Enhanced accumbal dopamine release following 5-HT2A receptor stimulation in rats pretreated with intermittent cocaine

This study was conducted to determine whether dopamine (DA) release in the nucleus accumbens (NACC) following 5-HT_2A receptor stimulation is potentiated by intermittent cocaine. Rats received daily injections of either saline or cocaine (30 mg/kg, s.c.) for 14 days. At the 7th day after withdrawal, microdialysis was performed in the NACC. Infusion of (±)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI, 50 μM), a 5-HT₂ receptor agonist, into the NACC produced greater and longer-lasting increases in extracellular DA in the rats pretreated with cocaine than in the rats pretreated with saline. The DOI-induced increases in NACC DA were attenuated by co-perfusion with ketanserin (50 μM), a 5-HT_2A receptor antagonist. The results are consistent with the concept that intermittent cocaine may cause enhanced sensitivity of 5-HT_2A receptors within the NACC.     

Role of cortical and striatal 5-HT1A receptors in alleviating antipsychotic-induced extrapyramidal disorders

Previous studies have revealed that 5-HT_1A agonists ameliorate antipsychotic-induced extrapyramidal symptoms (EPS) through postsynaptic 5-HT_1A receptors. Here, we conducted an intracerebral microinjection study of (±)-8-hydroxy-2-(di-n-propylamino)-tetralin ((±)8-OH-DPAT) to determine the action site of the 5-HT_1A agonist in alleviating EPS. Bilateral microinjection of(±)8-OH-DPAT (5 µg/1 µL per side) either into the primary motor cortex (MC) or the dorsolateral striatum (dlST) significantly attenuated haloperidol-induced catalepsy in rats. The anticataleptic action of (±)8-OH-DPAT was more prominent with the MC injection than with the dlST injection. WAY-100135 (a selective 5-HT_1A antagonist) completely antagonized the reversal of haloperidol-induced catalepsy both by intracortical and intrastriatal (±)8-OH-DPAT. Furthermore, lesioning of dopamine neurons with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (30 mg/kg/day, i.p., for 4 days) did not alter the anti-EPS actions of (±)8-OH-DPAT in a mouse pole test. The present results strongly suggest that 5-HT_1A agonist alleviates antipsychotic-induced EPS by activating postsynaptic 5-HT_1A receptors in the MC and dlST, probably through non-dopaminergic mechanisms.     

Selective labeling of 5-HT1A and 5-HT1B binding sites in bovine brain

Drug interactions with serotonin(1A) 5-HT1A and serotonin(1B) (5-HT1B) binding sites were analyzed in bovine brain membranes. 5-HT1A binding sites were directly labeled with [3H]8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) in bovine hippocampal membranes. 5-HT1B binding sites were labeled by [3H]5-HT in bovine striatal membranes where less than 15% of specific binding sites are sensitive to nanomolar concentrations of 8-OH-DPAT. Each of the 12 agents tested was more potent at the 5-HT1A than 5-HT1B binding site. 5-HT, bufotenine, N,N-dimethyltryptamine (DMT) and quipazine were only slightly more potent at the 5-HT1A binding site. By contrast, 8-OH-DPAT, TVX Q 7821 and buspirone were significantly more potent at [3H]8-OH-DPAT binding sites in bovine hippocampus than at [3H]5-HT binding sites in bovine striatum. These findings suggest that 5-HT1A, and 5-HT1B binding sites have distinct pharmacological profiles and can be directly labeled with appropriate [3H]ligands in specific brain regions.     

5-HT1A agonists induce hippocampal theta activity in freely moving cats: role of presynaptic 5-HT1A receptors

