Chronic Administration Of Buspirone Research Articles

Harmful Effects at Early Age Alter Pain Sensitivity in Adult Female Rats and Its Correction with Buspirone

Most studies of the influences of harmful pain and stress during the neonatal period of development on pain sensitivity are performed in males. We report here our studies of inflammatory pain and/or maternal deprivation stress in neonatal female rats on pain sensitivity in adulthood; an attempt was made to correct these changes using the 5-HT1A receptor agonist buspirone. Adult females subjected to early pain showed increased hypoalgesia in the hotplate test, while those subjected to maternal separation stress showed increased hyperalgesia in the formalin test. Pain and subsequent maternal separation had no effect on pain sensitivity in adult females. Chronic administration of buspirone from day 25 to day 39 of life to females subjected to inflammatory pain or maternal separation in the neonatal period normalized pain sensitivity in adults. In female rats, the prepurbertal period was found to be critical for correction of abnormalities in the nociceptive system induced by harmful actions at neonatal age.

Effects of Buspirone on Behavior in Female Mice in a Social Discomfort Model

We report here studies of the effects of single and chronic (14 days) administration of buspirone (1 mg/kg, i.p.) on the behavior of female C57BL/6J mice in conditions of social discomfort induced by prolonged periods of time in a cage with an aggressive male on the other side of a perforated partition and the presence at daily intermale confrontations. These experiments showed that in conditions of social discomfort, female mice showed dynamic changes in the sensitivity of brain 5-HT1A receptors, assessed in terms of the animals’ behavior 30 min after single doses of buspirone. Sensitivity was found to increase at the initial stages of formation of pathological behavior (10 days) and to decrease at 20‐30 days. Females with decreased 5-HT1A receptor sensitivity due to 30 days of living in conditions of social discomfort also demonstrated decreased sensitivity to chronic administration of buspirone.

Effects of Chronic Administration of Buspirone to Female Mice in Conditions of Prolonged Psychoemotional Stress

The effects of chronic administration (30 days) of the partial 5-HT1A receptor agonist buspirone (0.05, 1, and 10 mg/kg i.p.) on the behavior of female C57BL/6 J mice in conditions of prolonged psychoemotional stress were studied. Stress was produced by keeping females in a cage with an aggressive male on the other side of a perforated partition, along with the daily occurrence of 10-min intermale confrontations between the aggressor and another male placed with it. Chronic administration of buspirone at all the doses tested had no effect on the behavior of the females assessed in the partition and open field tests at the end of the treatment period. The elevated plus maze test showed that buspirone had anxiolytic effects, but only at a dose of 1 mg/kg. In the Porsolt test, buspirone (1 mg/kg) produced a minor increase in the duration of immobility, pointing to some antidepressant effect. Thus, chronic administration of buspirone to females in conditions of prolonged psychoemotional stress had different effects on their behavior depending on the dose and test conditions.

Increased plasma corticosterone levels after periaqueductal gray stimulation-induced escape reaction or panic attacks in rats

The hypothalamo–pituitary–adrenal (HPA) axis is involved in stress, depression and anxiety. Controversy exists on HPA axis activation during panic attacks (PAs). We examined whether the HPA axis is involved in the escape or panic-like response in an animal model of PAs induced by electrical stimulation of the dorsolateral periaqueductal gray (dlPAG) in rats. Additionally, rats were also treated with chronic administration of buspirone (BUSP) and escitalopram (ESCIT), respectively; and they were stimulated in the open-field arena for panic-like reaction. Levels of stress hormone corticosterone were measured following 30min after escape or panic condition. Our results demonstrated that the levels of plasma corticosterone were significantly increased after the induction of escape or panic-like response in comparison with the sham animals. The levels of corticosterone were significantly decreased in the dlPAG stimulated groups after rats were treated chronically with the ESCIT but not the BUSP as compared to the saline treated animals. Importantly, the increase of corticosterone level after escape or panic-like response was paralleled by an increase of neuronal activation of c-Fos in both the parvocellular and magnocellular paraventricular nucleus of the hypothalamus. Moreover, the c-Fos data also showed a decrease in the number of positive cells particularly for the ESCIT as well as the BUSP in comparison with the saline stimulated animals. In conclusion, the present study clearly demonstrated that PA or escape response activates the HPA axis and it remains difficult to anticipate the mechanism underlying HPA axis during PAs and its relationship with 5-HT drugs.

