Solubilized hypericin and pseudohypericin from Hypericum perforatum exert antidepressant activity in the forced swimming test

Lipid targets can be difficult to attain in familial hypercholesterolaemia. To compare atorvastatin with simvastatin-fenofibrate and simvastatin-cholestyramine therapy, we studied 54 patients with familial hypercholesterolaemia over periods of 2-6 months on each therapeutic regimen. The atorvastatin regimen reduced total cholesterol by 41.2 +/- 11.2%, LDL by 45.6 +/- 15.5%, triglycerides by 33.8 +/- 24.8%, and increased HDL by 2.3 +/- 37.0%. Simvastatin-fenofibrate therapy achieved reductions of 33.9 +/- 8.5% in cholesterol, 42.0 +/- 12.2% in LDL, 34.7 +/- 38.3% for triglycerides, and a 25.4 +/- 55.1% increase in HDL. Simvastatin-cholestyramine gave a reduction of 31.3 +/- 11.8% in cholesterol, 36.0 +/- 14.4% in LDL, 13.7 +/- 36.3% in triglycerides, and a 1.1 +/- 30.3% rise in HDL. The atorvastatin regimen was marginally but not significantly better than simvastatin-fenofibrate in improving the LDL:HDL ratio, LDL:apoB and and apolipoprotein B:A1 ratios. Eleven patients (20.4%) had side-effects: two discontinued atorvastatin due to side-effects; two patients had rashes; six had myalgia and two had diarrhoea. Gastrointestinal side-effects were described in 16 (30.1%) patients on simvastatin-cholestyramine therapy and four cases of myalgia (11.2%) were seen with simvastatin-fenofibrate. In nine patients on atorvastatin (20.4%) a 30% or greater fall in HDL was observed, compared to five patients with resin therapy (9.2%) and two with fibrate therapy (5.5%). There were no significant differences in liver or muscle biochemistry between the regimens, but atorvastatin did raise transaminase and creatine kinase concentrations significantly compared to pre-treatment values (p = 0.001). Atorvastatin significantly improves the lipid profile in most patients compared with other regimens. It has a comparable incidence of side-effects to combination therapy regimens.     

Role of 5-HT4 receptors in the mouse passive avoidance test

The effects of the administration of different 5-HT4 receptor antagonists (SDZ 205557, GR 125487) and 5-HT4 receptor agonists (BIMU 1, BIMU 8) on memory processes were evaluated in the mouse passive avoidance test. The administration of SDZ 205557 (10 mg kg-1 i.p.) and GR 125487 (10 mg kg-1 i.p.) immediately after termination of the training session produced an amnesic effect. BIMU 1 (20 mg kg-1 i.p.) and BIMU 8 (30 mg kg-1 i.p.), administered 20 min before the training session, prevented the 5-HT4 receptor antagonist-induced amnesia. In the same experimental conditions BIMU 1 (10 mg kg-1 i.p.; 25 microgram/mouse intracerebroventricularly) and BIMU 8 (30 mg kg-1 i.p.; 30 microgram per mouse intracerebroventricularly) prevented scopolamine (1 mg kg-1 i.p.) and dicyclomine (2 mg kg-1 i.p.) amnesia and, at the dose of 10 and 30 mg kg-1 i.p. respectively, prevented amnesia induced by exposure to a hypoxic environment. At the highest effective doses, none of the drugs impaired motor coordination, as revealed by the rota rod test, or modified spontaneous motility and inspection activity, as revealed by the hole board and Animex tests. The 5-HT3 antagonist ondansetron (0.1-1 mg kg-1 i.p.) was unable to prevent scopolamine-, 5-HT4 antagonist- and hypoxia-induced amnesia. These results suggest that the modulation of 5-HT4 receptors plays an important role in the regulation of memory processes. On these bases, the 5-HT4 receptor agonists could be useful in the treatment of cognitive deficits although 5-HT4 receptor antagonists may represent pharmacological tools for investigation of new potential antiamnesic drugs.     

