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The influence of two anxiolytics on basal heart rate and on the evoked cardiac response elicited by auditory stimuli, was studied in humans. Diazepam (Valium) (7.5 mg) and buspirone (Buspar) (7.5 mg), which differ in their psycho-pharmacological profiles, were used. Prestimulus vigilance and cognitive load were manipulated by instructions allowing the subjects to ignore the stimuli, or requiring them to count the tones. Drug effects were obtained in subjective alertness, basal heart rate level, and the evoked cardiac response. Diazepam reduced subjective alertness, while buspirone did not. Diazepam apparently increased heart rate levels relative to placebo, in contrast to buspirone, which produced an apparent decrease in heart rate. These drug-induced prestimulus heart rate level effects were associated with differential decelerations immediately following stimulus onset and appear to reflect differences in prestimulus vigilance. Opposite effects of the drugs were also observed in the second, acceleratory, component of the of the evoked cardiac response, and these were found to be independent of the prestimulus drug effects. Compared with placebo, buspirone appeared to enhance the acceleratory component in the count condition, while diazepam led to an apparent reduction of this component. Enhancement of this acceleration after buspirone may reflect an increase in cognitive effort directed to the performance of task-relevant behaviour, while the reduction of this component after diazepam can be regarded as a cognitive-motivational neutralisation of signal value. The differential effects of the two anxiolytics support the separation of the evoked cardiac response into different components and may also have implications for the clinical use of the drugs.
The present study characterizes a serotonin (5-HT) binding site on human platelet membranes, using [3H]8-OH-DPAT as the radioligand. [3H]8-OH-DPAT binds specifically and saturably to a site on human platelet membranes with an average KD of 43 nM and Bmax of 1078 fmol/mg protein. Determinations of IC50 values for various serotonergic characterizing agents in platelets for displacement of [3H]8-OH-DPAT were performed. For example, 8-OH-DPAT 5HT1A had an IC50 of 117 nM; TFMPP 5HT1B (2.3 microM0 and PAPP 1A + 5HT2 (9 microM); ipsapirone 5HT1A (21.1 microM) and buspirone 5HT1A (greater than 100 microM); ketanserin 5HT2 (greater than 100 microM); 5-HT uptake inhibitors: paroxetine (13 nM); chlorimipramine (73 nM) and fluoxetine (653 nM). The pharmacological inhibitory profile of the platelet 8-OH-DPAT site is not consistent with profiles reported for brain. 8-OH-DPAT does not inhibit [3H]imipramine binding, however, it does inhibit [3H]5-HT uptake in human platelets near 5-HT's Km value (IC50 = 2-4 microM). These results suggest that the human platelet site labeled by [3H]8-OH-DPAT is pharmacologically different from the neuronal site and probably is a component of the 5-HT transporter.
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In previous studies, we demonstrated that tandospirone, a serotonin-5-HT1A partial agonist, added to ongoing treatment with small to moderate doses of typical antipsychotic drugs, improved executive function and verbal learning and memory. However, tandospirone is not available in most countries, and atypical antipsychotic drugs (AAPDs) have largely replaced typical antipsychotic drugs as the primary treatment for schizophrenia. Therefore, the goal of this randomly assigned placebo-controlled double-blind study was to determine if the addition of buspirone, a widely available 5-HT1A partial agonist, would enhance cognitive function, in subjects with schizophrenia treated with AAPDs. Seventy-three patients with schizophrenia, who had been treated with an AAPD for at least three months, were randomly assigned to receive either buspirone, 30 mg/day, or matching placebo. All other medications remained unchanged. Attention, verbal fluency, verbal learning and memory, verbal working memory, and executive function, as well as psychopathology, were assessed at baseline, and 6 weeks, and 3 and 6 months after baseline. A significant Time x Group interaction effect was noted on the Digit Symbol Substitution Test, a measure of attention/speeded motor performance, due to better performance of the buspirone group compared to the placebo group at 3 months. No significant interaction effects were noted for other domains of cognition. Scores on the Brief Psychiatric Rating Scale (Total, Positive) were improved during treatment with buspirone but not placebo, but the effects did not reach statistical significance. The results of this study showed a possible benefit of buspirone augmentation of AAPDs to enhance attention. However, we did not replicate the results of the previous study with tandospirone, which may be due to the differences between tandospirone and buspirone, between typical antipsychotics and AAPDs, or a combination of the above. Further study to determine the usefulness of 5-HT1A agonist treatment in schizophrenia is indicated.