Attenuation of fear-like response by escitalopram treatment after electrical stimulation of the midbrain dorsolateral periaqueductal gray

Electrical stimulation of the dorsolateral periaqueductal gray (dlPAG) has frequently been shown to induce escape and freezing/decreased locomotion responses which mimic panic- and fear-like behaviour. In the present study we tested whether such spontaneous fear-like behaviour could be observed in an open-field test 12 h after dlPAG stimulation. Further, we tested whether this fear-like behaviour could be attenuated by acute or chronic administration of buspirone and escitalopram. Our data demonstrate for the first time that animals showed fear-like behaviour 12 h after dlPAG stimulation, which may possibly reflect panic disorder with anticipatory anxiety/agoraphobic symptoms. Acute and chronic escitalopram, but not buspirone, treatment attenuated the fear-related behaviour. Besides, our data also showed that the stimulation intensities to evoke an escape reaction, a panicogenic response, were significantly higher after chronic buspirone and escitalopram treatment. These results suggest that the fear-like response, which was observed 12 h after dlPAG stimulation, could be considered as a relevant animal model for panic disorder with anticipatory anxiety/agoraphobic symptoms.

Buspirone-induced changes in the serotonergic and non-serotonergic cells in the dorsal raphe nucleus of rats

Buspirone, a 5-HT (5-hydroxytryptamine, serotonin) 1A partial agonist, is being used as an anxiolytic drug. The mechanism of action is explained by an effect on the 5-HT system. The main source of 5-HT in the forebrain is the dorsal raphe nucleus (DRN). However, there are also other populations of non-5-HT neurons in the DRN. Here, we investigated the effect of acute and chronic buspirone treatments on the 5-HT and non-5-HT cells, the neuronal nitric oxide synthase (nNOS) and tyrosine hydroxylase (TH) cells, in the DRN. Rats received either an acute or chronic administration of buspirone or saline. Hereafter, the brains were processed for 5-HT, nNOS, and TH immunohistochemistry. We found that acute and chronic buspirone treatments significantly lowered the mean optical density of nNOS in the DRN as compared to controls. Meanwhile only the chronic buspirone treatment reduced the mean density of 5-HT and TH immunoreactivity but not the acute buspirone as compared to saline treated animals. Our findings suggest that buspirone treatment affects not only the intracellular content of 5-HT but also nNOS and TH. Therefore, the cellular effect of buspirone is more complex than thought.

Antihypertensive Effect of 5-HT1A Agonist Buspirone and 5-HT2B Antagonists in Experimentally Induced Hypertension in Rats

We investigated the antihypertensive effect of 5-HT_1A agonist (buspirone) and 5-HT_2B antagonists (SB204741 and SB200646) in deoxycorticosterone acetate (DOCA)-salt-induced hypertensive rats. Experiments were divided into two sets: in the first set, sham-operated control and DOCA-treated hypertensive rats received buspirone (1 mg/kg/day p.o. for 4 weeks) and in the second set, in vivo and in vitro studies were carried out. In the case of in vivo studies, sham-operated control and DOCA-treated hypertensive rats received SB204741 or SB200646 (1 mg/kg/week i.v. for 4 weeks). Blood pressure was measured weekly by tail-cuff method. After completion of the treatment schedule, blood pressure and vascular reactivity to various agonists like 5-HT, noradrenaline and adrenaline were recorded. Chronic administration of buspirone, SB204741 and SB200646 produced a significant reduction in blood pressure and vascular reactivity to agonists in DOCA-salt hypertensive rats, implying an antihypertensive effect. However, chronic administration of the same drugs in sham control rats did not alter blood pressure and vascular reactivity to various agonists. For in vitro studies a similar treatment schedule was followed as in vivo studies and a cumulative concentration response curve of 5-HT was recorded on isolated thoracic aorta. Treatment with 5-HT_2B antagonists shifted the concentration response curve of 5-HT to the right on isolated aorta. We conclude that 5-HT_1A agonist and 5-HT_2B antagonists possess an antihypertensive effect.