Selective activation of postsynaptic 5-HT1A receptors induces rapid antidepressant response

It has been reported that the 5-HT1A autoreceptor antagonist pindolol can accelerate the antidepressant response to the selective serotonin (5-HT) reuptake inhibitor (SSRI) paroxetine, presumably by preventing the initial decrease in firing activity of 5-HT neurons produced by the SSRI. The present study was aimed at further exploring this treatment strategy in three groups of 10 patients with unipolar major depression allocated sequentially to three treatment arms for 28 days. The administration of the selective 5-HT1A agonist buspirone (20 mg/day for 1 week and 30 mg/day thereafter) with pindolol (2.5 mg TID) was used to activate selectively postsynaptic 5-HT1A receptors. This combination produced a greater than 50% reduction of depressive symptoms in the first week in 8 of 10 patients and the response was sustained for the remainder of the trial. In contrast, the combination of tricyclic antidepressant drugs devoid of effect on the 5-HT reuptake process (desipramine or trimipramine, 75 mg/day for 1 week and 150 mg/day thereafter) with pindolol resulted in only one of ten patients achieving a 50% improvement after 28 days. The combination of the SSRI fluvoxamine (50 mg/day for 1 week and 100 mg/day thereafter) with pindolol produced a marked antidepressant effect but did not act as rapidly as the buspirone plus pindolol combination with none, four, and eight patients achieving a 50% amelioration after 7, 14, and 21 days of treatment, respectively. These results provide further evidence that pindolol may accelerate the antidepressant effect of drugs that alter the function of the 5-HT neurons and that the selective activation of postsynaptic 5-HT1A receptors may induce a rapid and robust antidepressant response.     

Acute and chronic antidepressant drug treatment in the rat forced swimming test model of depression.

The forced swimming test (FST) is a widely used behavioral screen in rodents that is both sensitive and selective for clinically effective antidepressant drugs. However, antidepressant drugs produce changes in the FST within 24 hr of treatment, in contrast to weeks required for the recovery from clinical depression, and high doses seem to be required to produce effects in most animal tests. This study examined behavioral effects in the FST after subacute and chronic treatment with low doses (1-5 mg/kg) of antidepressant drugs to determine whether chronic treatment produced behavioral effects at doses that were ineffective after subacute treatment. The antidepressants studied were desipramine, a selective norepinephrine uptake inhibitor, and fluoxetine, a selective serotonin uptake inhibitor. The results indicated that low doses of desipramine and fluoxetine produced different behavioral patterns in the FST, but only after chronic administration. The results strengthen the validity of the FST as a behavioral screen for antidepressant drugs with features similar to an animal model of depression. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dimerization of 8-OH-DPAT increases activity at serotonin 5-HT1A receptors

We have identified and partially purified two DNA polymerase activities from purified Trypanosoma brucei mitochondrial extracts. The DNA polymerase activity eluted from the single-stranded DNA agarose column at 0.15 M KCl (polymerase M1) was significantly inhibited by salt concentrations greater than 100 mM, utilized Mg2+ in preference to Mn2+ as a cofactor on deoxyribonucleotide templates with deoxyribose primers, and in the presence of Mn2+ favored a ribonucleotide template with a deoxyribose primer. A 44 kDa peptide in this fraction crossreacted with antisera against the Crithidia fasciculata beta-like mitochondrial polymerase. In activity gels the catalytic peptide migrated at an apparent molecular weight of 35 kDa. The DNA polymerase activity present in the 0.3 M KCl DNA agarose fraction (polymerase M2) exhibited optimum activity at 120-180 mM KCl, used both Mg2+ and Mn2+ as cofactors, and used deoxyribonucleotide templates primed with either deoxyribose or ribose oligomers. Activity gel assays indicate that the native catalytic peptide(s) is approximately 80 kDa in size. The two polymerases showed different sensitivities to several inhibitors: polymerase M1 shows similarities to the Crithidia fasciculata beta-like mitochondrial polymerase while polymerase M2 is a novel, salt-activated enzyme of higher molecular weight.     

