Levels of dopamine in blood and brain following nasal administration to rats

Dahlin, Maria; Jansson, Björn; Björk, Erik

doi:10.1016/s0928-0987(01)00151-8

Cited by 84 publications

(53 citation statements)

References 25 publications

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“…These subarachnoid extensions surrounding the axon create a low-resistance fluid pathway between the olfactory mucosa and the CSF in the subarachnoid space (5). Many nose-to-brain drug delivery studies have described high concentrations of drug appearing in and around the olfactory bulb within minutes after drug administration (6)(7)(8). In addition, several drugs have been visualized crossing these fluid pathways in the cribriform plate region from the nasal cavity to the CNS (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Effects of Localized Hydrophilic Mannitol and Hydrophobic Nelfinavir Administration Targeted to Olfactory Epithelium on Brain Distribution

Hoekman

2011

AAPS PharmSciTech

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Abstract. Many nasally applied compounds gain access to the brain and the central nervous system (CNS) with varying degree. Direct nose-to-brain access is believed to be achieved through nervous connections which travel from the CNS across the cribriform plate into the olfactory region of the nasal cavity. However, current delivery strategies are not targeted to preferentially deposit drugs to the olfactory at cribriform. Therefore, we have developed a pressurized olfactory delivery (POD) device which consistently and non-invasively deposited a majority of drug to the olfactory region of the nasal cavity in rats. Using both a hydrophobic drug, mannitol (log P=−3.1), and a hydrophobic drug, nelfinavir (log P=6.0), and POD device, we compared brain and blood levels after nasal deposition primarily on the olfactory region with POD or nose drops which deposited primarily on the respiratory region in rats. POD administration of mannitol in rats provided a 3.6-fold (p<0.05) increase in cortex-to-blood ratio, compared to respiratory epithelium deposition with nose drop. Administration of nelfinavir provided a 13.6-fold (p<0.05) advantage in cortex-to-blood ratio with POD administration, compared to nose drops. These results suggest that increasing the fraction of drug deposited on the olfactory region of the nasal cavity will result in increased direct nose-to-brain transport.

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Section: Introductionmentioning

confidence: 99%

Effects of Localized Hydrophilic Mannitol and Hydrophobic Nelfinavir Administration Targeted to Olfactory Epithelium on Brain Distribution

Hoekman

2011

AAPS PharmSciTech

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“…This supports the view that DA can readily enter the brain via the nose-brain pathway. With respect to this, Dahlin et al [13,14] compared intra-nasal to intravenous DA injection and reported an enhanced DA bioavailability in the brain upon intra-nasal administration of DA in mice and rats. Furthermore, Chemuturi et al [15] demonstrated that portions of the nasal mucosa are innervated by olfactory neurons expressing dopamine transporter (DAT), which may be responsible for the uptake of DA within the central nervous system.…”

Section: Introductionmentioning

confidence: 99%

Behavioral Actions of Intranasal Application of Dopamine: Effects on Forced Swimming, Elevated Plus-Maze and Open Field Parameters

et al. 2008

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Background: Recently, we found evidence that intra-nasally administered dopamine (DA), can enter the brain, leading to an immediate increase in extracellular DA levels in striatal subregions. This offers a potential alternative approach to target the brain with exogenous DA, which otherwise cannot cross the blood-brain barrier. Here, we examined whether intra-nasally applied DA also exerts behavioral activity on mesocortical and nigrostriatal dopaminergic functions. Method: Male Wistar rats (3–4 months) were tested for potential behavioral effects of intra-nasally applied DA (0.03, 0.3 or 3.0 mg/kg) in the forced swimming test (FST) for antidepressant-like activity, elevated plus-maze for anxiety-related behavior, and on motor activity in a novel and familiar environment. Results: Intra-nasally administered dopamine in a dose of 0.3 mg/kg exerted antidepressant-like activity in the FST, but had neither anxiolytic-like nor anxiogenic-like effects in the elevated plus-maze. Furthermore, intra-nasal dopamine stimulated locomotor activity in a familiar, but not novel, open field. Conclusions: These results support the view that intra-nasally applied DA can act on the central nervous system by entering the brain via the nose-brain pathway, making this kind of application procedure a promising alternative for targeting the brain, and thus treating disorders involving mesocortical and/or nigrostriatal dopaminergic disturbances.

