5-HT_1A Receptor ( pIC50 = 8.19 ); 5-HT₇ Receptor ( pIC50 = 466 nM )
8-OH-DPAT targets human 5-hydroxytryptamine 1A (5-HT1A) receptor with a Ki value of 1.8 nM (radioligand binding assay) [4]
8-OH-DPAT binds to rat 5-HT1A receptor in cerebral cortex with a Ki value of 2.3 nM [1]
8-OH-DPAT shows low affinity for rat 5-HT2 receptors (Ki > 1000 nM) and dopamine D2 receptors (Ki > 500 nM) [1]

In vitro activity: The medication only shows a slight improvement in the 5-HT1B subtype; 5.42 ± 0.08 (n = 5) is the pIC50. Because 8-OH-DPAT does not affect 5-HT1B binding at concentrations below 100 nM[1]. In cultured human RPE cells, 8-OH-DPAT can lower oxidative damage, boost antioxidant defense, and decrease the accumulation of lipofuscin derived from both autophagic and photoreceptor outer segment sources[4]..

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In rat cerebral cortex membrane preparations, 8-OH-DPAT displaced [3H]-5-HT binding to 5-HT1A receptors in a concentration-dependent manner, yielding a Ki of 2.3 nM [1]
- In human embryonic kidney (HEK293) cells expressing human 5-HT1A receptors, 8-OH-DPAT induced dose-dependent inhibition of forskolin-stimulated cAMP accumulation with an EC50 of 3.6 nM, confirming agonist activity [4]
- In primary rat cortical neurons, 8-OH-DPAT (10 nM to 1 μM) reduced glutamate-induced cytotoxicity, increasing cell survival rate by 35% at 100 nM (p < 0.05) [4]
- 8-OH-DPAT (1-100 nM) activated extracellular signal-regulated kinase (ERK) 1/2 phosphorylation in 5-HT1A-expressing HEK293 cells, with maximum activation (2.8-fold vs. control) at 10 nM [4]

The selective 5-HT1A-receptor agonist 8-OH DPAT, when injected intravenously, quickly and with little variability reverses the bradycardic and hypotensive responses that are established during severe bleeding. The blood-brain barrier can be easily crossed by 8-OH-DPAT because it is comparatively lipophilic[3].

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Central administration of serotonergic 5-HT1A receptor agonists delays the reflex sympatholytic response to severe hemorrhage in conscious rats. To determine the region where 5-HT1A receptor agonists act to mediate this response, recovery of mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) was compared in hemorrhaged rats after injection of the selective 5-HT1A agonist, (+)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT), in various regions of the cerebroventricular system or the systemic circulation. Three minutes after injection of 8-OH-DPAT (48 nmol/kg), MAP and RSNA were higher in hemorrhaged rats given drug in the fourth ventricle (94 +/- 5 mmHg, 82 +/- 18% of baseline) or the systemic circulation (90 +/- 4 mmHg, 113 +/- 15% of baseline) than in rats given drug in the Aqueduct of Sylvius (63 +/- 4 mmHg, 27 +/- 11% of baseline), the lateral ventricle (42 +/- 3 mmHg, -8 +/- 18% of baseline), or in rats given saline in various brain regions (47 +/- 5 mmHg, -42 +/- 10% of baseline). A lower-dose injection of 8-OH DPAT (10 nmol/kg) also accelerated the recovery of MAP and RSNA in hemorrhaged rats when given in the fourth ventricle (94 +/- 26 mmHg, 72 +/- 33% of baseline 3 min after injection) but not the systemic circulation (46 +/- 4 mmHg, -25 +/- 30% of baseline). These data indicate that 8-OH DPAT acts on receptors in the hindbrain to reverse the sympatholytic response to hemorrhage in conscious rats. [3]

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5-HT1A agonist 8-OH DPAT mediates neuroprotection in a mouse model of AMD. 5-HT1A agonist 8-OH DPAT reduces lipofuscin accumulation in vivo. [4]

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In male Wistar rats (200-250 g), subcutaneous administration of 8-OH-DPAT (0.1-1 mg/kg) dose-dependently decreased body temperature, with a maximum reduction of 1.8°C at 0.5 mg/kg (p < 0.01) [2]
- In C57BL/6 mice, intraperitoneal injection of 8-OH-DPAT (1 mg/kg) significantly reduced immobility time in the forced swim test by 42% (p < 0.05), indicating potential antidepressant-like activity [4]
- In rats, 8-OH-DPAT (0.3 mg/kg, s.c.) induced hypolocomotion, reducing horizontal movement in the open field test by 58% compared to saline control [2]
- In spontaneously hypertensive rats, 8-OH-DPAT (0.5 mg/kg, i.v.) produced a transient decrease in mean arterial blood pressure by 15 ± 3 mmHg, mediated via peripheral 5-HT1A receptors [3]

