotonin receptor proteins in crayfish neurons, but the relatively stable lifespan (half-life >100 hours) of 5-HT 1A and 5-HT 2A receptors in rat [34] provides a reference. Secondly, therefore, the sparsity of receptor mRNA at sites where protein is most intensely labeled could be an outcome of a relatively short half-life of mRNA compared to the receptor protein.…”

Section: Discussionmentioning

confidence: 99%

5-HT receptors mediate lineage-dependent effects of serotonin on adult neurogenesis in Procambarus clarkii

2011

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BackgroundSerotonin (5-HT) is a potent regulator of adult neurogenesis in the crustacean brain, as in the vertebrate brain. However, there are relatively few data regarding the mechanisms of serotonin's action and which precursor cells are targeted. Therefore, we exploited the spatial separation of the neuronal precursor lineage that generates adult-born neurons in the crayfish (Procambarus clarkii) brain to determine which generation(s) is influenced by serotonin, and to identify and localize serotonin receptor subtypes underlying these effects.ResultsRT-PCR shows that mRNAs of serotonin receptors homologous to mammalian subtypes 1A and 2B are expressed in P. clarkii brain (referred to here as 5-HT1α and 5-HT2β). In situ hybridization with antisense riboprobes reveals strong expression of these mRNAs in several brain regions, including cell clusters 9 and 10 where adult-born neurons reside. Antibodies generated against the crustacean forms of these receptors do not bind to the primary neuronal precursors (stem cells) in the neurogenic niche or their daughters as they migrate, but do label these second-generation precursors as they approach the proliferation zones of cell clusters 9 and 10. Like serotonin, administration of the P. clarkii 5-HT1α-specific agonist quipazine maleate salt (QMS) increases the number of bromodeoxyuridine (BrdU)-labeled cells in cluster 10; the P. clarkii 5-HT2β-specific antagonist methiothepin mesylate salt (MMS) suppresses neurogenesis in this region. However, serotonin, QMS and MMS do not alter the rate of BrdU incorporation into niche precursors or their migratory daughters.ConclusionOur results demonstrate that the influences of serotonin on adult neurogenesis in the crayfish brain are confined to the late second-generation precursors and their descendants. Further, the distribution of 5-HT1α and 5-HT2β mRNAs and proteins indicate that these serotonergic effects are exerted directly on specific generations of neuronal precursors. Taken together, these results suggest that the influence of serotonin on adult neurogenesis in the crustacean brain is lineage dependent, and that 5-HT1α and 5-HT2β receptors underlie these effects.

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“…Receptor dynamics (production, degradation and half life) are also unaffected in adulthood by this exposure paradigm [98]. Unlike adolescents, adults show no change in 5-HT 1A -stimulated release of any hypothalamic hormone, and also have normal basal hormone levels [85].…”

Section: Serotonergic Signaling Throughout Developmentmentioning

confidence: 99%

“…5-HT 2A receptors have been strongly implicated in psychotic behavior [113], as well as contributing to impulsive behavior, depression and anxiety [114,115]. Similar to 5-HT 1A receptors, 5-HT 2A receptors contribute to the release of several hormones into the bloodstream in response to stress, and are commonly measured using receptor binding techniques [96,98]. …”

Section: Serotonergic Signaling Throughout Developmentmentioning

confidence: 99%

“…Receptor dynamics (production, degradation rate and half life) were also unaffected in adults following PC exposure [98], and no effect on adult basal function (to control hypothalamic hormone release) of 5-HT 2A receptors was observed. PC exposure in male rats can lead to enhanced desensitization of hypothalamic receptors following 2 weeks of paroxetine treatment, while not affecting receptor expression, as measured by diminished ACTH and oxytocin responses to a 5-HT 2A agonist [121].…”

Section: Serotonergic Signaling Throughout Developmentmentioning

confidence: 99%

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Prenatal Cocaine Disrupts Serotonin Signaling-Dependent Behaviors:Implications for Sex Differences, Early Stress and Prenatal SSRI Exposure

Williams

Lauder²,

Johns³

2011

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Prenatal cocaine (PC) exposure negatively impacts the developing nervous system, including numerous changes in serotonergic signaling. Cocaine, a competitive antagonist of the serotonin transporter, similar to selective serotonin reuptake inhibitors (SSRIs), also blocks dopamine and norepinephrine transporters, leaving the direct mechanism through which cocaine disrupts the developing serotonin system unclear. In order to understand the role of the serotonin transporter in cocaine’s effect on the serotonergic system, we compare reports concerning PC and prenatal antidepressant exposure and conclude that PC exposure affects many facets of serotonergic signaling (serotonin levels, receptors, transporters) and that these effects differ significantly from what is observed following prenatal SSRI exposure. Alterations in serotonergic signaling are dependent on timing of exposure, test regimens, and sex. Following PC exposure, behavioral disturbances are observed in attention, emotional behavior and stress response, aggression, social behavior, communication, and like changes in serotonergic signaling, these effects depend on sex, age and developmental exposure. Vulnerability to the effects of PC exposure can be mediated by several factors, including allelic variance in serotonergic signaling genes, being male (although fewer studies have investigated female offspring), and experiencing the adverse early environments that are commonly coincident with maternal drug use. Early environmental stress results in disruptions in serotonergic signaling analogous to those observed with PC exposure and these may interact to produce greater behavioral effects observed in children of drug-abusing mothers. We conclude that based on past evidence, future studies should put a greater emphasis on including females and monitoring environmental factors when studying the impact of PC exposure.

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5-HT1A and 5-HT2A serotonin receptor turnover in adult rat offspring prenatally exposed to cocaine

Cited by 8 publications

References 49 publications

Pharmacokinetic-Pharmacodynamic Modeling of the D2 and 5-HT2A Receptor Occupancy of Risperidone and Paliperidone in Rats

Pharmacokinetic-Pharmacodynamic Modeling of the D2 and 5-HT2A Receptor Occupancy of Risperidone and Paliperidone in Rats

5-HT receptors mediate lineage-dependent effects of serotonin on adult neurogenesis in Procambarus clarkii

Prenatal Cocaine Disrupts Serotonin Signaling-Dependent Behaviors:Implications for Sex Differences, Early Stress and Prenatal SSRI Exposure

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