5-HT1A and benzodiazepine receptors in the basolateral amygdala modulate anxiety in the social interaction test, but not in the elevated plus-maze

In order to investigate the role of the 5-HT1A receptors of the amygdala in modulating anxiety, rats were implanted with bilateral cannulae aimed at the basolateral nucleus of the amygdala complex and infused with either artificial cerebrospinal fluid (aCSF) or the selective 5-HT1A receptor agonist 8-OH-DPAT (50-200 ng) and tested in two animal models of anxiety. In the elevated plus-maze test, no significant effects were detected in this dose range. In contrast, 8-OH-DPAT caused an overall reduction in levels of social investigation, thus indicating anxiogenic actions in the social interaction test. At 50 ng, 8-OH-DPAT had a selective action on anxiety, while at 200 ng there was a concomitant reduction in locomotor activity and, in some animals, signs of the 5-HT1A syndrome. Evidence that the anxiogenic effect of 8-OH-DPAT (50 ng) was due to activation of 5-HT1A receptors came from the finding that (-)-tertatolol, a 5-HT1A receptor antagonist, reversed this effect at a dose (1.5 micrograms) which was silent when given alone. The benzodiazepine receptor agonist, midazolam (1 and 2 micrograms) was bilaterally administered into the basolateral nucleus of the amygdala and evoked clear-cut anxiolytic effects in the social interaction test. These data indicate that the agonist activation of post-synaptic 5-HT1A receptors in the basolateral nucleus of the amygdala may produce anxiogenic effects, while agonist activation of BDZ receptors in the same areas evokes anxiolytic effects. Our results from the social interaction test are similar to those previously reported from tests of anxiety using punished paradigms, but contrast with those found in the elevated plus-maze. Thus, it is concluded that either the two tests have different sensitivities to midazolam and 8-OH-DPAT or more intriguingly, the tests are evoking fundamentally different states of anxiety, with that evoked by the plus-maze being mediated via brain areas or receptors different from those studied here.     

Effect of activation of 5-HT1A receptors at the ventral medulla on phrenic nerve activity

The purpose of this study was to determine the effects of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-N-propylamino)tetralin hydrobromide (8-OH-DPAT), on respiratory activity (phrenic nerve activity) following application to the ventral medullary surface in the cat. In addition, in order to determine if the action of 8-OH-DPAT was localized to structures at the ventral medulla, we examined the distribution of [3H]8-OH-DPAT to other brain regions and to the peripheral circulation. 8-OH-DPAT (0.0625-8 micrograms) produced a dose-related increase in respiratory rate when applied at either the intermediate or caudal areas on the ventral surface of the medulla. The maximal change in respiratory rate was 9 +/- 2 and 8 +/- 1 breaths/min at the intermediate and caudal areas, respectively. Integrated phrenic nerve amplitude was not significantly affected at these sites except at the 8 micrograms dose where it was decreased. No change in phrenic nerve activity was observed with 8-OH-DPAT application at the rostral area. [3H]8-OH-DPAT was not found to distribute to other brain regions or to the peripheral circulation following application to the ventral medullary surface. The results of this study suggest that 8-OH-DPAT causes changes in respiratory activity, primarily respiratory rate, by acting on neuronal structures at the ventral surface of the medulla.     

The 5-HT1-like receptors mediating inhibition of sympathetic vasopressor outflow in the pithed rat: operational correlation with the 5-HT1A, 5-HT1B and 5-HT1D subtypes

1. It has been suggested that the inhibition of sympathetically-induced vasopressor responses produced by 5-hydroxytryptamine (5-HT) in pithed rats is mediated by 5-HT1-like receptors. The present study has re-analysed this suggestion with regard to the classification schemes recently proposed by the NC-IUPHAR subcommittee on 5-HT receptors. 2. Intravenous (i.v.) continuous infusions of 5-HT and the 5-HT1 receptor agonists, 8-OH-DPAT (5-HT1A), indorenate (5-HT1A), CP 93,129 (5-HT1B) and sumatriptan (5-HT(1B/1D)), resulted in a dose-dependent inhibition of sympathetically-induced vasopressor responses. 3. The sympatho-inhibitory responses induced by 5-HT, 8-OH-DPAT, indorenate, CP 93,129 or sumatriptan were analysed before and after i.v. treatment with blocking doses of the putative 5-HT receptor antagonists, WAY 100635 (5-HT1A), cyanopindolol (5-HT(1A/1B)) or GR 127935 (5-HT(1B/1D)). Thus, after WAY 100635, the responses to 5-HT and indorenate, but not to 8-OH-DPAT, CP 93,129 and sumatriptan, were blocked. After cyanopindolol, the responses to 5-HT, indorenate and CP 93,129 were abolished, whilst those to 8-OH-DPAT and sumatriptan (except at the lowest frequency of stimulation) remained unaltered. In contrast, after GR 127935, the responses to 5-HT, CP 93,129 and sumatriptan, but not to 8-OH-DPAT and indorenate, were abolished. 4. In additional experiments, the inhibition induced by 5-HT was not modified after 5-HT7 receptor blocking doses of mesulergine. 5. The above results suggest that the 5-HT1-like receptors, which inhibit the sympathetic vasopressor outflow in pithed rats, display the pharmacological profile of the 5-HT1A, 5-HT1B and 5-HT1D, but not that of 5-HT7, receptors.     

