Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new buspar research articles will be listed here shortly after becoming available to us.
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Medical research on buspar
Psychopharmacology (Berl). 2008 Aug 16;
Dekeyne A, Millan MJ
RATIONALE: Though interoceptive properties of antidepressants have been described, discriminative stimulus (DS) properties of mirtazapine, which does not affect monoamine reuptake, remain uncharacterized. OBJECTIVES: The objectives of the study are to train rats to recognize a mirtazapine DS, then perform substitution studies with other antidepressants and drugs acting at sites occupied by mirtazapine. MATERIALS AND METHODS: Using a two-lever, fixed-ratio 10 schedule, rats were trained to discriminate mirtazapine (2.5 mg/kg, i.p.) from saline. RESULTS: Sessions, 63 +/- 8, were necessary to reach the criterion for 14 rats that all subsequently recognized (100%) mirtazapine at the training dose. Mirtazapine blocks serotonin (5-HT)(2C) receptors, and the 5-HT(2C) antagonists, SB242,084, SB243,213 and S32006, revealed dose-dependent and full (>/=80%) substitution at doses of 2.5, 2.5, and 0.63 mg/kg, respectively. By contrast, the 5-HT(2A) antagonists, MDL100,907 and SR46349-B, the 5-HT(2B) antagonist, SB204,741, and the 5-HT(3) antagonist, ondansetron, showed no significant substitution. Though mirtazapine indirectly recruits 5-HT(1A) receptors, the 5-HT(1A) agonists, buspirone and 8-OH-DPAT, did not substitute. Mirtazapine blocks alpha(2)-adrenoceptors, but several alpha(2)-adrenoceptor antagonists (yohimbine, RX821,002 and atipamezole) failed to substitute. Despite blockade by mirtazapine of histamine H(1) receptors, no substitution was seen with the selective H(1) antagonist, pyrilamine. Finally, the selective noradrenaline reuptake inhibitor, reboxetine (0.16), fully substituted for mirtazapine, whereas the 5-HT/noradrenaline reuptake inhibitors, duloxetine and S33005, several 5-HT reuptake inhibitors (citalopram, fluvoxamine, and paroxetine) and the dopamine reuptake inhibitors, bupropion and GBR12,935, did not substitute. CONCLUSION: Mirtazapine elicits a DS in rats for which selective antagonists at 5-HT(2C) receptors display dose-dependent substitution, whereas drugs acting at other sites recognized by mirtazapine are ineffective.
Does stimulation of 5-HT(1A) receptors improve cognition in schizophrenia?
Behav Brain Res. 2008 May 29;
Meltzer HY, Sumiyoshi T
Cognitive impairment is a key feature of schizophrenia and may be the most important determinant of outcome in schizophrenia. This impairment is diffuse and may reflect abnormalities in frontal cortex, hippocampus and other brain regions. While deficits in glutamatergic, GABAergic, dopaminergic and cholinergic impairment have received the most attention as the basis of this impairment, there are many reasons for considering the role of serotonin (5-HT) in contributing to these deficits. This may be via its influence on dopaminergic, cholinergic, glutamatergic and GABAergic function, as well as various growth factors that have been implicated in schizophrenia. Of the 14 known serotonin receptors, the 5-HT(1A) receptor is a key candidate for mediating at least some of the influence 5-HT has on cognition. 5-HT(1A) receptors are upregulated in postmortem specimens from patients with schizophrenia, suggesting a deficit in 5-HT(1A) function in this disorder. Atypical but not typical antipsychotic drugs stimulate the efflux of dopamine from cortex by a 5-HT(1A)-dependent mechanism. A series of studies from this laboratory involving the 5-HT(1A) partial agonists tandospirone and buspirone have reported a modest ability of these agents to improve some domains of cognition in patients receiving typical or atypical antipsychotic drugs. Preclinical studies have been mixed in regard to the ability of 5-HT(1A) partial agonists to improve cognition in various paradigms; some studies report that 5-HT(1A) antagonists are effective to improve cognition. Aripiprazole, clozapine, olanzapine, perospirone, quetiapine risperidone, and ziprasidone are examples of atypical antipsychotic drugs which are either direct or indirect 5-HT(1A) agonists which have been shown to improve cognitive function in patients with schizophrenia. Further study is needed to determine the role of the 5-HT(1A) receptor to improve cognitive function in schizophrenia.
