Pharmacokinetics and bioavailability after intramuscular injection of the 5-HT1A serotonin agonist R-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in domestic goats (Capra aegagrus hircus).

To determine the bioavailability and pharmacokinetic properties of the serotonin 5-HT1A receptor agonist R-8-OH-DPAT in goats, and 0.1 mg kg-1 R-8-OH-DPAT hydrobromide was administered intramuscularly (i.m.) and intravenously (i.v.) to six goats in a two-phase cross-over design experiment. Venous blood samples were collected from the jugular vein 2, 5, 10, 15, 20, 30, 40 and 60 min following treatment and analysed by liquid chromatography tandem mass spectrometry. Bioavailability and pharmacokinetic parameters were determined by a one-compartment analysis. Mean bioavailability of R-8-OH-DPAT when injected i.m. was 66%. The mean volume of distribution in the central compartment was 1.47 L kg-1 . The mean plasma body clearance was 0.056 L kg-1  min-1 . All goats injected i.v. and two of six goats injected i.m. showed signs of serotonin toxicity. In conclusion, R-8-OH-DPAT is well absorbed following i.m. injection and the observed pharmacokinetics suggest that administration via dart is feasible. Administration of R-8-OH-DPAT hydrobromide, at a dosage of 0.1 mg kg-1 , resulted in the observation of clinical signs of serotonin toxicity in the goats. It is suggested that dosages for the clinical use of the compound should be lower in order to achieve the desired clinical effect without causing serotonin toxicity.

Neuron density and serotonin receptor binding in prefrontal cortex in suicide.

Although serotonin receptor and cytoarchitectonic alterations are reported in prefrontal cortex (PFC) in suicide and depression, no study has considered binding relative to neuron density. Therefore, we measured neuron density and serotonin transporter (SERT), 5-HT1A and 5-HT2A binding in matched suicides and controls. Suicides and normal controls (n=15 matched pairs) were psychiatrically characterized. Neuron density and binding were determined in dorsal [Brodmann area (BA) 9] and ventral (BA 47) PFC by stereology and quantitative autoradiography in near-adjacent sections. Binding index was defined as the ratio of receptor binding to neuron density. Suicides had lower neuron density in the gyrus of both areas. The binding index was lower for SERT in BA 47 but not in BA9; the 5-HT1A binding index was higher in BA 9 but not in BA 47, while the 5-HT2A binding index was not different between groups. SERT binding was lower in suicides in BA 47 but not BA 9, while 5-HT1A binding was higher in BA 9 but not BA 47. SERT binding negatively correlated with 5-HT1A binding in BA 47 in suicides. Neuron density decreased with age. The 5-HT1A binding index was higher in females than males. We found lower neuron density and lower SERT binding index in both PFC regions in suicides. More 5-HT1A binding with less SERT binding and the negative correlation in depressed suicides suggests post-synaptic receptor up-regulation, and it is independent of the difference in neuron density. Thus, abnormalities in both cortical neurons and in their serotonergic innervation are present in suicides and future studies will need to determine whether cortical changes reflect the trophic effect of altered serotonin innervation.

WAY100635 prevents the changes induced by fluoxetine upon the 5-HT1A receptor functionality.

5-HT1A receptor-mediated signalling in rat brain was evaluated after chronic administration (14 days; s.c.) of the selective serotonin reuptake inhibitor (SRRI) fluoxetine (10 mg/kg/day) alone, or in combination with the 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg/day). The density of 5-HT1A binding sites was unchanged following fluoxetine, WAY100635, or the combination of fluoxetine and WAY100635. However, the net stimulation of [35S]GTPgammaS binding induced by the 5-HT1A agonist 8-OH-DPAT was significantly attenuated in dorsal raphe nucleus (DRN), but not in hippocampus, after chronic fluoxetine. Moreover, depending of the area analysed, the basal binding of [35S]GTPgammaS was differentially affected by this treatment: increased in DRN and decreased in hippocampal dentate gyrus. Interestingly, the changes in [35S]GTPgammaS basal binding and on 5-HT1A receptors functionality were prevented by the concomitant administration of WAY100635. The inhibition of dorsal raphe firing by 8-OH-DPAT was also attenuated in fluoxetine-treated rats (ED50 = 2.12 +/- 0.32 microg/kg and 4.34 +/- 0.09 microg/kg, for vehicle and fluoxetine respectively), an effect which was also prevented by the concomitant administration of WAY100635 (ED50 = 2.10 +/- 0.58 microg/kg). Chronic administration of WAY100635 alone did not affect the 5-HT1A receptor-induced stimulation of [35S]GTPgammaS binding, nor the 8-OH-DPAT-induced inhibition of 5-HT neuron firing. These results demonstrate that the concomitant blockade of 5-HT1A receptors when administering fluoxetine prevents those adaptive changes of 5-HT1A receptor function associated with the chronic administration of this antidepressant. These findings could be relevant from the therapeutic point of view, and further support the potential benefit of treatments with a SSRI/5-HT1A receptor antagonist combination.