Interaction of 5-HT1B/D ligands with recombinant h 5-HT1A receptors: intrinsic activity and modulation by G-protein activation state

Many 5-HT1B/D receptor ligands have affinity for 5-HT1A receptors. In the present study, the intrinsic activity of a series of 5-HT1B/D ligands was investigated at human 5-HT1A (h 5-HT1A) receptors by measuring G-protein activation in recombinant C6-glial and HeLa membranes, using agonist-stimulated [35S]GTPgammaS binding. In these two membrane preparations, the density of h 5-HT1A receptors (i.e., 246 to 320 fmol mg(-1) protein) and of their G-proteins, and the receptor: G-protein density ratio (0.08 to 0.18) appeared to be similar. It was found that: (i) the maximal [35S]GTPgammaS binding responses induced by the 5-HT1B/D receptor ligands in the HeLa preparation at 30 microM GDP were comparable to that of the native agonist 5-HT; (ii) as compared to 5-HT (1.00), similar potencies but lower maximal responses were observed in the C6-glial preparation at 0.3 microM GDP for zolmitriptan (0.89), dihydroergotamine (0.81), rizatriptan (0.71), CP122638 (0.69), naratriptan (0.60) and sumatriptan (0.53); and that (iii) maximal [35S]GTPgammaS binding responses induced by 5-HT1B/D ligands in the C6-glial preparation were either unaffected or significantly enhanced by increasing the GDP concentration from 0.3 to 30 microM and higher concentrations. These features differ from those observed with 5-HT1A receptor agonists; the latter display the same rank order of potency and efficacy in both membrane preparations, and increasing the amount of GDP with C6-glial membranes results in an attenuation of both the agonist's maximal effect and the apparent potency of partial agonists. The differential regulation of 5-HT1A and 5-HT1B/D agonist responses by GDP suggests that different G-protein subtypes are involved upon 5-HT1A receptor activation by 5-HT1A and 5-HT1B/D agonists.     

Evidence for specific involvement of 5-HT1A and 5-HT2A/C receptors in the expression of patterns of spontaneous motor activity of the rat

The 5-HT1A and the 5-HT2A/C receptor agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.006-0.4 mg kg-1 s.c.) and (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.05-4.0 mg kg-1 s.c.), respectively, produced a similar stereotyped forward locomotion in rats, although the intensity of the behavioral change was considerably less with DOI. The stereotyped forward locomotion was accompanied by a slight decrease in total activity, suppression of rearing behavior and an increased activity in the periphery of the open-field arena. In support of receptor specificity, the effects of 8-OH-DPAT and DOI could be antagonised by pretreatment with the 5-HT1A/B and the 5-HT2A/C receptor antagonists (-)-pindolol (2 mg kg-1 s.c.) and ritanserin (2 mg kg-1 s.c.), respectively. In addition, (-)-pindolol, but not the selective beta-adrenoceptor antagonist betaxolol, markedly enhanced the behavioral effects produced by DOI. The nature of these specific actions and interactions in terms of pre- and post-synaptic serotonergic mechanisms remains an important question.     