Chem Res Toxicol. 2008 Aug 9;
Obach RS, Kalgutkar AS, Soglia JR, Zhao SX
In vitro covalent binding assessments of drugs have been useful in providing retrospective insights into the association between drug metabolism and a resulting toxicological response. On the basis of these studies, it has been advocated that in vitro covalent binding to liver microsomal proteins in the presence and the absence of NADPH be used routinely to screen drug candidates. However, the utility of this approach in predicting toxicities of drug candidates accurately remains an unanswered question. Importantly, the years of research that have been invested in understanding metabolic bioactivation and covalent binding and its potential role in toxicity have focused only on those compounds that demonstrate toxicity. Investigations have not frequently queried whether in vitro covalent binding could be observed with drugs with good safety records. Eighteen drugs (nine hepatotoxins and nine nonhepatotoxins in humans) were assessed for in vitro covalent binding in NADPH-supplemented human liver microsomes. Of the two sets of nine drugs, seven in each set were shown to undergo some degree of covalent binding. Among hepatotoxic drugs, acetaminophen, carbamazepine, diclofenac, indomethacin, nefazodone, sudoxicam, and tienilic acid demonstrated covalent binding, while benoxaprofen and felbamate did not. Of the nonhepatotoxic drugs evaluated, buspirone, diphenhydramine, meloxicam, paroxetine, propranolol, raloxifene, and simvastatin demonstrated covalent binding, while ibuprofen and theophylline did not. A quantitative comparison of covalent binding in vitro intrinsic clearance did not separate the two groups of compounds, and in fact, paroxetine, a nonhepatotoxin, showed the greatest amount of covalent binding in microsomes. Including factors such as the fraction of total metabolism comprised by covalent binding and the total daily dose of each drug improved the discrimination between hepatotoxic and nontoxic drugs based on in vitro covalent binding data; however, the approach still would falsely identify some agents as potentially hepatotoxic.
Effect of buspirone on the behavioral regulation of rats in low versus high anxiety conditions.
Arzneimittelforschung. 2008; 58(6): 269-76
Lim LW, Temel Y, Visser-Vandewalle V, Steinbusch H, Schruers K, Hameleers R, Esquivel G, Griez E, Blokland A
INTRODUCTION: Buspirone (CAS 33386-08-2) is reported to have anxiolytic effects in humans and is mostly described for mild anxiety. To further explore the effects of buspirone on different levels of anxiety, the effect of buspirone was evaluated in two different conditions of the open field which were distinguished as low and high anxiety (enclosed and exposed open field, respectively). MATERIALS AND METHODS: Twenty-eight albino Wistar rats (350-400 g) were tested in two different arena settings, an enclosed and an exposed open field. Fourteen animals were initially injected with 1 ml saline while the others (n = 14) received buspirone 3 mg/kg. RESULTS: The data showed clear differences in the two open-field settings, suggesting a higher anxiety level in the exposed open field. In addition, correlation analysis showed that the two anxiety tests measure different aspects of anxiety. Buspirone treatment reduced the behavioral activity in both the enclosed and exposed open-field, which is generally interpreted as an anxiogenic effect. However, buspirone increased the time in the center areas and decreased the frequencies in the outer regions. These behavioral changes are generally seen as an anxiolytic effect. Correlation analysis showed that buspirone treatment disrupted the relation between indices of anxiety. CONCLUSION: These results showed that in an open-field setting buspirone appears to have a dual effect. The reduced activity and increase in time spent in the center areas are indicative of both an anxiogenic and an anxiolytic effect, respectively. This was found in both open-field settings, suggesting that the effects of buspirone are independent of the anxiety level.
Clinical drugs that interact with St. John's wort and implication in drug development.
Curr Pharm Des. 2008; 14(17): 1723-42
Di YM, Li CG, Xue CC, Zhou SF
St. John's wort (Hypericum perforatum, SJW) is one of the most commonly used herbal antidepressants for the treatment of minor to moderate depression. A major safety concern about SJW is its ability to alter the pharmacokinetics and/or clinical response of a variety of clinically important drugs that have distinctive chemical structure, mechanism of action and metabolic pathways. This review highlights and updates the knowledge on clinical interactions of prescribed drugs with SJW and the implication in drug development. A number of clinically significant interactions of SJW have been identified with conventional drugs, including anticancer agents (imatinib and irinotecan), anti-HIV agents (e.g. indinavir, lamivudine and nevirapine), anti-inflammatory agents (e.g. ibuprofen and fexofenadine), antimicrobial agents (e.g. erythromycin and voriconazole), cardiovascular drugs (e.g. digoxin, ivabradine, warfarin, verapamil, nifedipine and talinolol), central nervous system agents (e.g. amitriptyline, buspirone, phenytoin, methadone, midazolam, alprazolam, and sertraline), hypoglycaemic agents (e.g. tolbutamide and gliclazide), immuno-modulating agents (e.g. cyclosporine and tacrolimus), oral contraceptives, proton pump inhibitor (e.g. omeprazole), respiratory system agent (e.g. theophylline), statins (e.g. atorvastatin and pravastatin). Both pharmacokinetic and pharmacodynamic components may play a role in the interactions of drugs with SJW. For pharmacokinetic changes of drugs by SJW, induction of cytochrome P450s (e.g. CYP2C9 and 3A4) and P-glycoprotein (P-gp) are considered the major mechanism. Thus, it is not a surprise that many drugs that interact with SJW are substrates of CYP3A4, CYP2C9 and P-gp. A comprehensive understanding of clinical drugs that interact with SJW has important implications in drug development. New drugs may be designed to minimize interactions with SJW; and new SJW formulations may be designed to avoid drug interactions. Further clinical and mechanistic studies are warranted to explore the interaction of SJW with other important drugs and the potential clinical impact.