Serotonin-1A autoreceptor binding in the dorsal raphe nucleus of depressed suicides.

Serotonergic dysfunction is present in mood disorders and suicide. Brainstem 5-HT1A somatodendritic autoreceptors regulate serotonin neuron firing but studies of autoreceptor binding in the dorsal raphe nucleus (DRN) in depressed suicides report conflicting results. We sought to determine: (1) the anatomical distribution of 5-HT1A receptor binding in the DRN in depressed suicides and psychiatrically normal controls; and (2) whether sex differences in 5-HT1A binding in the DRN contribute to differences between depressed suicides and controls. Previously collected quantitative receptor autoradiograms of [3H]8-hydroxy-2-(di-n-propyl)aminotetralin (3H-8-OH-DPAT) in postmortem tissue sections containing the DRN from drug-free suicide victims (n=10) and matched controls (n=10) were analyzed. Less total receptor binding (fmol/mg tissuexmm3) was observed in the entire DRN in depressed suicides compared with controls (p<0.05). Group differences along the rostrocaudal extent of the DRN were observed for cross-sectional 5-HT(1A) binding (fmol/mg tissue) and receptor binding (fmol/mgxmm3, p<0.05). Cross-sectional 5-HT1A DRN binding in depressed suicides compared with controls was higher rostrally and lower caudally. The differences between depressed suicides and controls were present in males and females, although females had more binding than males. Less autoreceptor binding in the DRN of depressed suicides may represent a homeostatic response to less serotonin release, increasing serotonin neuron firing. More autoreceptor binding in rostral DRN might contribute to deficient serotonin release in ventromedial prefrontal cortex by lower neuronal firing.

Cortical serotonin 1A receptor levels are associated with depression in patients with dementia with Lewy bodies and Parkinson's disease dementia.

BACKGROUND: Serotonin 1A receptors (5-HT(1A)) have not been studied in dementia with Lewy bodies (DLB) or Parkinson's disease dementia (PDD) patients with depression. AIM: To examine 5-HT(1A) in DLB and PDD postmortem in relation to depression. METHODS: [(3)H]8-hydroxy-2-dipropylaminotetralin binding to 5-HT(1A) was determined in temporal cortex (Brodmann areas, BA20 and BA36) from 10 DLB patients, 17 PDD patients and 9 controls. RESULTS: 5-HT(1A) density was significantly higher in BA36 in combined DLB/PDD patients with depression, but was unaltered in BA20. CONCLUSION: Higher BA36 5-HT(1A) density in PDD and DLB patients than in control is dependent on whether the patient had experienced depression during life, not DLB/PDD diagnosis. A 5-HT(1A) antagonist adjuvant may improve treatment of depression in dementia.

Pharmacokinetics and pharmacodynamics analysis of transdermal iontophoresis of 5-OH-DPAT in rats: in vitro-in vivo correlation.