Region-specific changes in 5-HT 1A receptor-activated G-proteins in rat brain following chronic buspirone

5-Hydroxytryptamine 1A (5-HT 1A) receptors, which activate inhibitory G-proteins, are implicated in psychiatric disorders including anxiety and depression. Studies suggest that chronic 5-HT 1A receptor agonist administration alters 5-HT 1A receptor function, but the effect of chronic treatment on 5-HT 1A receptor-activated G-proteins is unclear. In this study, agonist-stimulated [ 35S]guanylyl-5′- O-(γ-thio)-triphosphate (GTPγS) binding was examined following chronic administration of buspirone. Brains were processed for [ 35S]GTPγS autoradiography using R(+)-8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT) for 5-HT 1A receptors or baclofen for GABA B receptors. Net 8-OH-DPAT-stimulated [ 35S]GTPγS binding was decreased by 25–30% in the septum and dorsal raphe nucleus of buspirone-treated animals. No significant changes in 8-OH-DPAT-stimulated [ 35S]GTPγS binding were found in the prefrontal, entorhinal or cingulate cortices or hippocampus in buspirone-treated rats. GABA B receptor-stimulated [ 35S]GTPγS binding was increased by 25% in the hippocampus, with no significant changes in any other region examined. These results demonstrate region-specific alterations in 5-HT 1A and GABA B receptor-activated G-proteins following chronic buspirone treatment, which may contribute to the clinical effects of this drug.

Effects of Acute and Chronic Administration of the Serotonin1A Agonist Buspirone on Serotonin Synthesis in the Rat Brain

The effects of acute and chronic administration of buspirone, a serotonin 5-HT1A agonist, on the 5-HT synthesis rates in various rat brain structures were investigated using alpha-[14C]methyl-L-tryptophan (alpha-[14C]MTrp) and an autoradiographic method. In the acute treatment study, buspirone (10 mg/kg) was injected subcutaneously 30 min before alpha-[14C]MTrp administration (30 microCi over 2 min) into a femoral vein. In the chronic treatment study, buspirone was given in a sustained fashion (10 mg/kg/day) for 14 days using an osmotic minipump implanted subcutaneously. Rats were killed 60 and 150 min after alpha-[14C]MTrp administration (two-time point method). A single dose of buspirone induced a significant decrease of 5-HT synthesis throughout the brain with the exception of the pineal body. However, the chronic treatment with buspirone did not induce significant differences in 5-HT synthesis in the brain. There was no significant difference in plasma free tryptophan concentration between any of the groups. The unaltered 5-HT synthesis rates in the chronic treatment study likely reflect a normalization of this parameter due to a desensitization of 5-HT1A autoreceptors on the cell body of 5-HT neurons, which has been previously shown to occur following long-term treatment with 5-HT1A agonists.

Sustained 5-hydroxytryptamine release-inhibitory and anxiolytic-like action of the partial 5-HT 1A receptor agonist, buspirone, after prolonged chronic administration

The effect of prolonged administration of high doses of buspirone on its 5-hydroxytryptamine (5-HT) release-inhibitory and anxiolytic-like properties was investigated. The 5-HT release-inhibitory effect of a challenge dose of buspirone (0.5 mg/kg, s.c.) was identical in rats chronically treated with vehicle or buspirone (10 mg/kg, b.i.d. for 10 weeks), as estimated by in vivo microdialysis in the ventral hippocampus. In the same set of animals there was a significant anxiolytic-like effect in the elevated plus-maze after 5 weeks of treatment with buspirone. The results indicate that the functional capacity of 5-HT release-controling 5-HT 1A autoreceptors is retained upon chronic administration of buspirone, and that this effect may well be associated with the anxiolytic-like action of the compound.