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It has been observed that agents with agonist activity at 5-HT2A receptors prevent neurotoxicity induced by the non-competitive NMDA antagonist, dizocilpine (MK-801). Subsequent behavioral studies reported complete antagonism by LSD and DOM of the stimulus effects of the related NMDA antagonist, phencyclidine [PCP]. The present study sought to extend those observations to include other psychoactive drugs. Male F-344 rats were trained in a 2-lever, fixed-ratio 10, food-reinforced task with PCP (3.0 mg/kg; IP; 30 min pretreatment) as a discriminative stimulus. Tests of generalization were then conducted using the training dose of PCP in combination with a range of doses of DOM, LSD, d-amphetamine, MDMA, psilocybin, buspirone, and GHB. All of the drugs tested in combination with PCP produced a statistically significant diminution of PCP-appropriate responding but for none was antagonism complete. These data, obtained using a stimulus control model of the hallucinogenic effects of PCP, fail to support the hypothesis that LSD and DOM completely antagonize stimulus control by PCP. Instead, the data suggest complex interactions between PCP-induced stimulus control and a variety of psychoactive drugs including GHB, an agent with no known affinity for serotonergic receptors.
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Randomised controlled trials that compared azapirones with placebo for panic disorder in adults.
This 12-week open label study was performed to assess the efficacy of buspirone-5-HT1A receptor agonist in the treatment of bulimia, and to compare it with the efficacy of fluoxetine --the standard treatment of BN.
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Serotonin uptake inhibitors (SUIs) have been established as the first-line pharmacotherapy of obsessive compulsive disorder (OCD). However, approximately one half of patients who receive an adequate trial with these agents remain clinically unchanged. The addition of drugs that enhance serotonin (5-HT) neurotransmission, such as lithium and buspirone, to ongoing treatment in SUI-refractory patients has generally proved to be an ineffective strategy. The addition of dopamine antagonists to the regimens of SUI-resistant patients appears to be a useful approach for OCD patients with a comorbid chronic tic disorder (e.g., Tourette's syndrome) and possibly for those with concurrent psychotic spectrum disorders. These drug response data suggest that both the 5-HT and dopamine systems may be involved in the treatment, and possibly the pathophysiology, of specific subtypes of OCD.
By the author.
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One session of FS induced anxiolytic-like behavior in mice tested in both the EBT and the BBT. This effect of FS was blocked by a previous administration of either picrotoxin or WAY 100635. The 5-HT(1A) compounds produced a clear anxiolytic-like effect in UST animals. By contrast, with low doses of either 8-OH-DPAT (0.01 mg/kg), buspirone (0.03 mg/kg) or indorenate (0.3, 0.6 mg/kg) ST mice showed a decrease in the anti-anxiety-like effect observed after FS. No change in ambulation that could mask the results of the anxiety test was registered.