Pharmacokinetics and dopaminergic effect of dopamine agonist 5-OH-DPAT in vivo were determined following transdermal iontophoresis in rats based on drug concentration in plasma (C(p)) and dopamine levels in striatum (C(DA)). Correlation of the in vitro transport with the pharmacokinetic-pharmacodynamic (PK-PD) profiles was characterized in the transport in dermatomed rat skin (DRS) and rat stratum corneum (RSC). The integrated in vivo PK-PD and in vitro transport models successfully described time course of C(p), C(DA), and in vitro flux in DRS and RSC. Population value of steady-state flux (J(ss)) in vivo (31 nmol/cm(2) . h with 95% confidence interval (CI) = 20-41) is closer to J(ss) in vitro in DRS (61 nmol/cm(2) . h, CI = 54-67) than in vitro J(ss) in RSC (98 nmol/cm(2) . h, CI = 79-117). On the other hand, skin release rate constant (K(R)) in vivo was similar to the K(R) in RSC (4.8/h, CI = 2.4-7.1 vs. 2.6/h, CI = 2.5-2.6). Kinetic lag time (t(L)) in vivo was negligible, which is close to in vitro t(L) in RSC (0.0 h, CI = 0.0-0.1). Based on nonlinear mixed-effect modeling, profiles of C(p) and C(DA) were successfully predicted using in vitro values of J(ss) in DRS with K(R) and t(L) in RSC. A considerable dopaminergic effect was achieved, indicating the feasibility to reach therapeutically effective concentrations of 5-OH-DPAT upon transdermal iontophoresis.

Differential effects of intra-midbrain raphe and systemic 8-OH-DPAT on VTA self-stimulation thresholds in rats.

RATIONALE: Intra-median raphe nucleus (MRN) administration of the 5-HT(1A) receptor agonist 8-OH-DPAT decreases lateral hypothalamic self-stimulation thresholds and is reported to have biphasic effects following systemic administration. These experiments attempted to extend the previous findings to mesolimbic pathway self-stimulation at ventral tegmental area (VTA) electrodes. OBJECTIVES: This study was conducted to provide comparative data for systemic and intra-dorsal raphe nucleus (DRN) and intra-MRN effects of 8-OH-DPAT on VTA self-stimulation. METHODS: Male Sprague-Dawley rats with VTA electrodes were trained to respond for electrical stimulation. Systemic and intra-midbrain raphe 8-OH-DPAT effects on rate-frequency thresholds were measured. Systemic administration of WAY 100635 was used to confirm 5-HT(1A) receptor mediation of 8-OH-DPAT effects. RESULTS: 8-OH-DPAT (0.003-0.3 mg kg(-1) SC) increased rate-frequency thresholds and decreased maximal response rates. WAY 100635 alone (0.0125-0.1 mg kg(-1) SC) did not alter these measures. Intra-DRN and intra-MRN 8-OH-DPAT (5.0 microg) decreased rate-frequency thresholds without altering maximal response rates. Intra-DRN 8-OH-DPAT (0.1-5.0 microg) induced a slight decrease and intra-MRN 8-OH-DPAT a slight increase in locomotor activity. WAY 100635 (0.1 mg kg(-1)) blocked effects of 8-OH-DPAT on VTA self-stimulation. CONCLUSION: These results confirm threshold-decreasing effects of intra-MRN 8-OH-DPAT and extend this to the DRN and to VTA thresholds. Monophasic dose dependent increases in VTA thresholds following systemic 8-OH-DPAT are not equivalent to reports for hypothalamic self-stimulation. Differences between studies may be attributable to stimulation site and/or differences in threshold measurement procedures. Effects of WAY 100635 in this study indicate 5-HT(1A) receptor mediation of these 8-OH-DPAT effects.

Transdermal iontophoresis of the dopamine agonist 5-OH-DPAT in human skin in vitro.