Eur J Pharm Biopharm. 2008 Jun 26;
Alkhatib HS, Aiedeh KM, Bustanji Y, Hamed S, Mohammad MK, Alkhalidi B, Najjar S
Chitosan succinate (CS) was synthesized through the acylation of chitosan with succinic anhydride. The interaction of CS with buspirone HCl (BUSP) was evaluated using dialysis experiments and shown to result in complex with a stability constant of 2.26mM and a capacity of 0.0362mumol BUSP/mg CS. The extent of complexation upon dry and wet mixing of CS and BUSP was determined quantitatively using differential scanning calorimetry. The extent of the interaction was highest in wet mixtures and was found to be dependent on the pH of the granulation liquid. CS was incorporated in BUSP-containing hypromellose (HPMC) tablets using dry mixing and wet granulation with BUSP. Tablet dissolution was tested in 0.1N HCl and phosphate buffer, pH 6.8. According to f(2) and mean dissolution time results, the similarity of profiles increased as CS content increased with the highest f(2) value observed when CS was wet granulated with BUSP. Dissolution was also tested in deionized water and 5% NaCl; where increased ionic strength resulted in faster dissolution suggesting an ion exchange involvement in drug release. CS was proved effective in modulating BUSP release from HPMC matrices for pH-independent release through ionic complex formation.
Buspirone induced acute and chronic changes of neural activation in the periaqueductal gray of rats.
Neuroscience. 2008 Jul 31; 155(1): 164-173
Lim LW, Temel Y, Sesia T, Vlamings R, Visser-Vandewalle V, Steinbusch HW, Blokland A
5-HT(1A) modulation within the midbrain periaqueductal gray (PAG) is closely associated with anxiety- or panic-like behavior. Several findings have demonstrated that the properties of buspirone (a 5-HT(1A) partial agonist) would function as either anxiolytic or panicolytic in both clinical and laboratory animal research. In this study, we have investigated the neuronal activity occurring within the different regions of the PAG induced by buspirone treatment. Twenty-eight albino Wistar rats (350-400 g) were injected with either acute or chronic saline/buspirone (each, n=7), respectively. Our results show that buspirone treatment reduced locomotor activity, body weight and fecal boli, particularly in the chronic buspirone group. Two-way ANOVA revealed a significant decrease of c-Fos-immunoreactive (ir) cells expression in all regions of the rostral PAG after both acute and chronic buspirone (acute buspirone (AB) and chronic buspirone (CB), respectively) treatment. However, no effects on c-Fos-ir were detected in the caudal lateral periaqueductal gray (lPAG) and ventrolateral periaqueductal gray (vlPAG) in both the AB and CB groups, and in the dorsolateral periaqueductal gray (dlPAG) of the CB group. Interestingly, c-Fos-ir cells in the dorsomedial periaqueductal gray (dmPAG) column were reduced consistently in both the rostral and caudal PAG in both AB and CB groups. Besides, in all regions the number of c-Fos-ir cells was higher in the AB than in the CB group with exception of the rostral lPAG. In conclusion, the main anxiolytic effect of buspirone was specifically localized in all regions of the rostral PAG and in the caudal dmPAG. However, the caudal dlPAG, lPAG and vlPAG were found to be ineffective to buspirone treatment, probably due to their distinctive function in mediating higher level of anxiety in defensive behavior. This indicates that the longitudinal anatomical structure of the PAG possesses a different level of receptor sensitivity of 5-HT(1A) in the pathophysiology of anxiety and panic disorder.