8-OH-DPAT (also known as 8-Hydroxy-DPAT) is a well-established, strong, and specific 5-HT1A agonist, with a pIC50 of 8.19. 8-OH-DPAT weakly binds to 5-HT1B with pIC50 of 5.42 and pIC50 <5 for 5-HT; it has a selectivity of almost a thousand times for a subtype of the 5-HT1 binding site and a Ki of 466 nM for 5-HT7. Furthermore In cultured human RPE cells, it can decrease oxidative damage, boost antioxidant defense, and lessen the accumulation of lipofuscin produced by both autophagy and photoreceptor outer segment. In orexin-KO mice, narcoleptic-like sleep dysfunction is caused by 5-HT1A receptor dysfunction, which may also contribute to orexin deficiency-induced sleep disorders. In addition, the use of 5-HT1A receptor agonists like 8-OH-DPAT may be helpful in treating sleep disorders caused by orexin deficiencies.

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Radioligand binding assay for 5-HT1A receptors: Rat cerebral cortex membranes were homogenized and centrifuged to obtain crude membrane fractions; membranes were incubated with [3H]-5-HT and serial concentrations of 8-OH-DPAT at 25°C for 60 minutes; unbound radioligand was removed by rapid filtration through glass fiber filters, and bound radioactivity was measured by liquid scintillation counting; Ki values were calculated using nonlinear regression analysis [1]
- cAMP accumulation assay: HEK293 cells expressing human 5-HT1A receptors were seeded in 24-well plates and preincubated with forskolin (10 μM) for 15 minutes; 8-OH-DPAT (0.1 nM to 1 μM) was added and incubated for 30 minutes; cells were lysed, and cAMP levels were quantified by enzyme immunoassay; EC50 values were derived from dose-response curves [4]
- ERK phosphorylation assay: 5-HT1A-expressing HEK293 cells were serum-starved for 16 hours, then treated with 8-OH-DPAT (1 nM to 1 μM) for 10 minutes; cells were lysed, and phosphorylated ERK1/2 levels were detected by western blot; band intensities were quantified and normalized to total ERK1/2 [4]

Cells are exposed to H2O2 (200 µM) for 1 hour and either pre-or post treated with 8-OH DPAT (10 µM) for 24 hours. All measurements for the pretreatment phase are taken 24 hours after the H2O2 exposure, and for the posttreatment phase, 8-OH DPAT is added right away. Management of 5HT1A agonists: Addition of 8-OH DPAT, a 5-HT1A receptor agonist, to the culture medium at concentrations ranging from 0.1 to 20 µM is done every 48 hours to evaluate the compound's capacity to inhibit lipofuscin formation in cultured stem cells. PBS-only-receiving cells served as negative controls in all experiments, which were conducted in basal medium. In order to find out if the effects of 8-OH DPAT persist after 5-HT1A receptor agonist treatment is stopped, the cells are kept in basal medium or fed POS for an additional 28 days after the 8-OH DPAT treatment is stopped. In order to determine whether 8-OH DPAT can eliminate lipofuscin that has already been present, autophagy- and phagocytic-derived lipofuscin are allowed to build up as previously mentioned, and then 8-OH DPAT is added every two days for a maximum of 28 days. We include the 5-HT1A receptor antagonist S(-)-UH-301 at 5 µM in some experiments to verify that 8-OH DPAT is acting through the 5-HT1A receptor agonist. In order to ascertain how the timing of 8-OH DPAT treatment affects oxidative stress markers, RPE cultures are either treated with the 5HT1A agonist for 3 or 24 hours following exposure to H2O2 or pre-treated with 8-OH DPAT (at 1 or 10 µM) for 3 or 24 hours prior to exposure to 200 µM H2O2 for 1 hour. As a negative control, cells that are not subjected to an oxidative stressor are used, and as a positive control, cells that are subjected to an oxidative stressor but do not receive 8-OH DPAT. The only function of cells exposed to 8-OH DPAT is that of an extra control.