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TVX Q 7821 is active in several behavioral models of anxiety in animals and has a high selective affinity for brain serotonin 5-HT1A receptors in binding assays. In order to determine if interaction with 5-HT1A receptors is important for some of the behavioral effects of this compound, 11 rats were trained to reliably discriminate the interoceptive stimuli induced by TVX Q 7821 (10 mg/kg, IP) from those of saline. Following discrimination acquisition, TVX Q 7821 administration resulted in drug-appropriate responding with an ED50 of 1.5 mg/kg, as did other substances with high affinity for the 5-HT1A receptor: 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT, ED50 = 0.16 mg/kg), 5-methoxy-N,N-dimethyltryptamine (5-OMe-DMT, ED50 = 2.5 mg/kg), and buspirone (ED50 = 5.4 mg/kg). Anxiolytics not acting via the 5-HT1A receptor, like diazepam and pentobarbital, did not induce full TVX Q 7821-appropriate responses. In addition, non-selective 5-HT agonists and antagonists such as bufotenin, quipazine, and methysergide, as well as substances with high affinity for the 5-HT1B receptor (m-trifluoromethylphenylpiperazine, TFMPP; 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole succinate, RU 24969) did not substitute for TVX Q 7821. These data support a selective 5-HT1A mechanism of action in vivo for TVX Q 7821 and indicate the suitability of TVX Q 7821 for the investigation of behavioral correlates of the 5-HT1A receptor.
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Here we describe a liquid chromatography-tandem mass spectrometry method for the blood determination of tricyclic antidepressant drugs (amitriptyline, clomipramine, trimipramine, and imipramine, doxepin, mianserin, maprotyline, dosulepine, amoxapine), their active metabolites (desipramine, nortriptyline, demethylclomipramine, and nordoxepin), and monoamine oxidase inhibitors (toloxatone and moclobemide). A nontricyclic antidepressant (viloxazine) and two other anxiolytic drugs (buspirone and hydroxyzine) that could be encountered in toxicology have been included to this method. After a liquid-liquid extraction from blood, the compounds and their internal standard (methylrisperidone) were eluted on a XTerra RP18 column with a gradient of acetonitrile/ammonium formate buffer 4 mmol/L (pH 3.2). They were then detected by electrospray ionization mass spectrometry with multiple reaction monitoring mode. The calibration curves were linear over the range 5-100 ng/mL. The limit of quantification was 2 ng/mL for each compound. The bias were lower than 10%. Intraday and interday precisions, expressed as variation coefficient, were lower than 13%. The extraction recoveries were between 60 and 80% except for moclobemide, viloxazine, and toloxatone (10-60%). This specific and sensitive method allows management of intoxication and is suitable for the routine determination of antidepressants in forensic investigation.
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Dyspepsia is a common symptom for which an organic cause is found in only 40% of patients. When no cause is apparent and the dyspepsia is considered to be idiopathic, a diagnosis of non-ulcer dyspepsia is made. The pathophysiology of non-ulcer dyspepsia is poorly understood and numerous theories have been put forward, including a theory of enhanced central serotoninergic receptor sensitivity.
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Using rat and mouse models of aversive behaviour, we have further investigated the properties of the 5-HT3 receptor antagonist ondansetron (GR38032F) that are relevant to its proposed use as an anxiolytic agent. Tolerance to the disinhibitory properties of diazepam was readily demonstrated in the social interaction test in the rat, but did not occur after subchronic treatment with ondansetron. In both the light/dark exploration test in mice and the social interaction test in rats, withdrawal from subchronic treatment with diazepam increased behavioural suppression, whereas this was not observed with ondansetron. The behavioural suppression and weight loss induced by either the withdrawal of diazepam or the administration of the benzodiazepine receptor antagonist, flumazenil, in animals treated subchronically with diazepam, was prevented or antagonised by diazepam or ondansetron. Buspirone was ineffective. It is concluded that, in rats and mice, tolerance to the disinhibitory effects of ondansetron does not occur, that withdrawal from subchronic treatment with ondansetron is not associated with any behavioural disturbances and that ondansetron is highly effective in preventing the behavioural suppression and weight loss following withdrawal from subchronic diazepam treatment. These data suggest that ondansetron may have major therapeutic advantages over currently available anxiolytic agents, particularly in patients who have previously received prolonged benzodiazepine therapy.
