Effects Of Buspirone Research Articles

Role of 5-HT receptor mechanisms in sub-chronic PCP-induced reversal learning deficits in the rat

5-HT receptor mechanisms have been suggested to mediate improvements in cognition in schizophrenia. The aim of this study was to investigate the involvement of 5-HT receptor mechanisms in sub-chronic phencyclidine (PCP)-induced reversal learning deficits in female rats, a task of relevance to schizophrenia. Adult female hooded Lister rats were trained to perform an operant reversal learning task and then received sub-chronic PCP (2 mg/kg) or vehicle intraperitoneally (i.p.) twice daily for 7 days, followed by 7-day washout. Rats then received an acute dose of the 5-HT(7) receptor antagonist SB-269970A (1.0, 3.0, and 10.0 mg/kg, i.p.) or vehicle. In experiment 2, PCP-treated rats received the selective 5-HT(2C) receptor antagonist, SB-243213A acutely (1.0, 3.0, and 10.0 mg/kg, i.p.) or vehicle. In experiment 3, PCP-treated rats received the 5-HT(1A) receptor partial agonist, buspirone (0.15625, 0.3125, and 0.625 mg/kg, i.p.) in combination with the selective 5-HT(1A) receptor antagonist WAY-100635 (0.3 and 1.0 mg/kg). In all experiments, sub-chronic PCP significantly impaired reversal phase performance (P < 0.01-0.001), with no effect in the initial phase. SB-269970A at 3.0 and 10.0 mg/kg significantly improved the PCP-induced deficit (P < 0.05). SB-243213A also significantly attenuated the deficit at 10 mg/kg (P < 0.05). In experiment 3, buspirone attenuated the deficit with significant effects at 0.3125 and 0.625 mg/kg (P < 0.05). WAY-100635 at 0.3 and 1.0 mg/kg produced a partial attenuation of buspirone's effect as buspirone (0.3125 mg/kg) in the presence of WAY-100635 did not significantly reverse the PCP-induced deficit. These studies implicate the role of 5-HT(7), 5-HT(2C), and 5-HT(1A) receptors in the improvement of cognitive dysfunction of relevance to schizophrenia.

Effect of buspirone on thermal sensory and pain thresholds in human volunteers

BackgroundBuspirone is a partial 5-HT1A receptor agonist. Animal studies have shown that modulation of serotoninergic transmission at the 5-HT1A receptor can induce analgesia in acute pain models. However, no studies have been published so far on the effects of serotonin receptor agonists on pain perception in humans.MethodsThe effects of buspirone (30 mg p.o.) on thermal sensory and pain thresholds were investigated in twelve female volunteers (26 ± 2 yrs) in a prospective, randomized, double-blind, double-dummy, placebo-controlled study with morphine (10 mg i.v.) as positive control.ResultsMorphine significantly increased the heat pain detection threshold (ΔT: placebo 1.0°C and 1.3°C, p < 0.05) at 60 minutes. Buspirone caused mild sedation in six participants at 60 minutes, but was without effect on any of the measured parameters.ConclusionBuspirone in the maximal recommended dose was without significant effect on thermal pain. However, as it is only a partial agonist at the 5-HT1A receptor and also acts on other receptor types, the negative results of the present study do not rule out a possible analgesic effect of more specific 5-HT1A receptor agonists.

Both acute and chronic buspirone treatments have different effects on regional 5-HT synthesis in Flinders Sensitive Line rats (a rat model of depression) than in control rats