The feasibility of transdermal iontophoretic delivery of a potent dopamine agonist 5-OH-DPAT was studied in vitro in side by side diffusion cells across human stratum corneum (HSC) and dermatomed human skin (DHS) according to the following protocol: 6 h of passive diffusion, 9 h of iontophoresis and 5 h of passive diffusion. The influences of the following parameters on the flux were studied: donor solution pH, NaCl concentration, drug donor concentration, current density and skin type. A current density of 0.5 mA cm(-2) was used, except for one series of experiments to study the current density effect. Probably due to the influence of the skin perm-selectivity and the competition with H(+), increase in pH from 3 to 5 resulted in a significant increase in flux. Further increase in pH to 6 did not further increase the flux. The iontophoretic transport was found to increase linearly with concentration and current density, providing a convenient way to manage dose titration for Parkinson's disease therapy. Increase in concentration of NaCl dramatically reduced the flux of 5-OH-DPAT as a result of ion competition to the transport. When DHS was used, the iontophoretic transport was less. Also, with DHS the response in flux profile, by switching the current on and off, was shallower than that with HSC. With the optimum condition, a delivery of 104 microg of 5-OH-DPAT per cm(2) patch per hour is feasible, indicating that the therapeutic level could be achieved with a smaller patch size than required in case of rotigotine. Thus, based on this in vitro study, transdermal iontophoretic delivery of 5-OH-DPAT is very promising.

Serotonin receptor binding in a colony model of chronic social stress.

Male rats housed in mixed-sex groups quickly established dominance hierarchies in which subordinates appeared severely stressed. Subordinate rats had elevated basal corticosterone (CORT) levels relative to dominants and individually housed controls. Several subordinates had blunted CORT responses to a novel stressor, leading to the classification of subordinates as either stress-responsive or nonresponsive. Binding to 5-HT1A receptors was reduced in stress-responsive subordinates compared to controls throughout hippocampus and dentate gyrus. Decreased binding was observed in nonresponsive subordinates only in CA3 of hippocampus. In addition, 5-HT1A binding was decreased in CA1, CA3, and CA4 in dominants compared to controls. Binding to 5-HT2 receptors was increased in parietal cortex in both responsive and nonresponsive subordinates compared to controls. No changes were observed in binding to 5-HT1B receptors. These results are discussed in the context of regulation of the serotonergic system by stress and glucocorticoids and possible relevance to the pathophysiology of depression.

Chronic effects of triiodothyronine in combination with imipramine on 5-HT transporter, 5-HT(1A) and 5-HT(2A) receptors in adult rat brain.

Triiodothyronine (T3) has been shown to accelerate and potentiate the clinical response to tricyclic antidepressant (TCA) treatment in depressive disorders. The neurobiological mechanisms underlying these therapeutic effects of T3 are still unknown. Since brain serotonin (5-HT) changes have been implicated in the mode of action of TCA drugs, the effects of a chronic (7 or 21 days) administration of imipramine (10 mg/kg/day) and of a low dose of T3 (4 microg/kg/day), given alone or in combination, were investigated on the density of midbrain 5-HT transporters and of hippocampal 5-HT(1A) and cortical 5-HT(2A) receptors in adult Wistar rats. Neither single nor combined administration of imipramine and T3 for 7 days modified the density of 5-HT transporters and of 5-HT(1A) receptors. On day 21, the combination did not change imipramine- or T3-induced decrease in 5-HT transporter density whereas it prevented imipramine-induced increase in 5-HT(1A) receptor density. Whatever the treatment duration, imipramine-T3 combination potentiated imipramine-induced decrease in 5-HT(2A) receptor density. On both day 7 and day 21, T3 given alone had no effects on the density of 5-HT(1A) and 5-HT(2A) receptors. These data indicate that T3 is able to modulate the long-term adaptive changes which occur at the postsynaptic level of 5-HT neurotransmission after antidepressant treatment.

Regional analysis of 5-HT1A and 5-HT2 receptors in the fawn-hooded rat.

The Fawn-Hooded strain of rats exhibits a hemorrhagic disorder, known as platelet storage pool deficiency. In addition to the platelet dysfunction, there is an altered response to certain serotonin drugs. To assess the characteristics of the binding to 5-HT1A and 5-HT2 receptors in this strain, regions of the brain from Fawn-Hooded, Sprague-Dawley and Wistar male rats were examined. The drug [3H]8-OH-DPAT was used to label 5-HT1A receptors and the Kd values for frontal cortex, hippocampus, striatum, hypothalamus and brainstem were similar in all three strains of rat. As with the 5-HT1A receptors, no differences were observed in the Kd values for 5-HT2 receptors, in any of the regions examined, among the three strains. However, the Bmax for the binding of [3H]8-OH-DPAT in the striatum and brainstem of Fawn-Hooded rats was less than in the Sprague-Dawley and Wistar animals. Furthermore, 5-HT2 receptors displayed a greater Bmax value in the striatum and in the frontal cortex of Fawn-Hooded animals, compared to Sprague-Dawley and Wistar rats. These differences in receptors are consistent with previous studies in which Fawn-Hooded rats were found to have altered serotonergic function, relative to Wistar and Sprague-Dawley animals.