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The safety and antianxiety and antidepressive effects of buspirone (average 16.5 mg/day) were compared in a double-blind trial with those of diazepam (15 mg/day). The two drugs were nearly equivalent in relieving symptoms of both anxiety and depression in 100 patients. Scores on the impaired cognition factor of the SCL-56 and confusion factor of the POMS showed significantly greater improvement with buspirone than with diazepam. Side effects, such as sedation and drowsiness, were significantly more frequent and severe with diazepam. Buspirone may be particularly indicated for anxious patients with associated depression.
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The present study was designed to elucidate the effects of sesamol, buspirone and their combination in immobilization stress induced behavioral and biochemical alterations in mice.
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Selective 5HT1a agonist binding to membranes from rabbit cerebral cortex was concentration-dependent and saturable; the Kd was 1.1 nM and Bmax of 480 fmols/mg protein. Scatchard as well as Hill plots were linear; the Hill coefficient was 0.96, suggesting a single, non-interacting binding site. Agonist binding was inhibited in a concentration-dependent fashion by gamma S GTP, a result consistent with the coupling of this binding site to the G protein signal transduction system. In competition experiments involving agonist and a series of agents with known affinities and specificities at 5HT1a receptors, a rank order relationship was found consistent with this binding site being a 5HT1a binding site. Direct comparisons of agonist and antagonist binding at rat cerebral cortex 5HT1a receptors and cloned human 5HT1a receptors also suggested that the rabbit binding site belongs to the 5HT1a class. The only rank order anomalies were with methiothepin in rabbit cerebral cortex, where a comparatively high Ki was observed and with buspirone in cloned human 5HT1a receptor, where a low Ki was determined; these anomalies bear further study in light of the comparative pharmacology of 5HT1a receptors. Finally, the natural product parthenolide was tested for affinity in the rabbit, rat, and human systems, where it uniformly was unable to displace agonist, suggesting that the 5HT1a receptor is not a target for this compound. Overall, these results suggest that a functional 5HT1a receptor exists in rabbit cerebral cortex.
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A multicenter, double-blind, placebo-controlled study was conducted to determine the safety of concurrently using buspirone with alprazolam before and during a gradual tapering of the alprazolam dose. Thirty-six patients received placebo t.i.d. and 36 received buspirone 5 mg. t.i.d. Findings included significantly greater anxiety (as measured by the Hamilton Rating Scale for Anxiety) in the placebo group and significantly reduced manifestations of abstinence (as measured by the Abstinence Rating Scale) in the buspirone group. Buspirone and alprazolam may be used together safely, and buspirone may be started early in the alprazolam tapering process.
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The acute effects induced by these compounds were qualitatively assessed by the patient, a 38-year-old man who underwent surgery 17 years ago to remove an intracavernous angioma located at the mid-thoracic level (T5-T6) of the spinal cord.
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Depression is often a chronic illness that requires a methodical, long-term approach to manage it optimally. A single antidepressant trial is often insufficient for patients to achieve remission. Remission rates for selective serotonin reuptake inhibitors are about 30% to 35%. Using successive treatment steps with optimal medication dosing and making measurement-based treatment decisions can help patients achieve remission, but, at each step, remission is less likely than at the first step. Depression is considered treatment-resistant if 2 adequate trials of medication fail. Clinicians can use validated symptom checklists such as the 16-Item Quick Inventory of Depressive Symptomatology, 9-Item Patient Health Questionnaire, Global Assessment of Functioning, and Sheehan Disability Scale to identify patients with treatment-resistant depression. Treatment resistance is likely in patients with a history of depressive chronicity and concurrent psychiatric and medical disorders and may be mistakenly suspected in patients who have had an inadequate trial of medication or who have been misdiagnosed. Strategies that can be effective to combat treatment resistance include optimizing treatment, switching to another antidepressant, combining antidepressants, and augmenting antidepressants with nonantidepressant treatments such as buspirone, lithium, liothyronine, atypical antipsychotics, or other agents. In addition, clinicians need to cultivate strong therapeutic alliances with patients, use objective measurements, practice evidence-based medicine, and educate patients about the disease and its treatments.