Selective in vivo labelling of brain 5-HT1A receptors by [3H]WAY 100635 in the mouse

The novel selective 5-HT1A receptor antagonist radioligand [3H]WAY 100635 ([O-methyl-3H]N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2- pyridyl)cyclohexane-carboxamide) was injected i.v. to mice in an attempt to label in vivo central 5-HT1A receptors. Although 5 min after the i.v. injection of [3H]WAY 100635 (4-7.6 muCi per mouse) the amount of tritium found in the whole brain only accounted for 1.5-1.8% of the injected radioactivity, regional differences in 3H accumulation already corresponded to those of 5-HT1A receptor density. Optimal data were obtained 1 h after [3H]WAY 100635 injection as the distribution of 3H in brain was exactly that of 5-HT1A receptor binding sites in mouse brain sections labelled in vitro with [3H]WAY 100635. In particular, high level of labelling was found in the lateral septum, gyrus dentatus and CA1 area of Ammon's horn in the hippocampus, dorsal raphe nucleus and entorhinal cortex. No labelling was found in he substantia nigra, and 3H accumulated in the cerebellum represented only 12-14% of that found in the hippocampus. Pretreatment with various drugs indicated that only 5-HT1A receptor ligands were able to decrease the accumulation of 3H in all the brain areas examined except in the cerebellum. Assuming that only non-specific binding took place in the latter structure, it was possible to calculate the ID50 values of 5-HT1A receptor agonists (8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), S 14506 (1-[2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphthyl+ ++)piperazine) and S 20499 ((+)-4-[N-(5-methoxy-chroman-3-yl)-N-propylamino]butyl-8- azaspiro-(4,5)-decane-7,9-dione)) and antagonists (spiperone, (-)-tertatolol, (+)-WAY 100135 (N-tert-butyl-3,4-(2-methoxyphenyl)piperazin-1-yl-2-phenyl- propanamide)) as inhibitors of 3H accumulation in the hippocampus of [3H]WAY 100635-injected mice. Comparison of these values with the in vitro affinity of the same ligands for hippocampal 5-HT1A receptors revealed marked variations in the capacity of 5-HT1A receptor agonists and antagonists to reach the brain when injected via the subcutaneous route in mice.     

The effect of water temperature on immobility in the forced swimming test in rats

In the Porsolt swimming test intact rats acquire and retain the immobile response indistinguishably at 25 and 30 degrees C; at both temperatures retention is abolished by administration of the glucocorticoid antagonist RU38486 and the kappa-selective opiate receptor antagonist MR2266 when given together, but not when either is given alone. At 20 degrees C, however, the animals do not acquire the response, and have levels of retention significantly lower than at the higher temperature. This deficit is not restored by administration of glucocorticoids, kappa-opioid receptor-selective agonists, thyroid hormone or glucose.     

5-HT4 receptor antagonism does not affect motor and reward mechanisms in the rat

5-HT4 receptors are concentrated in areas of the brain which are rich in dopamine neuronal markers, which may suggest that they influence motor and reward processes. We tested this hypothesis by examining the effects of a 5-HT4 receptor antagonist, 8-amino-7-chloro-(N-butyl-4-piperidyl)methylbenzo-1,4-dioxan-5-car boxylate hydrochloride (SB-204070-A) on amphetamine- and nicotine-induced locomotor stimulation in intact rats. In rats with unilateral 6-hydroxydopamine-induced lesions of the ascending nigrostriatal dopaminergic projection, SB-204070-A was tested for its effects on amphetamine-induced rotation. SB-204070-A was also tested for its effects on rewarded behaviour maintained by intracranial self-stimulation. SB-204070-A did not alter behaviour under any of these conditions, suggesting a lack of involvement of the 5-HT4 receptor in motor and reward processes.     

REM sleep deprivation potentiates the effects of imipramine and desipramine but not that of clomipramine in the forced swimming test

The human amnestic syndrome associated with lesions of the hippocampus and amygdala is characterized by a selective impairment of recent (explicit, episodic) memory. Benzodiazepine (BZ) treated normal subjects demonstrate similar, marked impairments in episodic memory, but in addition, BZ also induces sedation and inattention. Thus, the amnestic effects of BZ may be secondary to drug-induced sedation. However, when subjects were pretreated with the specific BZ receptor antagonist, flumazenil, the sedative and attentional effects of diazepam were blocked, but a marked impairment in episodic memory still occurred. This demonstrates that, using neuropharmacological methods, it is possible to produce a dissociation of memory impairment from inattention and sedation. Such distinct patterns of cognitive dysfunction may serve as models for clinical cognitive syndromes.     