The ontogeny of tolerance to the 5-HT1A agonist 8-OH-DPAT: a study in the rat.

The 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) induces hypothermia and a flat body posture in rats. Tolerance to 8-OH-DPAT develops in adult rats with regard to these responses. The ontogeny of the ability to induce tolerance to the hypothermia and the flat body posture elicited by 8-OH-DPAT was studied. Rat pups of both sexes were given 8-OH-DPAT, 100 micrograms/kg (0.352 mumol/kg) or saline for 1, 4 or 12 days between 22 and 34 days of age. At 26 days of age no attenuation was induced by treatment during the previous 4 days. In contrast, at 34 days of age there was a clear attenuation of both responses induced by 8-OH-DPAT after an analogous 4 day treatment. The data indicate that the ability to induce tolerance to 8-OH-DPAT is not developed before 26 days of age in the rat.

Orally active central dopamine and serotonin receptor ligands: 5-, 6-, 7-, and 8-[[trifluoromethyl)sulfonyl]oxy]-2-(di-n-propylamino)tetralins and the formation of active metabolites in vivo.

The racemic triflate derivatives 5-8 of the 5-, 6-, 7-, and 8-hydroxylated 2-(di-n-propylamino)-teralins 1-4 were shown to possess similar pharmacological profiles to their phenolic counterparts in in vitro binding and in vivo biochemical and behavioral assays in rats. Consequently, subcutaneous administration of the 5-, 6-, and 7-triflates displayed essentially dopaminergic agonist properties, while the 8-triflate was shown to be a selective 5-HT1A receptor agonist. With respect to their agonist activities, the triflates were less potent than their phenolic analogs. The absolute oral bioavailability of compound 8 (8-triflate) was 4-5 times greater than the corresponding hydroxylated compound. Interestingly, in the in vivo biochemical assay compound 8 was found to be more potent after oral than after subcutaneous administration, indicating formation of one or more active metabolites. Following a study of the metabolism of compound 8 in rat hepatocytes, the monopropyl analog 9 was identified as the major metabolite and was surprisingly found to be more potent than compound 8. Oral administration of compound 5 (5-triflate) resulted in behavioral and biochemical effects indicative of mixed DA/5-HT1A agonist properties not seen after subcutaneous administration. These results may also be indicative of the formation of active metabolites.

Long-term in vivo desipramine or estrogen treatment fails to affect serotonin-induced outward current in hippocampal pyramidal cells of the rat.

The effect of castration combined with either long-term treatment with the tricyclic antidepressant drug desipramine or the sex steroid 17 beta-estradiol on serotonin responses in area CA1 of the hippocampus of male and female rats was examined. Using single-electrode current and voltage-clamp techniques serotonin-induced hyperpolarizations and outward currents were recorded from hippocampal pyramidal cells. Neither in male nor in female castrated rats treatment effects were observed on the magnitude of the 5-hydroxytryptamine 1A mediated outward currents (0.26 nA) and membrane hyperpolarizations (11 mV) induced by superfusion of serotonin (15 microM), or on the effect of serotonin on the afterhyperpolarization and extracellularly recorded population spike. In voltage-clamp experiments using microelectrodes filled with potassium-chloride, but not with potassium-acetate, the sole observable effect was that the membrane resistance drop due to application of serotonin was significantly larger in the ovariectomized group (31% approximately 19 M omega) as compared to the ovariectomized/estrogen supplemented group (23% approximately 15 M omega). Spiperone (3 microM) completely antagonized the serotonin-induced outward currents and input resistance changes under all treatments. Apart from these changes the majority of passive and active membrane properties of cells from ovariectomized animals were not affected by chronic desipramine or steroid treatment. Neither did castration alone, nor in combination with long-term 17 beta-estradiol treatment, affect CA1 pyramidal cell membrane properties of male rats. Since we attained physiological levels of 17 beta-estradiol in the blood plasma (30-50 pg/ml) using subcutaneous silastic implants containing a mixture of cholesterol/estrogen, we conclude that both long-term estrogen and long-term desipramine treatment do not affect serotonergic neurotransmission in CA1 of the rat hippocampus.