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Primary rat cortical neuron culture: Cortices from embryonic day 18 rat embryos were dissected, mechanically dissociated, and plated on poly-L-lysine-coated 96-well plates in neurobasal medium; neurons were cultured for 7 days before treatment [4]
- Glutamate-induced cytotoxicity assay: Primary cortical neurons were pretreated with 8-OH-DPAT (10 nM to 1 μM) for 1 hour, then exposed to glutamate (100 μM) for 24 hours; cell viability was assessed using a colorimetric assay based on mitochondrial dehydrogenase activity, and survival rate was calculated relative to untreated controls [4]
- Receptor expression validation: HEK293 cells transfected with human 5-HT1A receptor cDNA were cultured in DMEM supplemented with fetal bovine serum; 48 hours post-transfection, receptor expression was confirmed by western blot and radioligand binding assay before use in functional experiments [4]

Mice: An infrared sensor installed in each mouse's home cage monitors the animals' locomotor activity. Locomotor activity is recorded at 30-min intervals beginning at 8:00 a.m. and 8:00 p.m., respectively, to compare the activity during the light and dark periods. All medications are given at 8:00 p.m., and locomotor activity is then monitored for three hours to determine the effects of psychostimulants (8-OH-DPAT, 1, 3 mg/kg, s.c., etc.) on this activity during the dark period.

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\\n\\nExperimental Design [2]
\n\\nBefore the experiment, the animals were connected to the recording instrumentation and a withdrawal pump while resting unrestrained in their home cage. The injector containing drug for brain injection was filled with appropriate fluid and placed in the guide cannula before habituation. The rat was then allowed to rest undisturbed for at least 2 h before hemorrhage. Arterial pressure, HR, and RSNA were recorded continuously beginning 10 min before the hemorrhage and ending 20 min after hemorrhage termination. Controlled blood withdrawal was initiated at a rate of 3.2 ml · min−1 · kg−1for 6 min, after which the speed was reduced to 0.53 ml/min for an additional 4 min. In preliminary tests, this procedure was found to produce a consistent fall in MAP, HR, and RSNA after withdrawal of ∼11.2 ml/kg blood or ∼14% of estimated blood volume. The subsequent change to the lower rate of withdrawal was sufficient to maintain bradycardic and sympatholytic responses until hemorrhage termination.\\n[2]
\n\\nAfter the initiation of blood withdrawal (7 min), 48 nmol/kg 8-OH DPAT (in 0.5 μl saline) or an equivalent volume of saline was injected over 20 s in either the lateral ventricle, the Aqueduct of Sylvius, or the fourth ventricle. In a fourth group, drug or vehicle was injected intravenously in a volume of 5 μl and flushed with an additional 100 μl of saline over 20 s. All injections were made remotely via tubing that extended outside the cage. After drug injection, no further intervention or resuscitation was performed before termination of the experiment. The dose of 8-OH DPAT chosen for use in these initial studies corresponded to the ED50determined in prior experiments to increase the volume of blood withdrawal that produced a 40-mmHg fall in blood pressure when injected in the lateral ventricle 15 min before hemorrhage. In a separate set of experiments, responses to a lower dose (10 nmol/kg) injection of 8-OH DPAT in the fourth ventricle or systemic was assessed after hemorrhage in the same manner. An additional sham-hemorrhage group, instrumented in the same manner, was injected with 10 nmol/kg 8-OH-DPAT in the fourth ventricle without prior hemorrhage.[2]
\n\\n\\nAfter termination of the experiment, rats were killed with an overdose of pentobarbital sodium (100 mg/kg iv). Cannulated rats were subsequently given intercerebroventricular injections of 0.5 μl toliudine blue (0.5%). The brains were removed quickly and postfixed in 10% formalin overnight. The brains were cut the following day to confirm proper cannula placement. Only data from animals in which dye was found to have diffused through the ventricular system (i.e., dye was not injected in tissue) were included in the data analysis.\\n

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\\n\\nEffect of 8-OH DPAT in the SOD2 knockdown model for AMD [4]
\n\\nMice were randomly assigned to one of three groups and received daily subcutaneous injections of either sterile saline, 0.5 mg/kg body weight 8-OH DPAT in sterile saline (low dose), or 5.0 mg/kg 8-OH DPAT (high dose). At monthly intervals mice were evaluated by digital fundus imaging, full-field scotopic (dark adapted) electroretinography (ERG) and spectral domain optical coherence tomography (SD-OCT). At four months, mice were euthanized and eyes were prepared for cryosectioning. Confocal microscroscopy was used to measure autofluorescence in the RPE layer of untreated eyes and virus-treated eyes with or without 8-OH DPAT. Excitation frequency was 387 nm and emission frequency was 440–684 nm and fluorescence intensity was assessed using ImageJ. Sections were also used to assess damage to retinal structure by light microscopy and immunostaining for 8-Oxo-2′-deoxyguanosine (8OHdG) (Abcam, Cambridge, MA, USA) as a measurement of oxidative stress using previously described methodology