The main objective of this investigation was to evaluate the effects of buspirone, a 5-HT 1A agonist with some partial agonist properties and also an antidepressant, on regional 5-HT synthesis in Flinders Sensitive Line (FSL) rats (“depressed”), and to compare the effects to the Flinders Resistant Line (FRL) control rats (not “depressed”). In addition results were compared to those previously reported in normal Sprague–Dawley (SPD) rats (normal control). Serotonin synthesis in both FSL and FRL rats was measured following acute and chronic treatments with buspirone. Both of these strains were derived from the SPD rats. No direct comparison was done between the FSL saline and FRL saline groups, or the FSL buspirone and FRL buspirone groups, because the objective of the studies was to evaluate effects of buspirone in these two strains. The results show that acute treatment with buspirone elevates 5-HT synthesis throughout the brain in the FRL rats. In the FSL rats, there were reductions in some brain regions ( e.g., dorsal and median raphe, amygdala, anterior olfactory nucleus, substantia nigra reticulate), while in other regions, there were increases in the synthesis observed ( e.g., frontal, parietal, visual and somatosensory cortices, ventral hippocampus). In 20 out of the 30 brain regions investigated in the FSL rats, there was no significant change in the synthesis following acute buspirone treatment. During the chronic treatment, buspirone produced a significant reduction of 5-HT synthesis in 15 out of 30 brain regions in the FRL rats. In the FSL rats, buspirone produced a significant elevation of the synthesis in 10 out of 30 brain regions. In both the FSL and FRL rats, buspirone produced rather different effects than those reported previously for SPD (normal) rats. The acute effect in the FSL rats was somewhat similar to the effect reported previously for the SPD rats, while in the FRL rats, the acute buspirone treatment produced an effect observed previously in treatments with 5-HT 1A antagonists suggesting an action of buspirone as partial agonist in FRL rats. The data suggest that with respect to 5-HT synthesis, FRL rats differ from SPD rats (a natural control; normal rats) and, as such, indicate that when the effects related to the serotonergic system ( e.g., influence of serotonergic drugs) are studied in the FSL rats and compared to those in the FRL rats, any conclusions drawn may not reflect differences relative to a normal rat.

Influence of buspirone on gastric sensorimotor function in man

Previous studies have suggested involvement of 5HT(1) receptors in the control of gastric tone. To study the effect of buspirone, a 5HT(1A) agonist, on gastric sensorimotor function in healthy volunteers. Ten healthy volunteers (six males and four females, ages 20-29 years) participated in a barostat study evaluating the influence of single oral doses of buspirone (5, 10, 20, 30 and 40 mg) on tone and sensitivity of the proximal stomach. In addition, the effect of placebo or the three lowest doses of buspirone on gastric emptying was assessed using a solid and liquid gastric emptying breath test. Compared to preadministration volumes, buspirone increased proximal stomach volumes in a dose-dependent manner, with significant fundic relaxation after 30 and 40 mg doses (intra-balloon volume increases of respectively 258 +/- 80 mL and 273 +/- 49 mL, P < or = 0.05). Pressure thresholds during gastric distention were not altered, but corresponding intraballoon volumes were significantly increased after 30 and 40 mg doses (respective discomfort volumes 596 +/- 73 vs. 791 +/- 87 mL and 630 +/- 73 vs.741 +/- 60 mL, both P < 0.05). Buspirone significantly slowed solid and liquid gastric emptying at the 20-mg dose. Buspirone dose-dependently relaxes the proximal stomach in the fasting state and decreases the gastric emptying rate in healthy volunteers.

Buspirone induced acute and chronic changes of neural activation in the periaqueductal gray of rats

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.

Effects of buspirone on posthypoxic ventilatory behavior in the C57BL/6J and A/J mouse strains

Buspirone, a partial agonist of the serotonergic 5-HT1A receptor, improves breathing irregularities in humans with Rett syndrome or brain stem injury. The purpose of this study was to examine whether buspirone alters posthypoxic ventilatory behavior in C57BL/6J (B6) and A/J mouse strains. Measurements of ventilatory behavior were collected from unanesthetized adult male mice (n=6 for each strain) using the plethysmographic method. Mice were given intraperitoneal injections of vehicle or several doses of buspirone and exposed to 2 min of hypoxia (10% O2) followed by rapid reoxygenation (100% O2). Twenty minutes later, mice were tested for hypercapnic response (8% CO(2)-92% O2). On a separate day, mice were injected with the 5-HT1A receptor antagonist 4-iodo-N-{2-[4-(methoxyphenyl)-1-piperazinyl] ethyl}-N-2-pyridinylbenzamide (p-MPPI) before the injection of buspirone, and measurements were repeated. In separate studies, arterial blood-gas analysis was performed for each strain (n=12 in B6 and 10 in A/J) with buspirone or vehicle. In both strains, buspirone stimulated ventilation at rest. In the B6 mice, the hypoxic response was unchanged, but the response to hypercapnia was reduced with buspirone (5 mg/kg; P<0.05). With reoxygenation, vehicle-treated B6 exhibited periodic breathing and greater variation in ventilation compared with A/J (P<0.01). In B6 animals, >or=3 mg/kg of buspirone reduced variation and prevented the occurrence of posthypoxic periodic breathing. Both effects were reversed by p-MPPI. Treatment effect of buspirone was not explained by a difference in resting arterial blood gases. We conclude that buspirone improves posthypoxic ventilatory irregularities in the B6 mouse through its agonist effects on the 5-HT1A receptor.