Changes in [3H]-PK 11195 and [3H]-8-OH-DPAT binding following forebrain ischaemia in the gerbil.

1. A high density of [3H]-PK 11195 binding sites was present in gerbil cortical membranes (Bmax [3H]-PK 11195 1360 +/- 71 fmol mg-1 protein) in comparison to rat cortical membranes (254 +/- 21 fmol mg-1 protein). This effect was species-specific as similar findings were obtained with hippocampal membranes (Bmax 1430 +/- 111 fmol mg-1 protein in gerbil, compared to 196 +/- 31 in rat). 2. RO 5-4864, also a peripheral type benzodiazepine compound, displayed low affinity for the [3H]-PK 11195 site in the gerbil (pKi 6.57 +/- 0.02 and 6.70 +/- 0.12 in hippocampus and cortex respectively) compared to rat (pKi 8.16 +/- 0.07 and 8.48 +/- 0.02). Central benzodiazepine compounds, diazepam and flunitrazepam, also displayed this trend. 3. RO 5-4864 displaced [3H]-PK 11195 binding from gerbil and rat cortical membranes through a competitive interaction with Hill slopes close to unity. In both tissues, saturation isotherms of [3H]-PK 11195 binding indicated that the presence of RO 5-4864 caused changes in Kd without any effect on Bmax. In kinetic experiments, the presence of RO 5-4864 failed to modify the rate of dissociation of [3H]-PK 11195 from equilibrium in both rat and gerbil cortical membranes. 4. Forebrain ischaemia in the Mongolian gerbil (5 min bilateral carotid artery occlusion) with 7 days recovery caused a significant (P<0.05) decrease in the density of hippocampal 5-HTlA binding sites labelled by [3H]-8-OH-DPAT (Bmax control, 393 +/- 33 fmol mg-1 protein; ischaemic, 289 +/- 21 fmol mg protein)and an increase (P<0.01) in [3H]-PK 11195 binding sites (Bmax control, 1430 +/- 111 fmol mg-1 protein; ischaemic, 2160 +/- 170 fmol mg-1 protein). Ischaemia and recovery had no effect on the affinity of either ligand.5. Autoradiography experiments in gerbil brain sections revealed that the ischaemia-induced increase in[3H]-PK 11195 binding was consistent and significant in the CA, subfield on the hippocampus (control,152 +/- 42 fmol mg-1 tissue; ischaemic, 314 +/- 43 fmol mg-1 tissue).

Cross-familiarisation conditioned taste aversion procedure as a method to reveal stimulus resemblance between drugs: studies on the 5-HT1A agonist 8-OHDPAT.

In the present study a cross-familiarisation conditioned taste aversion (CTA) paradigm was utilized to reveal stimulus resemblance between the selective 5-HT1A agonist 8-OHDPAT and a variety of serotonergic and non-serotonergic drugs. In male mice, a 0.22 mg/kg dose of 8-OHDPAT was used as the reference compound inducing CTA. Dose-dependent effects of pre-exposure to 24 different test drugs on the magnitude of the 8-OHDPAT-induced CTA were tested as a measure for stimulus similarity between these test drugs and 8-OH-DPAT (the reference compound). Pre-exposure to 8-OH-DPAT itself, ipsapirone, buspirone, RU 24969, sertraline, d-amphetamine, LSD, metergoline and idazoxan effectively prevented the development of CTA induced by 8-OHDPAT. Pre-exposure to apomorphine, diazepam, SCH 23390, LiCl, spiperone, DOI, spiroxatrine, umespirone, pindolol, mCPP, haloperidol, MK 212, clonidine, quipazine and also 5-MeODMT was not effective in completely abolishing the CTA produced by 8-OHDPAT. It is concluded from these results that the relatively simple and fast cross-familiarisation taste aversion method is a suitable paradigm to study similarities in stimulus properties of different drugs.