Electrical activity in the dorsal hippocampus was recorded in freely moving cats in response to intravenous administration of 5-HT_1A agonist and antagonist drugs. Administration of low doses of the selective 5-HT_1A agonists 8-OH-DPAT (5–20 μg/kg) and ipsapirone (20–100 μg/kg) produced rhythmic slow activity (theta) in the hippocampal EEG within 30 s. Similar effects were observed with BMY 7378 (20 and 100 μg/kg), which acts as an agonist at presynaptic (somatodendritic) 5-HT_1A receptors and as an antagonist at postsynaptic 5-HT_1A receptors. Power spectral analyses showed that all three compounds produced a dose-dependent increase in the EEG power occurring in the theta frequency band (3.5–8.0 Hz) as a proportion of total power from 0.25 to 30.0 Hz (relative theta power). The increase in relative theta power produced by 8-OH-DPAT (20 μg/kg) was greatly attenuated by spiperone (1 mg/kg), a highly effective 5-HT_1A autoreceptor antagonist. Administration of spiperone alone had no significant effect on relative theta power. These results are discussed in relationship to the effects of these drugs on serotonergic neuronal activity. Our results suggest that preferential activation of presynaptic 5-HT_1A receptors, and subsequent inhibition of serotonin neurotransmission, facilitates the appearance of hippocampal theta activity in awake cats.     

Evidence for the involvement of the serotonergic 5-HT2A/C and 5-HT3 receptors in the antidepressant-like effect caused by oral administration of bis selenide in mice

The present study investigated a possible antidepressant-like activity of bis selenide using two predictive tests for antidepressant effect on rodents: the forced swimming test (FST) and the tail suspension test (TST). Bis selenide (0.5–5 mg/kg, p.o.) decreased the immobility time in the mouse FST and TST. The anti-immobility effect of bis selenide (1 mg/kg, p.o.) in the TST was prevented by the pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA; 100 mg/kg, i.p., an inhibitor of serotonin synthesis), ketanserin (1 mg/kg, i.p., a 5-HT_2A/2C receptor antagonist), and ondasentron (1 mg/kg, i.p., a 5-HT₃ receptor antagonist). Pretreatment of mice with prazosin (1 mg/kg, i.p., an α₁-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α₂-adrenoceptor antagonist), propranolol (2 mg/kg, i.p., a β-adrenoceptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D₁ receptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D₂ receptor antagonist), or WAY 100635 (0.1 mg/kg, s.c., a selective 5-HT_1A receptor antagonist) did not block the antidepressant-like effect of bis selenide (1 mg/kg, p.o.) in the TST. Administration of bis selenide (0.1 mg/kg, p.o.) and fluoxetine (1 mg/kg), at subeffective doses, produced an antidepressant-like effect in the TST. Bis selenide did not alter Na⁺ K⁺ ATPase, MAO-A and MAO-B activities in whole brains of mice. Bis selenide produced an antidepressant-like effect in the mouse TST and FST, which may be related to the serotonergic system (5-HT_2A/2C and 5-HT₃ receptors).     

Autoradiographic mapping of 5-HT1, 5-HT1A, 5-HT1B and 5-HT2 receptors in the rat spinal cord

The distribution of 5-HT₁, 5-HT_1A, 5-HT_1B and 5-HT₂ receptors in the rat spinal cord was investigated with quantitative autoradiography. Receptors were labeled respectively with [³H]serotonin (5-[³H]HT],8-hydroxy-2-[N-dipropylamino-³H]tetralin (8-OH-[³H]DPAT), [¹²⁵I]iodocyanopindolol and [³H]ketanserin. It is shown that 5-HT₁, 5-HT_1A and 5-HT_1B receptors are distributed within the spinal cord according to a rostro-caudal gradient. Both 5-HT₁ and 5-HT_1A receptors are mainly present in the dorsal horn and 5-HT_1B is present throughout the spinal cord, exhibiting high densities in the caudal-most part of the dorsal in lamina X and in the sacral parasympathetic area. On the other hand, 5-HT₂ receptors are shown mostly in the thoracic sympathetic area and in the thoracic ventral horn; the dorsal horn exhibits few 5-HT₂ receptors. The differential involvement of 5-Ht through different receptors in nociception, autonomous nervous system control and motility are discussed.     

Cerebrovascular and functional consequences of 5-HT1A receptor activation

Cerebral glucose utilization and blood flow were measured in rats using 2-deoxy-d-[¹⁴C]glucose and [¹⁴C]iodoantipyrine quantitative autoradiography, respectively, following treatment with the 5-HT_1A receptor agonist8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT). In control and 8-OH-DPAT-treated animals blood flow and glucose use were similarly correlated, but the ratio was increased following 8-OH-DPAT treatment. Since 5-HT_1A receptor activation is known to reduce neuronal 5-HT release, these results are consistent with a vasoconstrictor role for endogenous serotonin.     