Behavioral effects of chronic buspirone administration in the pigeon: Comparison to midazolam

The effects of acute and chronic administration of buspirone and midazolam were examined in White Carneau pigeons (N = 5) responding under a fixed-ratio 30 (FR 30) schedule of food presentation. Each drug was studied in all pigeons. For three pigeons, buspirone was studied before midazolam, while the order was reversed for the other two subjects. For each drug, a dose-response curve was determined before (prechronic) and two weeks after (postchronic) discontinuation of chronic administration. Prior to chronic drug administration, buspirone (0.3–5.6 mg/kg) and midazolam (0.1–3.0 mg/kg) decreased response rates in all subjects, in a dose-dependent manner. Midazolam was more potent than buspirone; midazolam's ED 50 (95% C.I.) was 0.53 (0.41–0.69) mg/kg compared to 2.55 (1.48–4.41) mg/kg for buspirone. For each subject, the lowest dose that decreased responding by at least 50% was administered daily, immediately before the session, for up to 6 weeks. At the lowest daily dose of buspirone, complete recovery of baseline rates was observed in 3 pigeons. However, when the buspirone dose was increased, responding remained below control rates in all but one pigeon. During chronic midazolam administration, tolerance developed to the rate-decreasing effects of midazolam in 4 subjects. When saline was substituted for buspirone or midazolam, suppressed responding returned to predrug rates in all subjects. When the dose-response curves were redetermined, the postchronic ED 50 for buspirone was 3.79 (2.10–6.82) mg/kg, which was not significantly different from the prechronic ED 50, suggesting that tolerance did not develop to buspirone's rate-decreasing effects. However, the midazolam dose-response curve was shifted to the right after chronic midazolam administration, with an ED 50 of 1.18 (0.81–1.72) mg/kg. Thus, while the behavioral effects of acute administration of buspirone and midazolam were similar, the development of tolerance, as determined from shifts in acute dose-response curves and recovery of drug-free response rates during daily administration, was substantially less for buspirone compared to midazolam. Further, consistent with clinical reports, no evidence of withdrawal was seen when daily buspirone treatments were discontinued.

Chronic administration of buspirone down-regulates 5-HT2 receptor binding sites

Buspirone (BuSpar®), a clinically effective anxiolytic, has been found in clinical trials to produce effects which suggest antidepressant efficacy. As antidepressants down-regulate type 2 serotonin (5-HT2) receptors when given chronically to laboratory animals, we investigated whether buspirone would have similar effects; the possibility that chronic buspirone administration would affect β-adrenergic, D-2 dopaminergic, and γ-aminobutyric acid (GABA) receptor binding was also investigated. When chronically administered in a regimen which reflected activity in an animal model of anxiety, buspirone produced significant decreases in in vitro 5-HT2 and β-adrenergic receptor binding but was without effect on D-2 dopaminergic of GABAergic binding. Ligand saturation experiments revealed that the decrease in 5-HT2 binding was due to a decrease in the maximal concentration of binding sites. These data demonstrate that chronic administration of buspirone to animals produces effects which suggest the potential for antidepressant efficacy in clinical use.

Neurochemical changes in pigeon cerebrospinal fluid during chronic administration of buspirone or 8-hydroxy-2-(di-n-propylamino)Tetralin (8-OH-DPAT)

Cerebrospinal fluid (CSF), collected repeatedly from White Carneau pigeons chronically implanted with guide cannulae located in the lateral ventricles, was analyzed for metabolites of serotonin, dopamine and norepinephrine after acute and chronic administration of buspirone or 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Following the acute administration of 3.0 mg/kg buspirone, levels of 5-hydroxyindoleacetic acid (5-HIAA) decreased, while increases occurred in the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC). Decreases in 5-HIAA persisted throughout the chronic dosing regimen (36 days), while dopamine metabolites returned to control levels within 8 days. When chronic buspirone was discontinued, levels of 5-HIAA were restored to predrug control levels, while levels of HVA, DOPAC and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) decreased. All metabolites returned to predrug control levels within one week following buspirone discontinuation except for MHPG, which remained depressed. When the acute effects of buspirone were reexamined, levels of 5-HIAA were again significantly decreased, while HVA and DOPAC levels, as well as those of MHPG, increased significantly. Acute administration of the 5-HT1A receptor ligand 8-OH-DPAT (3.0 mg/kg) resulted in large decreases in 5-HIAA levels that persisted throughout the period of chronic administration. Neither acute nor daily administration of 8-OH-DPAT changed levels of HVA, DOPAC or MHPG. Large increases in 5-HIAA occurred when chronic 8-OH-DPAT was discontinued but declined within one week to control levels. Following a two-week drug-free period, 8-OH-DPAT again caused a significant reduction in 5-HIAA levels.(ABSTRACT TRUNCATED AT 250 WORDS)