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“…These results are in agreement with previous works showing a positive correlation between the lipid solubility of a compound and the ability to penetrate the barrier and the limited transmission of DA through the BBB [Oldendorf, 1971]. We chose the tissue sampling time, from injection to decapitation of the animal, of 15 min on the premise that a carotid artery carried bolus of a test substance would rapidly hit the brain endothelial barrier and equilibrate with brain extracellular spaces in the time plausibly comparable with the transmission along the olfactory epithelial pathways [Dahlin et al, 2001]. This time span also was commensurate with an inhibitory effect of intracarotid OL-DA injection on respiration we observed in previous test trials (unpublished observation), which cogently pointed to the action of OL-DA exerted beyond the BBB.…”

Section: Discussionmentioning

confidence: 99%

“…In the study by Dahlin et al [2001], nearly 100% of radioactivity was detected in the cerebrospinal fluid and brain during the first 30 min following nasal administration of [ 3 H]DA, but only 0.1% of it was ascribed to [ 3 H]DA with the rest belonging to DOPAC, a principal metabolic product of DA formed due to the action of monoamine oxidase. The metabolism of DA along with a restrictive BBB for it pointedly underscores the issue of replenishing the DA level from the systemic side in neurodegenerative DA deficient states.…”

Section: Discussionmentioning

confidence: 99%

Brain uptake of radiolabeled N‐oleoyl‐dopamine in the rat

Pokorski

Matysiak

Marczak

et al. 2003

Drug Development Research

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N-acyl-dopamines are a novel class of biologically active lipids that have recently been identified in the brain and have the potential to interact with neural signaling pathways. This study seeks to determine the ability of N-oleoyl-dopamine, a synthetic amide of oleic acid and dopamine, to cross the blood brain barrier. We determined the tissue content of radioactivity in selected brain regions, in a shortrun study design, following injections of [ 3 H]N-oleoyl-dopamine (0.4 mCi) into the internal carotid artery in the rat. These results were compared with intracarotid injections of [ 3 H]dopamine and with intravenous injections of both radiolabeled compounds. The level of radioactivity was determined using liquid scintillation and was expressed as the percentage of its total dose injected per gram of tissue. We found that the 15-min brain uptake of radioactivity, with no distinct regional variations, amounted to about 6% following the intracarotid [ 3 H]N-oleoyl-dopamine, which was a significant 3-4-fold increase over that following similar administration of [ H]dopamine. Intravenous injections of [3 H]N-oleoyl-dopamine gave a much smaller yield of radioactivity in brain tissue samples which was still severalfold greater than that for intravenous [ 3 H]dopamine. Qualitative thin-layered chromatography screening showed the presence of unchanged N-oleoyl-dopamine in the brain following injections. We conclude that N-oleoyl-dopamine has an appreciable ability to cross the blood-brain barrier, which contrasts the limited transfer of dopamine alone. N-oleoyl-dopamine might exert physiological effects due to its known affinity for the central vanilloid receptors or to better satisfying the brain tissue demand for dopamine. The study suggests a potential pharmacological role for N-oleoyl-dopamine delivered exogenously in helping regulate the brain function. Drug Dev. Res. 60:217-224, 2003.

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Levels of dopamine in blood and brain following nasal administration to rats

Cited by 84 publications

References 25 publications

Effects of Localized Hydrophilic Mannitol and Hydrophobic Nelfinavir Administration Targeted to Olfactory Epithelium on Brain Distribution

Effects of Localized Hydrophilic Mannitol and Hydrophobic Nelfinavir Administration Targeted to Olfactory Epithelium on Brain Distribution

Behavioral Actions of Intranasal Application of Dopamine: Effects on Forced Swimming, Elevated Plus-Maze and Open Field Parameters

Brain uptake of radiolabeled N‐oleoyl‐dopamine in the rat

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