J Ethnopharmacol. 2008 Sep 2; 119(1): 47-52
Balderas JL, Reza V, Ugalde M, Guzmán L, Serrano MI, Aguilar A, Navarrete A
ETHNOPHARMACOLOGICAL RELEVANCE: The decoction of dried fruits of Ternstroemia pringlei (Rose) Standl. (Theaceae), commonly known as "Flor de Tila", is used in the Mexican traditional medicine to diminish insomnia and fear. AIM OF THE STUDY: To examine the sedative effects of the dried fruits of Ternstroemia pringlei and investigate a possible synergistic pharmacodynamic interaction between the sedative effect of aqueous extract of this plant and six central nervous system (CNS) depressant drugs. MATERIALS AND METHODS: The sedative effect was performed using the exploratory cylinder test in ICR mice. The extracts and drugs were intraperitoneally administered 30min before testing in different doses, with exception of ethanol and buspirone which were administered 5 and 20min before testing, respectively. An isobolographic analysis was used to characterize the interaction between Ternstroemia pringlei extract and six CNS depressant drugs. RESULTS: The intraperitoneal administration of the hexane, dichloromethane, methanol and aqueous extracts of Ternstroemia pringlei showed a dose-dependent sedative effect. Ternstroemia pringlei aqueous extract combined with buspirone, diazepam, diphenhydramine, haloperidol or pentobarbital exerted a super-additive (synergistic) sedative interaction. Whereas the combination Ternstroemia pringlei extract plus ethanol resulted in a sub-additive (attenuate) sedative interaction. CONCLUSIONS: These findings are in agreement with the traditional use of Ternstroemia pringlei in the treatment of insomnia, however it is a plant that interacts in a complex form with CNS depressant drugs. It may represent an advertence on the use of this plant concomitantly with other neuroactive drugs.
Updated overview of the putative role of the serotoninergic system in obsessive-compulsive disorder.
Neuropsychiatr Dis Treat. 2005 Sep; 1(3): 231-43
Aouizerate B, Guehl D, Cuny E, Rougier A, Burbaud P, Tignol J, Bioulac B
The pathophysiology of obsessive-compulsive disorder (OCD) remains unknown. However, increasing attention has been paid to the putative role of the serotoninergic system, the strongest evidence being based on the widely demonstrated efficacy of serotonin (5HT) reuptake inhibitor antidepressants in the treatment of OCD. The therapeutic effects are correlated with changes in peripheral parameters of 5HT function, which have been found to be altered in OCD, suggesting the possibility of reduced 5HT reuptake capacity. This could reflect a compensatory mechanism presumably due to decreased availability of extracellular 5HT, as evidenced by data derived from direct assessment of central 5HT neurotransmission. The development of new neurochemical probes that explore the sensitivity of various 5HT receptor subtypes has provided precious information. m-Chlorophenylpyperazine (m-CPP), an agonist to 5HT1A, 5HT1D, and 5HT2C receptors, and which also blocks 5HT3 receptors, exacerbates OC symptoms. In contrast, neither MK-212 (6-chloro-2-[1-piperazinyl]-pyrazine), a 5HT1A and 5HT2C receptor agonist, nor ipsapirone or buspirone, which acts as an agonist to 5HT1A receptors, have any effect on OC symptom severity. This suggests the potential implication of the 5HT1D receptor, as shown by the aggravation of OC manifestations in response to sumatriptan, a selective 5HT1D receptor agonist. The 5HT3 plays no specific role, given the lack of influence of the 5HT3 antagonist ondansetron, on OC symptom intensity. Further studies are required to elucidate the pharmacological molecular determinants of the putative 5HT1D receptor dysfunction.
Post-sigh breathing behavior and spontaneous pauses in the C57BL/6J (B6) mouse.
Respir Physiol Neurobiol. 2008 Jul 31; 162(2): 117-25
Yamauchi M, Ocak H, Dostal J, Jacono FJ, Loparo KA, Strohl KP
The purpose was to examine sighs and spontaneous pauses in regard to the stability of resting breathing in the B6 strain, compared to the A/J strain. A 5-HT(1A) receptor agonist (buspirone) and a chromosomal substitution strain (B6a1) were used to further alter breathing patterning. Ten-minute recordings of room air breathing were collected from unanaesthetized B6, A/J, and B6a1 mice. Despite no differences between strains in the magnitude and incidence of sighs, post-sigh apneas, the variation for duration of expiration (T(e)) after sighs, and the number of spontaneous pauses were greater in the B6, while Shannon Entropy (nonlinear metrics) for T(e) after sighs was lower in B6, compared to the other strains. Buspirone and chromosomal substitution eliminated post-sigh apneas and decreased spontaneous pauses. A greater irregularity and the lower complexity of post-sigh breathing in B6 are reversed by elements on A/J chromosome 1 and by increased 5-HT(1A) serotonergic tone.