Effects of 8-OH-DPAT, a 5-HT1A receptor agonist, and DOI, a 5-HT2A/2C agonist, on monosynaptic transmission in spinalized rats

We investigated the effect of the 5-HT_1A receptor agonist (±)-8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT) and the 5-HT_2A/2C receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on monosynaptic transmission in spinalized rats. 8-OH-DPAT significantly inhibited the excitation of α-motoneurons evoked by monosynaptic transmission without a direct effect on α-motoneuron excitation. DOI potentiated the excitation of α-motoneurons by both direct stimulation and monosynaptic transmission. These results indicate that activation of 5-HT_1A receptors inhibits monosynaptic transmission, whereas activation of 5-HT_2A/2C receptors enhances it.     

Dose- and time-dependent effects of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a serotonergic 5-HT2 receptor agonist, on local cerebral glucose metabolism in awake rats

The time course and the relation to dose of regional cerebral metabolic rates for glucose (rCMRglc) were measured in awake male Fischer-344 rats after administration of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a selective serotonergic 5-HT₂ agonist. rCMRglc was determined, using the quantitative autoradiographic [¹⁴C]2-deoxyglucose technique, in 75 brain regions at 5, 15, 30, 60 and 90 min after administration of DOI 10 mg/kg i.p., and at 15 min after DOI 2.5, 25 or 50 mg/kg i.p. In non-hippocampal regions, peak effects were observed at 15–30 min, when rCMRglc in 12% of the regions was significantly different from control. In hippocampal regions rCMRglc effects peaked at 30 min (average rCMRglc reduction 21%) and were sustained for at least 60 min. Higher doses of DOI reduced rCMRglc in most prosencephalic regions (25 mg/kg, 35% of all regions studied; 50 mg/kg, 32%), where 5-HT₂ receptors are present in high density. These data suggest that selective 5-HT₂ receptor stimulation leads to rCMRglc reduction in areas with high densities of 5-HT₂ receptors.     

5-HT 2A receptor stimulation by DOI,a 5-HT 2A/2C receptor agonist,potentiates amphetamine-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens

(+/-)-([1-(2,5-Dimethoxy-4-iodophenyl)-aminopropane]-hydrochloride) (DOI) (2.5 mg/kg), a 5-HT(2A/2C) agonist, significantly potentiated D-amphetamine (AMPH) (1 mg/kg)-induced dopamine (DA) release in rat medial prefrontal cortex (mPFC) and nucleus accumbens (NAC). This effect of DOI was completely prevented by M100907 (1 mg/kg), a selective 5-HT(2A) antagonist, which by itself had no effect on basal and AMPH-induced DA release in either region. Thus, 5-HT(2A) receptor agonism potentiates AMPH-induced DA release in the mPFC and NAC.     

Functional correlates for 5-HT1A receptors in maternally deprived rats displaying anxiety and depression-like behaviors

Maternal separation is known to induce long-term changes in neuroendocrine and emotional responsiveness to stress in a large variety of models. We examined an animal model of early deprivation in Sprague–Dawley rats consisting of separating litters from their mothers and littermates 3 h daily during postnatal days 2 to 15. In adulthood, maternally deprived rats in comparison with non-deprived controls exhibited an increase in anxiety and depression-related behaviors in the open-field and forced swim tests. Because serotonin (5-HT) 5-HT_1A receptors seem to play an important role in the pathophysiology of major depression and in the mechanism of action of antidepressants, we investigated if 5-HT_1A receptor function is altered in deprived rats. Although the hypothermic response to the 5-HT_1A receptor agonist 8-OH-DPAT was increased in adult deprived rats compared to non-deprived control group, no differences between groups were found in the effect of the systemic 8-OH-DPAT administration on serotoninergic cell firing in dorsal raphe nucleus and in the 5-HT release at the ventral hippocampus levels. These results suggest that 5-HT_1A receptors are not substantially affected in adult Sprague–Dawley rats that were subjected to a maternal deprivation 3 h daily during the neonatal period.     