5-HT1A agonists: alcohol drinking in rats and squirrel monkeys.

RATIONALE: Increased alcohol intake after administration of low doses of 5-HT(1A )agonists is thought to be due to a reduction in 5-HT impulse flow due to activation of 5-HT(1A) somatodendritic receptors, whereas decreased alcohol drinking found after administration of higher doses of 5-HT(1A) agonists may be mediated by action at postsynaptic 5-HT(1A) receptors. OBJECTIVE: This study compares Long-Evans rats and squirrel monkeys to examine the hypothesis that low doses of the 5-HT(1A) selective agonists, 8-OH-DPAT and alnespirone, will preferentially increase, and at higher doses decrease alcohol drinking, and whether these effects can be antagonized by WAY 100635. METHODS: Male Long-Evans rats were induced to drink from two bottles, one containing a solution of 10% ethanol and 1% sucrose (w/v), the other containing an equally preferred concentration of sucrose. Squirrel monkeys also drank from two bottles, one containing a solution of 2% ethanol and 15% sucrose (w/v), the other, water. RESULTS: In rats, low doses of both 8-OH-DPAT (0.018-0.03 mg/kg) and alnespirone (0.3-3.0 mg/kg) increased alcohol drinking by ca. 100% without altering sucrose intake. The highest dose of 8-OH-DPAT (0.1 mg/kg) suppressed intake of both solutions without significant motor impairment. Pretreatment with WAY 100635 (0.1 mg/kg), shifted the entire dose-effect curve of 8-OH-DPAT to the right, and antagonized the effects of the 0.56 mg/kg dose of alnespirone. In the monkeys, administration of both agonists dose-dependently decreased alcohol intake and were behaviorally sedative. CONCLUSIONS: These results support the hypothesis that in rats, 5-HT(1A) receptor stimulation activates somatodendritic receptors at lower doses and postsynaptic receptors at higher doses, each with opposite effects on alcohol intake. The absence of such biphasic dose-effect curves in monkeys suggests a different function of 5-HT(1A) somatodendritic receptors in rats and monkeys, at least with regard to alcohol drinking.

Anticonflict and discriminative stimulus effects in the pigeon of a new methoxy-chroman 5-HT1A agonist, (+)S 20244 and its enantiomers (+)S 20499 and (-)S 20500.

The present experiments examined the behavioral and receptor binding characteristics of new 5-HT1A methoxy-chroman derivatives in procedures known to be sensitive to the activity of 5-HT1A compounds. Key peck responding of pigeons was maintained by a 30-response fixed-ratio schedule of food delivery. In studies involving punished responding, every 30th response during one keylight stimulus also produced shock ("conflict" procedure). In drug discrimination studies, pigeons were trained to discriminate injections of the 5-HT1A agonist 8-OH-DPAT (0.3 mg/kg) from saline. Three forms of the methoxy-chroman compounds were tested: the enantiomers (+)S 20499 (0.01-3.0 mg/kg) and (-) S 20500 (0.3-5.6 mg/kg), as well as the racemic mixture (+)S 20244 (0.03-5.6 mg/kg). (+)S 20499 was approximately 10-fold more potent than (-)S 20500 in producing maximal increases in punished responding. (+)S 20244 was comparable in potency to (-)S 20500 in producing maximal increases in punished responding, but increases also occurred at much lower doses with (+)S 20244 and the magnitude of the effect with (-)S 20500 was less than that of the two other compounds. While increases in punished responding were observed with all three drugs at doses that did not affect unpunished responding, the highest doses of all drugs decreased unpunished responding. All compounds substituted for 8-OH-DPAT in the drug discrimination procedure, suggestive of 5-HT1A agonist activity. (+)S 20499 was approximately 30-fold more potent than (-)S 20500 in substituting for 8-OH-DPAT and 3-fold more potent than the racemate. All three compounds bound with high affinity to pigeon cerebrum receptor sites labelled by [3H]8-OH-DPAT. As in behavioral studies, (+)S 20499 was approximately 10-fold more potent than (-)S 20500 in displacing [3H]8-OH-DPAT (IC50 = 2.79 versus 20.3 nM). These studies demonstrate that the enantiomers of this compound, as well as the racemic mixture, are effective 5-HT1A compounds and that (+)S 20499 in particular is likely to be a clinically effective anxiolytic and/or antidepressant.