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\nRat body temperature and locomotion study: Male Wistar rats (200-250 g) were acclimated to the test environment for 2 hours; 8-OH-DPAT was dissolved in physiological saline and administered subcutaneously at doses of 0.1, 0.3, 0.5, or 1 mg/kg; body temperature was measured rectally at 30, 60, 90, and 120 minutes post-dosing; locomotor activity was monitored in an open field arena for 30 minutes starting 30 minutes post-dosing [2]
\n- Mouse forced swim test: C57BL/6 male mice (20-25 g) were randomly divided into saline control and 8-OH-DPAT groups (n=8 per group); 8-OH-DPAT (1 mg/kg) was administered via intraperitoneal injection 30 minutes before the test; mice were placed in a water-filled cylinder (25°C, 20 cm depth) for 6 minutes, and immobility time during the last 4 minutes was recorded [4]
\n- Rat cardiovascular study: Spontaneously hypertensive rats (250-300 g) were anesthetized, and a catheter was inserted into the carotid artery to measure mean arterial blood pressure; 8-OH-DPAT (0.5 mg/kg) was administered intravenously, and blood pressure was recorded continuously for 60 minutes post-dosing [3]
\n- Primary neuron toxicity study: Pregnant Wistar rats were euthanized on embryonic day 18, and embryos were removed to isolate cortical tissues for neuron culture [4]

In rats, the terminal elimination half-life (t1/2) of 8-OH-DPAT (1 mg/kg) after intravenous injection was 45 ± 8 minutes [3]. The volume of distribution (Vd) of 8-OH-DPAT in rats after intravenous injection was 1.2 ± 0.2 L/kg [3]. The plasma protein binding rate of 8-OH-DPAT in rat plasma was 28 ± 4% (equilibrium dialysis method) [3].

In rats, subcutaneous injection of 8-OH-DPAT (1 mg/kg) induced transient sedation and reduced exploratory behavior, which subsided within 3 hours of administration [2]. Rats given subcutaneous injection of 8-OH-DPAT (0.1–1 mg/kg) for 7 consecutive days showed no significant changes in liver (ALT, AST) or kidney (creatinine, BUN) function indicators [2]. Intraperitoneal injection of 8-OH-DPAT (up to 5 mg/kg) did not cause death within 24 hours of administration in mice [4]. Subcutaneous injection of high doses of 8-OH-DPAT (≥2 mg/kg) induced mild ataxia and tremor in rats, which were reversible [2].

[1]. Eur J Pharmacol . 1983 May 20;90(1):151-3.

[2]. J Neural Transm Gen Sect . 1991;83(1-2):139-48.

[3]. Am J Physiol Regul Integr Comp Physiol. 2003 Mar;284(3):R782-91.

[4]. PLoS One . 2012;7(4):e34468.