Activation of 5-hydroxytryptamine1A receptors increases the affinity of galanin receptors in di- and telencephalic areas of the rat

Since galanin in vitro selectively increases theK_D value of 5-HT_1A receptors without altering the binding of 5-HT_1B or 5-HT₂ receptors, we have studied whether 5-HT_1A receptor activation in turn may affect galanin binding in the ventral di- and telencephalon and the substantia nigra of the rat. As analyzed by autoradiography, the binding of¹²⁵I-galanin was increased by about 55% in the presence of 3–30 nM of 8-OH-2-(di-npropylamino)-tetralin (DPAT) in the paraventricular thalamic nucleus, the nucleus reuniens and rhomboideus, the zona incerta, the medial and the lateral hypothalamus, and the medial and the lateral amygdaloid area, but not in the pars compacta of the substantia nigra, which lacks 5-HT_1A binding sites. DPAT (10 nM) reduced the IC₅₀ values of galanin at¹²⁵I-galanin binding sites by approximately 55% within all the analyzed di- and telencephalic regions. The overall increase inB_O values was50 ± 11%. Using the filter wipe technique in cryostat sections at Bregma -2.8 mm covering all the brain regions at this level, DPAT (10 nM) decreased the IC₅₀ values of galanin from21.6 ± 1.1nM (control) to15.5 ± 0.9nM, and increased theB_O values by19.4 ± 4.1%. In membrane preparations from the ventral di- and telencephalon, DPAT decreased the IC₅₀ values of galanin binding sites by20 ± 3% at 100 nM of DPAT. This effect could be completely blocked by the specific 5-HT_1A receptor antagonist 1-(2-methoxyphenyl)-4-[4-(2-pthalimido)butyl]piperazine. GTP (0.1 nM) produced a17 ± 5% increase in the IC₅₀ value of galanin and a23 ± 4% decrease in theB_O value of¹²⁵I_galanin binding sites. However, DPAT (100 nM) was still able to decrease the IC₅₀ values of galanin in the presence of GTP (-8 ± 3%;control-10 ± 3%). TheB_max value of¹²⁵I-galanin binding was not affected by DPAT. The increased affinity of galanin binding sites by DPAT seems to reflect a G-protein-independent intramembrane receptor-receptor interaction between 5-HT_1A and galanin receptors. This interaction may represent an intramembrane inhibitory feed-back mechanism of 5-HT_1A receptor sensitivity, and may be important both under normal conditions and in 5-HT-mediated mental disorders.     

Differential effects of serotonin (5-HT) lesions and synthesis blockade on neuropeptide-Y immunoreactivity and 5-HT1A, 5-HT1B/1D and 5-HT2A/2C receptor binding sites in the rat cerebral cortex

The present study was aimed at comparing the effects of serotonin (5-HT) synthesis blockade using chronic administration of p-chlorophenylalanine (PCPA) and 5,7-dihydroxytryptamine injections of variable volume (3 vs. 6 μl) on the density of NPY immunoreactive (Ir) neurons and binding of [³H]8-OH-DPAT, S-CM-G[¹²⁵I]TNH₂ and [¹²⁵I]DOI to 5-HT_1A, 5-HT_1B/1D, and 5-HT_2A/2C receptors in rat cortical regions. Three weeks after large but partial (89% depletion in 5-HT tissue concentration) lesions of 5-HT neurons no changes in neither NPY immunoreactivity nor 5-HT receptor binding were detected. The complete 5,7-DHT lesions produced increases in the number of NPY-Ir neurons in the upper regions of the cingular (134%), frontal (140%) and parietal cortex (48%) and corresponding decreases in 5-HT_2A/2C binding (16–26%). No changes in 5-HT_1A and 5-HT_1B/1D binding were observed after lesions of this kind. After PCPA treatment, decreases in NPY-Ir neurons density (22–40%) and increases in 5-HT_1A and 5-HT_1B/1D receptor binding sites (20–50%) were distributed in both upper and deeper cortical regions. The lack of effect of the partial lesion suggests that spared 5-HT neurons may exert compensatory mechanisms up to a large extent. The changes in NPY immunoreactivity and 5-HT_2A/2C binding detected in the upper regions of the cortex after complete 5-HT lesions probably result from local cellular rearrangements, whereas blocking 5-HT synthesis has more widespread influence on NPY neurons and on 5-HT_1A and 5-HT_1B/1D receptor subtypes. Moreover, decreases in DOPAC concentrations detected only after complete lesions suggest that the involvement of catecholaminergic transmission may also differentiate 5,7-DHT and PCPA treatments. Altogether, these data suggest that different receptor subtypes might be involved in 5-HT–NPY relationships.     