The 5-HT1A receptor antagonist p-MPPI blocks 5-HT1A autoreceptors and increases dorsal raphe unit activity in awake cats

The effects of the putative 5-HT1A receptor antagonist 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzam ide (p-MPPI) were examined on the activity of serotonergic dorsal raphe nucleus neurons in freely moving cats. Systemic administration of p-MPPI produced a dose-dependent increase in firing rate. This stimulatory effect of p-MPPI was evident during wakefulness (when serotonergic neurons display a relatively high level of activity), but not during sleep (when serotonergic neurons display little or no spontaneous activity). p-MPPI also blocked the ability of the 5-HT1A receptor agonist 8-hydroxy-(2-di-n-propylamino)tetralin (8-OH-DPAT) to inhibit serotonergic neuronal activity. This antagonism was evident both as a reversal of the neuronal inhibition produced by prior injection of 8-OH-DPAT and as a shift in the potency of 8-OH-DPAT following p-MPPI pretreatment. Overall, these results in behaving animals indicate that p-MPPI acts as an effective 5-HT1A autoreceptor antagonist. The increase in firing rate produced by p-MPPI supports the hypothesis that autoreceptor-mediated feedback inhibition operates under physiological conditions.     

Activation of 5-HT1A receptors potentiates the clonidine inhibitory effect in the locus coeruleus

Using in vivo extracellular recordings, we have examined the effect of the application of the prototypical 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), on the firing rate of locus coeruleus neurons. 8-OH-DPAT (1 microgram/kg, i.v.) did not modify the basal activity of the locus coeruleus but shifted to the left the dose-response curve for the clonidine induced inhibition of firing rate and reduced the corresponding ED50 by 77%. 2-[2-[4-(o-methoxyphenyl)piperazin-1-yl]ethyl]-4,4-dimethyl-1,3(2H ,4H)-isoquinolinedione (ARC 239; 75 micrograms/kg, i.v.), and chlorpromazine (75 micrograms/kg, i.v.) also shifted to the left the dose-response curve for clonidine and reduced by 38 and 46%, respectively, the ED50, while slightly increasing the basal firing rate. The results indicated that 5-HT1A receptors may modulate the responses mediated by alpha 2A-adrenoceptors in the locus coeruleus.     

Somatodendritic 5-HT1A receptors are critically involved in the anxiolytic effects of 8-OH-DPAT

A simple technique for the fast sampling of biological tissues for electron paramagnetic resonance (EPR) spectroscopy is described. By using tube-like stainless steel cutter, a cylindrical piece of tissue is dissected free; while holding the sample and cutter on a silicone rubber cutting base, the sample is transferred directly into the EPR test tube by pushing the tube into the instrument. The main features of the technique are its simplicity, speed, elimination of the necessity to manipulate frozen tissue (e.g., breaking, chopping, etc.), precise information on the sample volume, the ability to adjust sample size according to need, and avoidance of the use any foreign compounds (such as spin traps). The technique has been successfully applied to the EPR detection of free radicals in rabbit spinal cord exposed to ischemia. It can be easily modified for manipulation with samples in an inert atmosphere.     

Differential membrane targeting and pharmacological characterization of chimeras of rat serotonin 5-HT1A and 5-HT1B receptors expressed in epithelial LLC-PK1 cells

The serotonin 5-HT1A and 5-HT1B receptors are two structurally related but pharmacologically distinguishable 5-HT receptor types. In brain, the 5-HT1A receptor is localized on the soma and dendrites of neurons, whereas the 5-HT1B receptor is targeted to the axon terminals. We previously showed that these two receptors are targeted in different membrane compartments when stably expressed in the epithelial LLC-PK1 cell line. Further investigations on the mechanisms responsible for their differential targeting were done by constructing chimeras of 5-HT1A and 5-HT1B receptors still able to bind specifically [3H]lysergic acid diethylamide and selective agonists and antagonists. Their cellular localization examined by confocal microscopy suggests that the third intracellular domain of the 5-HT1B receptor was responsible for its Golgi-like localization in transfected LLC-PK1 cells. In contrast, the third intracellular domain of the 5-HT1A receptor apparently allowed the sorting of the chimeras to the plasma membrane. Further inclusion of the C-terminal domain of the 5-HT1A receptor in their sequence led to a basolateral localization, whereas that of the 5-HT1B receptor allowed an apical targeting, suggesting the existence of a targeting signal in this portion of the receptor(s).