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Risk of withdrawal was investigated in a prospective, double-blind comparison of clorazepate dipotassium, a benzodiazepine with a long half-life, and the nonbenzodiazepine buspirone hydrochloride in the long-term treatment of anxious outpatients. Patients were treated with therapeutic doses of clorazepate dipotassium (15 to 60 mg/d) or buspirone hydrochloride (10 to 40 mg/d) for six continuous months before their tranquilizer therapy was blindly and abruptly stopped. There was a significant increase in symptom severity consistent with a withdrawal reaction for the clorazepate group but not the buspirone group. For the clorazepate group, there was a suggestion that previous discontinuous exposure to benzodiazepines might sensitize patients to subsequent withdrawal effects. For the buspirone group, a higher dropout rate raised questions about patient satisfaction with therapy in this rather chronically anxious population.
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At the completion of clomipramine treatment, the patient no longer felt driven to recall the names of famous people. Her score from the Yale-Brown Obsessive-Compulsive Scale dropped from 29 to 3. Her Folstein Mini-Mental State Examination score increased from 21 to 23.
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In rats lightly restrained in plastic cylinders, subcutaneous administration of the selective, high efficacy 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), induced spontaneous tail-flicks, that is, tail-flicks in the absence of extraneous stimulation. The putative 5-HT1B receptor agonist, CGS 12066B, the mixed 5-HT1B/1C receptor agonists, 1-((3-(trifluoromethyl)phenyl]piperazine (TFMPP) and 1-(3-chlorophenyl)piperazine (mCPP), the 5-HT1C/2 receptor agonist, [+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the 5-HT1B/1C/2 receptor agonist, quipazine, did not, in contrast, elicit tail-flicks when applied alone. However, TFMPP, mCPP, DOI and quipazine, but not CGS 12066B, each potentiated the action of 8-OH-DPAT. Further, in the presence of TFMPP, mCPP and DOI, the dose-response curve for the induction of tail-flicks by 8-OH-DPAT was both steeper and shifted to the left. Tail-flicks induced by another high efficacy 5-HT1A receptor agonist, lisuride, were also enhanced by TFMPP, mCPP and DOI. The 5-HT1A receptor partial agonists, buspirone and (+/-)-flesinoxan, evoked tail-flicks only in the presence of TFMPP, mCPP or DOI. The mixed 5-HT1C/2 receptor antagonists, ritanserin and ICI 169,369, did not modify the action of 8-OH-DPAT alone but abolished the potentiation of 8-OH-DPAT-induced tail-flicks by DOI and TFMPP. Further, the selective 5-HT1A receptor antagonist, BMY 7378, blocked tail-flicks induced by both 8-OH-DPAT alone and 8-OH-DPAT plus DOI or TFMPP. A common property of those drugs potentiating 8-OH-DPAT-induced tail-flicks is an agonist action at 5-HT1C receptors and the data indicate that it is this mechanism which underlies the facilitation of tail-flicks.
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Social interaction (SI) between two unfamiliar male rats in a dimly lit, familiar environment has been investigated as a model of anxiety, where novelty of the partner remains as the principal anxiogenic stimulus. A range of centrally acting drugs have been tested in this situation. Chlordiazepoxide, nitrazepam, flunitrazepam, and flurazepam all increase SI, as does buspirone, CL 218872, suriclone, sodium valproate, and nicotinamide in the model described. Anxiogenic agents FG 7142 and yohimbine reduced SI without significant modification of motor activities. However, the stimulant amphetamine increased all behaviours in this condition. Amphetamine also increased all behaviours when rats were tested with their cagemates, when the desire for SI is largely satiated. CL 218872 also increased SI in this second situation, and it is suggested that this agent may have a non-specific component in its action in this test. Additionally, caffeine, theophylline, and piracetam may also have non-specific behavioural actions in this model.