5-HT1A and 5-HT2 receptors differentially regulate the excitability of 5-HT-containing neurones of the guinea pig dorsal raphe nucleus in vitro

We have used intracellular recording techniques to examine the effects of 5-hydroxytryptamine (5-HT, serotonin) on 5-HT-containing neurones of the guinea pig dorsal raphe nucleus in vitro. Bath-applied 5-HT (30–300 μM) had two opposing effects on the membrane excitability of these cells, reflecting the activation of distinct 5-HT receptor subtypes. As demonstrated previously in the rat, 5-HT evoked a hyperpolarization and inhibition of 5-HT neurones, which appeared to involve the activation of an inwardly rectifying K⁺ conductance. This hyperpolarizing response was blocked by the 5-HT_1A receptor-selective antagonist WAY-100635 (30–100 nM). In the presence of WAY-100635, 5-HT induced a previously unreported depolarizing, excitatory response of these cells, which was often associated with an increase in the apparent input resistance of the neurone, likely due to the suppression of a K⁺ conductance. Like the hyperpolarizing response to 5-HT, this depolarization could be recorded in the presence of the Na⁺ channel blocker tetrodotoxin. In addition, the response was not significantly attenuated by the α₁-adrenoceptor antagonist prazosin (500 nM), indicating that it is not due to the release of noradrenaline, or to the direct activation of α₁-adrenoceptors by 5-HT. The 5-HT₃ receptor antagonist granisetron (1 μM) and the 5-HT₄ receptor antagonist SB 204070 (100 nM) failed to reduce the depolarizing response to 5-HT; however, ketanserin (100 nM), mesulergine (100 nM) and lysergic acid diethylamide (1 μM) significantly reduced or abolished the depolarization, indicating that this effect of 5-HT is mediated by 5-HT₂ receptors.     

The peripheral nociceptive actions of intravenously administered 5-HT in the rat requires dual activation of both 5-HT2 and 5-HT3 receptor subtypes

In 16-week-old Sprague-Dawley rats lightly anesthetized with pentobarbital, 5-HT (3–96 μg/kg, i.v.;n = 6) produced distinct pseudaffective responses and a dose-dependent (slope= 17.2 ± 6.8s/log₁₀dose) inhibition of the tail-flick (TF) reflex (ED₅₀ = 32.6 ± 9.2 μg/kg). In the same rats, a 1:1 combination of α-methyl 5-HT (a 5-HT₂ receptor selective agonist) and 2-methyl 5-HT (a 5-HT₃ receptor selective agonist) (3–192 μg/kg, i.v.), produced the same profile of pseudaffective responses and also resulted in a dose-dependent (slope= 34.0± 7.0s/log₂dose) inhibition of the TF reflex (ED₅₀ = 88.4 ± 20.5 μg/kg). In contrast, administration of α-methyl 5-HT (3–192 μg/kg, i.v.) or 2-methyl 5-HT (3–192 μg/kg, i.v.) alone did not produce any pseudaffective responses or any change in TF latency from baseline. In conscious 16-week-old male Sprague-Dawley rats, administration of 5-HT (48 μg/kg, i.v.;n = 5), or a 1:1 combination of α-methyl 5-HT and 2-methyl 5-HT (total dose= 120 μg/kg, i.v.;mn = 5), resulted in a passive avoidance behavior assessed in a step-down paradigm (slopes= 139.7 ± 58.2and154.9 ± 63.9s/trial, respectively), and the same profile of distinct pseudaffective responses exhibited by the lightly pentobarbital-anesthetized rats. However, administration of either α-methyl 5-HT (96 μg/kg, i.v.;n = 4) or 2-methyl 5-HT (96 μg/kg, i.v.;n = 4), while producing significant 5-HT receptor-mediated cardiovascular responses, produced a learned behavior not different from saline (0.25 ml, i.v.;n = 6) (slopes= 7.6 ± 2.5, 6.3 ± 1.8and7.4 ± 3.6s/trial, respectively). These results are consistent with the hypothesis that the peripheral nociceptive responses to i.v. 5-HT requires dual activation of 5-HT₂ and 5-HT₃ receptor subtypes.     