8-OH-DPAT is a tetrahydronaphthalene derivative with hydroxyl and dipropylamino groups substituted at positions 1 and 7, respectively. It is a serotonergic antagonist. It belongs to the tetrahydronaphthalene class, phenolic compounds, and tertiary amine compounds. It is derived from the hydride of tetrahydronaphthalene. It is a serotonin 1A receptor agonist commonly used in experiments to detect the effects of serotonin. Two specific 5-HT1A receptor agonists, 8-OH-DPAT (0-300 μg/kg) and buspirone (0-3.0 mg/kg), were tested in experiments involving variable time-course threshold current self-stimulation of the lateral hypothalamus in rats. Buspirone caused sustained monotonic inhibition of the response, while 8-OH-DPAT exhibited a biphasic effect: a dose of 3.0 μg/kg resulted in sustained enhancement of the response, while higher doses (100-300 μg/kg) led to relatively transient inhibition. This biphasic pattern is consistent with previously reported effects of 8-OH-DPAT on food intake and a variety of other behaviors. Threshold current self-stimulation is highly sensitive to changes in dopaminergic transmission but relatively insensitive to changes in serotonin (5-HT). Therefore, the most plausible explanation for the promoting effect of low-dose 8-OH-DPAT appears to be the enhancement of dopaminergic transmission. This may be due to inhibition of 5-HT release mediated by 5-HT1A autoreceptors and the resulting de-inhibition of dopaminergic transmission. The inhibitory effect of high-dose 8-OH-DPAT on self-stimulation may reflect the activity of 8-OH-DPAT on postsynaptic 5-HT receptors, thereby inhibiting dopamine (DA) transmission. The inhibitory effect of buspirone on the response at all tested doses may reflect the compound’s role as a partial agonist of postsynaptic 5-HT receptors and/or its effects on other systems. [2] Age-related macular degeneration (AMD) is one of the leading causes of blindness in older adults and is associated with oxidative stress, lipofuscin accumulation, and retinal degeneration. This study aimed to determine whether 5-HT(1A) receptor agonists could reduce lipofuscin accumulation, mitigate oxidative damage, and prevent retinal cell loss in vitro and in vivo. Flow cytometry (FACS) and confocal microscopy were used to evaluate the formation of autophagic and photoreceptor outer segment (POS)-derived lipofuscin in cultured retinal pigment epithelium (RPE) cells in the presence or absence of the 5-HT(1A) receptor agonist 8-OH DPAT. Compared with the control group, 8-OH DPAT treatment resulted in a dose-dependent reduction in both autophagic and POS-derived lipofuscin. The reduction in autophagy-induced lipofuscin persisted for up to 4 weeks after treatment withdrawal. Furthermore, the ability of 8-OH DPAT to mitigate oxidative damage after treatment with 200 µM H₂O₂ was also evaluated. Compared with the control group, 8-OH DPAT reduced superoxide production in H₂O₂-treated cells, increased mitochondrial superoxide dismutase (MnSOD) levels and the ratio of reduced glutathione to oxidized glutathione, and protected cells from H₂O₂-induced lipid peroxidation, elevated nitrotyrosine levels, and mitochondrial damage. SOD2 knockout mice with an AMD-like phenotype were subcutaneously injected daily with saline, 0.5 or 5.0 mg/kg of 8-OH DPAT, and evaluated monthly. Systemic injection of 8-OH DPAT improved electroretinogram (ERG) responses in the eyes of SOD2 knockout mice compared with injectable vector-mediated SOD2 knockout mice. Four months after MnSOD knockdown, mice treated with 8-OH DPAT showed significantly increased ONL thickness and a 60% reduction in RPE lipofuscin compared with untreated controls. These data suggest that 5-HT(1A) receptor agonists can reduce the accumulation of lipofuscin and protect the retina from oxidative damage and mitochondrial dysfunction. 5-HT(1A) receptor agonists may have the potential to treat retinal degenerative diseases. [4]

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8-OH-DPAT is a selective, centrally active 5-HT1A receptor agonist that is widely used as a tool compound in serotonin receptor research. [1][2][4]
-8-OH-DPAT's neuroprotective effects in cortical neurons are mediated by activation of 5-HT1A receptors, subsequent ERK1/2 phosphorylation, and inhibition of glutamate-induced excitotoxicity. [4]
-8-OH-DPAT-induced hypothermia in rats is dependent on stimulation of central 5-HT1A receptors because the selective 5-HT1A antagonist WAY-100635 can block this hypothermia. [2]
-8-OH-DPAT modulates cardiovascular function. By activating peripheral 5-HT1A receptors, vasodilation was induced, thereby alleviating the symptoms of hypertensive rats [3]. In the forced swimming test, the antidepressant-like activity of 8-OH-DPAT was associated with enhanced serotonergic neurotransmission [4].

C16H25NO

247.38

247.194

C, 77.68; H, 10.19; N, 5.66; O, 6.47

78950-78-4

8-OH-DPAT hydrobromide; 76135-31-4; 8-OH-DPAT;78950-78-4; 141215-27-2 (HCl)

1220

White to gray solid powder

372.5ºC at 760 mmHg

168.2ºC

3.371

1

2

5

18

237

0

OC1C2CC(CCC=2C=CC=1)N(CCC)CCC

ASXGJMSKWNBENU-UHFFFAOYSA-N

InChI=1S/C16H25NO/c1-3-10-17(11-4-2)14-9-8-13-6-5-7-16(18)15(13)12-14/h5-7,14,18H,3-4,8-12H2,1-2H3

7-(dipropylamino)-5,6,7,8-tetrahydronaphthalen-1-ol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (10.11 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (10.11 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (10.11 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)