Effect of Buspirone, a Serotonin partial agonist, on cognitive function in schizophrenia: A randomized, double-blind, placebo-controlled study

Effect of Buspirone, a Serotonin partial agonist, on cognitive function in schizophrenia: A randomized, double-blind, placebo-controlled study

Validating an Ataxia Functional Composite Scale in spinocerebellar ataxia

The Ataxia Functional Composite Scale (AFCS) may provide a sensitive and reproducible assessment of treatment responses in studies of the spinocerebellar ataxias (SCA). We previously assessed the effects of buspirone in a cohort of patients with SCA via the International Cooperative Ataxia Rating Scale (ICARS). At each assessment period, AFCS scores were also obtained. A strong correlation of AFCS with ICARS scores was demonstrated at all assessment periods. This study supports the validity of the AFCS as a useful assessment of ataxia in this population.

Repeated cortisol administration attenuates the EEG response to buspirone in healthy volunteers: evidence for desensitization of the 5-HT1 A autoreceptor

It has previously been postulated that the therapeutic effect of antidepressants, particularly selective serotonin re-uptake inhibitors (SSRIs), is mediated by a down-regulation of somatodendritic (presynaptic) 5-HT(1A) autoreceptors with chronic treatment. Animal studies have revealed that repeated administration of corticosteroids similarly down-regulate this receptor. However, it has previously been difficult to explore if this receptor is similarly modulated in man in vivo. The objective of this study was to explore the effect of repeated administration of cortisol to healthy volunteers utilising a novel putative index of somatodendritic 5-HT(1A) autoreceptor function. This method involves the administration of the 5-HT(1A) agonist buspirone and observing the subsequent negative shift in the frequency spectrum of the electroencephalogram (EEG). Healthy male volunteers were treated with cortisol 20 mg, or placebo, orally twice daily for 7 days in a double-blind random-order crossover study. After each treatment period volunteers were administered buspirone 30 mg orally prior to EEG recordings. Following a week's treatment with placebo, buspirone led to a negative shift in the EEG frequency spectrum as previously reported. However, following treatment with cortisol, the effect of buspirone was significantly attenuated. This is consistent with corticosteroids having a similar effect on somatodendritic 5-HT(1A) autoreceptors in man as seen in rodents.

Comparison of the Effects of Deramciclane, Ritanserin and Buspirone on Extracellular Dopamine and Its Metabolites in Striatum and Nucleus Accumbens of Freely Moving Rats

In the present study, we assessed the effect of single graded doses of a putative anxiolytic compound, the 5-HT(2A/C )antagonist, deramciclane fumarate (EGIS-3886), on the dopamine efflux and metabolism in nucleus accumbens and striatum and thus evaluated the dose window for deramciclane to cause adverse effects related to the brain dopaminergic system. Dual probe in vivo microdialysis in freely moving rats was used to compare the effects of graded doses of deramciclane fumarate (3, 10 and 30 mg/kg), 5-HT(2A/C )antagonist ritanserin (1 mg/kg) and a partial 5-HT(1A) agonist buspirone hydrochloride (5 mg/kg) on the extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in nucleus accumbens and striatum assayed by high performance liquid chromatography with electrochemical detection. The indirect dopamine agonist, D-amphetamine sulfate (2 mg/kg), was used as a positive control. Ritanserin, buspirone and deramciclane 3 and 10 mg/kg had no significant effects on the extracellular dopamine levels in either brain area but deramciclane 30 mg/kg significantly increased accumbal dopamine as well as DOPAC and HVA in both brain areas. As expected, the positive control D-amphetamine significantly increased both striatal and accumbal dopamine levels. The effects of buspirone or the highest deramciclane dose and D-amphetamine on DOPAC and HVA levels were opposite; buspirone and deramciclane increased while D-amphetamine decreased the metabolite levels in both brain areas. The results indicate that a single high dose of deramciclane has the neuroleptic- or buspirone-like effect, particularly in mesolimbic regions. There is at least a 5-fold margin between the anxiolytic and neuroleptic doses of deramciclane in the rat.