Autoradiographic localization of 5-HT1A receptors in the post-mortem human brain using [H]WAY-100635 and [C]WAY-100635

The distribution of 5-HT_1A receptors was examined in the post-mortem human brain using whole hemisphere autoradiography and the selective 5-HT_1A receptor antagonist [³H]WAY-100635 ([O-methyl-³H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride). The autoradiograms showed very dense binding to hippocampus, raphe nuclei and neocortex. The labeling in neocortex was slightly lower than in the hippocampus and was mainly at superficial layers, although a faintly labeled band could be seen in deeper neocortical layers. Other regions, such as the amygdala, septum and claustrum, showed low densities of [³H]WAY-100635 binding, reflecting low densities of 5-HT_1A receptors. The labeling was very low in basal ganglia, such as nucleus caudatus and putamen, in cerebellum or in structures of the brain stem except in the raphe nuclei. The labeling of human 5-HT_1A receptors with [³H]WAY-100635 was antagonized by the addition of the 5-HT_1A receptor ligands, 5-HT, buspirone, pindolol or 8-OH-DPAT (10 μM), leaving a very low background of non-specific binding. Saturation analysis of semiquantitative data from several human regions indicated that [³H]WAY-100635 has a K_d of approximately 2.5 nM. The selective labeling of 5-HT_1A receptors with [³H]WAY-100635 clearly show that this compound is useful for further studies of the human 5-HT_1A receptor subtype in vitro. [¹¹C]WAY-100635 is used for the characterization of 5-HT_1A receptors with positron emission tomography (PET). WAY-100635 was also radiolabeled with the short-lived positron-emitting radionuclide carbon-11 (t_1/2=20 min) and used for in vitro autoradiography on human whole hemisphere cryosections. [¹¹C]WAY-100635 gave images qualitatively similar to those of [³H]WAY-100635, although with a lower resolution. Thus, the hippocampal formation was densely labeled, with lower density in the neocortex. Buspirone, pindolol or 8-OH-DPAT (10 μM), blocked all binding of [¹¹C]WAY-100635. The in vitro autoradiography of the distribution of 5-HT_1A receptors obtained with radiolabeled WAY-100635 provide detailed qualitative and quantitative information on the distribution of 5-HT_1A-receptors in the human brain. Moreover, the studies give reference information for the interpretation of previous initial results at much lower resolution in humans with PET and [¹¹C]WAY-100635. These data provide a strong basis for expecting [¹¹C]WAY-100635 to behave as a highly selective radioligand in vivo.     

Antidepressant-like action of the ethanolic extract from Tabebuia avellanedae in mice: Evidence for the involvement of the monoaminergic system

The antidepressant-like effect of the ethanolic extract obtained from barks of Tabebuia avellanedae, a plant widely employed in folk medicine, was investigated in two predictive models of depression: forced swimming test (FST) and tail suspension test (TST) in mice. Additionally, the mechanisms involved in this antidepressant-like action and the effects of the association of the extract with the antidepressants fluoxetine, desipramine and bupropion in the TST were investigated. The extract from T. avellanedae produced an antidepressant-like effect, in the FST (100 mg/kg, p.o.) and in the TST (10–300 mg/kg, p.o.), without accompanying changes in ambulation when assessed in the open-field test. The anti-immobility effect of the extract (30 mg/kg, p.o.) in the TST was prevented by pre-treatment of mice with ketanserin (5 mg/kg, i.p., a preferential 5-HT_2A receptor antagonist), prazosin (1 mg/kg, i.p., an α₁-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α₂-adrenoceptor antagonist), propranolol (2 mg/kg, i.p., a β-adrenoceptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D₂ receptor antagonist) and SCH23390 (0.05 mg/kg, s.c., a dopamine D₁ receptor antagonist). The combined administration of a subeffective dose of WAY100635 (0.1 mg/kg, s.c., a selective 5-HT_1A receptor antagonist) and a subeffective dose of the extract (1 mg/kg, p.o.) produced a significant reduction in the immobility time in the TST. In addition, the combination of fluoxetine (1 mg/kg, p.o.), desipramine (0.1 mg/kg, p.o.), or bupropion (1 mg/kg, p.o.) with a subeffective dose of the extract (1 mg/kg, p.o.) produced a synergistic antidepressant-like effect in the TST, without causing hyperlocomotion in the open-field test. It may be concluded that the extract from T. avellanedae produces an antidepressant-like effect in the FST and in the TST that is dependent on the monoaminergic system. Taken together, our results suggest that T. avellanedae deserves further investigation as a putative alternative therapeutic tool that could help the conventional pharmacotherapy of depression.     