Combined treatment of quetiapine with haloperidol in animal models of antipsychotic effect and extrapyramidal side effects: comparison with risperidone and chlorpromazine.

RATIONALE: Quetiapine, an atypical neuroleptic, has beneficial antipsychotic effects in schizophrenic patients, but with a lower incidence of extrapyramidal symptoms (EPS) compared with typical antipsychotics. While typical antipsychotics are often switched to atypical agents when adverse effects become limiting, there is little preclinical information to support this strategy, both in terms of efficacy and side effects. OBJECTIVES: The antipsychotic effects and EPS during concomitant administration of quetiapine with haloperidol, a typical antipsychotic agent, were evaluated in mice and compared with chlorpromazine and risperidone. METHODS: We first investigated the antipsychotic effects and EPS liability of quetiapine, risperidone, chlorpromazine, and haloperidol when administered alone to select optimal doses for subsequent combination studies. The second study was designed to evaluate the antipsychotic efficacy and EPS profile of concomitant administration of quetiapine, risperidone, or chlorpromazine with haloperidol. Antipsychotic effects were evaluated with the methamphetamine-induced hyperlocomotion test, and EPS liability was evaluated in a catalepsy-induction model. RESULTS: Quetiapine, risperidone, chlorpromazine, and haloperidol dose-dependently reduced methamphetamine-induced hyperlocomotion, with ED50 values of 5.6, 0.020, 1.8, 0.035 mg/kg, respectively. In the catalepsy test, quetiapine only weakly induced catalepsy at the highest dose of 100 mg/kg, whereas risperidone, chlorpromazine, and haloperidol dose-dependently induced catalepsy with ED50 values of 0.25, 4.6, and 0.10 mg/kg, respectively. While the combination of quetiapine (6 mg/kg) and haloperidol (0.04 mg/kg) significantly reduced methamphetamine-induced hyperlocomotion in comparison with haloperidol alone, quetiapine (10, 32 mg/kg) plus haloperidol did not potentiate the cataleptogenic activity of haloperidol. In contrast, risperidone (0.1, 0.32 mg/kg) or chlorpromazine (3.2 mg/kg) significantly augmented catalepsy induced by haloperidol. Catalepsy induced by co-administration of quetiapine (10 mg/kg) and haloperidol (0.1 mg/kg) was significantly potentiated by WAY100635, a 5-HT1A antagonist, and catalepsy induced by co-administration of risperidone (0.1 mg/kg) and haloperidol (0.1 mg/kg) was significantly antagonized by 8-OH-DPAT, a 5-HT1A agonist. CONCLUSION: The present study demonstrated that the combined administration of quetiapine with haloperidol did not aggravate EPS, possibly because of its affinity for 5-HT1A receptors. This finding may have the clinical implication that quetiapine could provide a successful regimen in switching from typical antipsychotic agents in the symptom management of schizophrenia, or even in adjunctive therapy with other antipsychotic agents.

Effects of chronic treatment with valproate on serotonin-1A receptor binding and function.

Valproate is effective in treating bipolar disorder characterized by rapid cycling or acute mania, although the mechanism of action is unclear. In contrast to other treatments for depression, 21 days of treatment in rats with valproate (1,, 200 or 400 mg/kg) did not significantly alter the hypothermia induced by 8-hydroxy-2-(di-n-propyl)aminotetralin (8-OH-DPAT), an agonist at serotonin-1A receptors. Treatment with valproate also had no effect on radioligand binding to serotonin-1A, serotonin-2 or beta-adrenergic receptors. Based on these animal studies in frontal cortex and hippocampus, the therapeutic benefit of valproate in mood disorders does not appear to involve adaptive changes in serotonin-1A, serotonin-2 or beta-adrenergic receptor number.