Stereotypy (e.g., repetitive hand waving) is a key phenotype of autism spectrum disorder, Fragile X and Rett syndromes, and other neuropsychiatric disorders, and its severity correlates with cognitive and attention deficits. There are no effective treatments, however, for stereotypy. Perturbation of serotonin (5-HT) neurotransmission contributes to stereotypy, suggesting that distinct 5-HT receptors may be pharmacotherapeutic targets to treat stereotypy and related neuropsychiatric symptoms. For example, preclinical studies indicate that 5-HT7 receptor activation corrects deficits in mouse models of Fragile X and Rett syndromes, and clinical trials for autism are underway with buspirone, a 5-HT1A partial agonist with relevant affinity at 5-HT7 receptors. Herein, we report the synthesis, in vitro molecular pharmacology, behavioral pharmacology, and pharmacokinetic parameters in mice after subcutaneous and oral administration of (+)-5-(2'-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine ((+)-5-FPT), a new, dual partial agonist targeting both 5-HT7 (Ki = 5.8 nM, EC50 = 34 nM) and 5-HT1A (Ki = 22 nM, EC50 = 40 nM) receptors. Three unique, heterogeneous mouse models were used to assess the efficacy of (+)-5-FPT to reduce stereotypy: idiopathic jumping in C58/J mice, repetitive body rotations in C57BL/6J mice treated with the NMDA antagonist, MK-801, and repetitive head twitching in C57BL/6J mice treated with the 5-HT2 agonist, DOI. Systemic (+)-5-FPT potently and efficaciously reduced or eliminated stereotypy in each of the mouse models without altering locomotor behavior on its own, and additional tests showed that (+)-5-FPT, at the highest behaviorally active dose tested, enhanced social interaction and did not cause behaviors indicative of serotonin syndrome. These data suggest that (+)-5-FPT is a promising medication for treating stereotypy in psychiatric disorders.
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The major finding, that there are virtually no controlled data that support the efficacy of most of these drugs for the treatment of psychiatric disorders in children and adolescents, is both surprising and unfortunate. For some drugs, e.g., buspirone and guanfacine, this is because no controlled studies have been carried out in children and/or adolescents. For other drugs, e.g., clonidine and naltrexone, most of the placebo-controlled studies have failed to demonstrate efficacy.
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Experimental evidence and clinical experience suggest that mild hypothermia protects numerous tissues from damage during ischemic insult. However, the extent to which hypothermia becomes a valued therapeutic option will depend on the clinician's ability to rapidly reduce core body temperature and safely maintain hypothermia. To date, general anesthesia is the best way to block autonomic defenses during induction of mild-to-moderate hypothermia; unfortunately, general anesthesia is not an option in most patients likely to benefit from therapeutic hypothermia. Induction of hypothermia in awake humans is complicated by both the technical difficulties related to thermal manipulation and the remarkable efficacy of thermoregulatory defenses, especially vasoconstriction and shivering. The most effective thermal manipulation devices are generally invasive and, therefore, more prone to complications than surface methods. In an effort to inhibit thermoregulation in awake humans, several agents have been tested either alone or in combination with each other. For example, the combination of meperidine and buspirone has already been applied to facilitate induction of hypothermia in human trials. However, pharmacological induction of thermoregulatory tolerance to cold without excessive sedation, respiratory depression, or other serious toxicity remains a major focus of current therapeutic hypothermia research.
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Indorenate has been proposed to possess antihypertensive, anorectic, stimulus control and anxiolytic-like actions. This compound has affinity mainly for the serotonergic(1A/1B) receptors, hence it could possess antidepressant-like activity.
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Rat somatodendritic 5-HT(1A) receptors controlling hippocampal 5-HT release were rapidly desensitized by chronic activation with a high-efficacy 5-HT(1A) agonist, but not by chronic activation with a partial agonist. Thus, rapid 5-HT(1A) autoreceptor desensitization by high-efficacy agonists may accelerate the onset of the therapeutic effects of antidepressants.