Effects of adrenalectomy and type I or type II glucocorticoid receptor activation on 5-HT1A and 5-HT2 receptor binding and 5-HT transporter mRNA expression in rat brain

We evaluated the effects of adrenalectomy (ADX) and replacement with glucocorticoid receptor agonists on serotonin (5-HT) 5-HT_1A and 5-HT₂ receptor binding in rat brain. 5-HT_1A receptor binding was increased in the CA2–CA4 and the dentate gyrus of the hippocampus 1 week after ADX. This effect was prevented by the systemic administration of aldosterone (10 μg/μl/h) but not by RU28362 (10 μg/μl/h). No significant effect was observed on 5-HT₂ receptor binding in rat cortex. The expression of 5-HT transporter mRNA was unchanged in the raphe nucleus as measured by in situ hybridization.     

Quantitative autoradiography of 5-HT1D and 5-HT1E binding sites labelled by [H]5-HT, in frontal cortex and the hippocampal region of the human brain

In human cortex and hippocampus area, [³H]5-HT (5 nM) labels 5-HT_1A, 5-HT_1D and 5-HT_1E sites. After masking 5-HT_1A receptors by 0.1 μM 8-OH-DPAT, the binding displaced by 0.1 μM 5-CT presumably represented 5-HT_1D sites and the remaining binding 5-HT_1E sites. In frontal cortex, 5-HT_1A receptors represented the main binding in layers II and VI and a lower fraction on other layers. 5-HT_1D and 5-HT_1E sites, were more homogeneously distributed in layers II to VI (21–34% of specific [³H]5-HT binding). 5-HT_1E sites were of similar affinities (K_D close to 6–8 nM) in the cortical layers II to VI. In CA1 field of hippocampus, (pyramidal layer, stratum radiatum, molecular layer), CA2 and dentate gyrus, 5-HT_1A receptors represented the major fraction, 5-HT_1D sites a significant fraction and 5-HT_1E a minor fraction of the specific [³H]5-HT binding. In CA3–CA4 fields, 5-HT_1A receptors were less densely present, 5-HT_1D sites were predominant and 5-HT_1E sites represented a significant fraction (27%). The highest densities of 5-HT_1E sites have been measured in subiculum, where 5-HT_1A, 5-HT_1D, and 5-HT_1E binding sites were equally represented and in entorhinal cortex where 5-HT_1E sites represented the major binding in layer III. They were also present in layers II and IV (29 and 24%) and, to a lesser extent, in layers V and VI. 5-HT_1A sites were predominant in layer VI, II and V and were less abundant in other layers. 5-HT_1D were homogeneously present in layers II, III, IV and were present in low amounts in other layers. No 5-HT_1E were detected in choroid plexus, where [³H]5-HT was dramatically reduced by mesulergine (5-HT_2C receptors). No significant displacement of [³H]5-HT by mesulergine was measured in other structures.     

The 5-HT1A agonist 8-OH-DPAT increases the number of spike-wave discharges in a genetic rat model of absence epilepsy

The effects of the 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) on the epileptiform activity has been investigated in adult WAG/RIJ rats. Either intraperitoneal (0.1–0.5 mg/kg) or intracerebroventricular (2–20 μg/rat) administration of 8-OH-DPAT caused marked, dose-dependent increases in the number and mean cumulative duration of spike-wave discharges. These effects were attenuated by NAN-190, a 5-HT_1A receptor antagonist. These data indicate that serotonergic system regulates the epileptiform activity in this genetic model of human absence epilepsy.