Chronic buspirone treatment normalizes open field behavior in olfactory bulbectomized rats: Assessment with a quantitative autoradiographic evaluation of the 5-HT 1A binding sites

The olfactory bulbectomized (OBX) rat model of depression has been widely used in studies on the behavioral and neurochemical aspects of human depression. The objective of the present investigation was to assess open field (OF) activity and the brain regional 5-HT 1A receptor densities of the sham operated (SHX) and OBX rats treated with saline (SHX-SAL, OBX-SAL), and either 10 mg/(kg day) (SHX-B10, OBX-B10) or 20 mg/(kg day) (SHX-B20, OBX-B20) of buspirone for 14 days, delivered by a subcutaneous osmotic minipump. Adult Sprague–Dawley rats were used for this experiment. The surgery was performed on the first day of the experiment and the rats were randomly assigned to either the SHX or OBX groups. The results of the OF tests were organized in eight groups. Following 14 days of treatment and the final OF tests, the rats were sacrificed and the brains were used for 5-HT 1A receptor autoradiography using [ 3H]8-OH-DPAT. The data showed that the OF activities, 14 days following surgery, in the OBX rats were significantly elevated when compared to the SHX rats. In the OBX rats, only the 14-day treatment with 20 mg/(kg day) of buspirone normalized the elevated OF activity, the same dose shown previously to be needed for the normalization of the regional 5-HT synthesis. A significant reduction in the number of 5-HT 1A receptor sites was found in most brain regions in the OBX rats when compared to the SHX rats. Data also show that the regional density of the 5-HT 1A receptors in OBX-SAL treated rats is lower than that of the SHX-SAL rats. The 14-day treatment with either 10 or 20 mg/(kg day) of buspirone reduced the 5-HT 1A receptors in most brain regions of the SHX rats, without an obvious dose-dependent effect of the buspirone. The comparison between the OBX-B20 and control (SHX-B20) rats suggests that the buspirone treatment resulted in a regional balance in the 5-HT 1A sites. A dose dependent reduction in the density of 5-HT 1A sites was observed in the sham rats, but the buspirone treatment had very little effect on the density of the 5-HT 1A receptors in the OBX rats. From these observations, we conclude that the antidepressant effects of buspirone in the OBX rat model of depression are likely mediated through the fine tuning of the regional imbalance of 5-HT 1A receptors with even increases of about 20% in some limbic regions. The data suggest that the neurochemical effects of antidepressants should be studied in animal models of depression rather than in normal rats.

Effect of buspirone, a serotonin 1A partial agonist, on cognitive function in schizophrenia: A randomized, double-blind, placebo-controlled study

In previous studies, we demonstrated that tandospirone, a serotonin-5-HT 1A 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-HT 1A 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 × 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-HT 1A agonist treatment in schizophrenia is indicated.

Treatment of spinocerebellar ataxia with buspirone

Preliminary data suggest potential benefit of 5-HT receptor agonists in the treatment of ataxias. We studied the effects of buspirone in a cohort of twenty patients with spinocerebellar ataxia (SCA). Twenty patients were treated in this double-blind, placebo controlled, cross-over trial with either buspirone HCl 30 mg twice daily or placebo for 3 months. Buspirone was not shown to be superior to placebo in the treatment of patients with SCA.

Effects of buspirone on the immediate positive and delayed negative properties of intravenous cocaine as measured in the conditioned place preference test

In prior work, we have demonstrated that the behavioral effects of cocaine adhere to the predictions of the opponent-process theory of drug action. Animals develop conditioned place preferences for distinct locations paired with the immediate effects of IV cocaine, but learn to avoid places paired with the effects present 15-min post-injection. It was of interest to assess the putative role of 5-HT in producing the negative properties of cocaine since cocaine acts to inhibit the reuptake of serotonin (5-HT) and since such actions have been associated with anxiogenic consequences. Male rats were administered a reinforcing dose of cocaine (1.0 mg/kg IV) and then placed – either immediately or after a 15-min delay – into one side of a two-compartment (black–white) conditioned place preference (CPP) box for 5-min. On alternate days, the animals received IV saline injections and were placed in the opposite side of the CPP box. This continued for eight days after which animals had experienced 4 pairings of cocaine with one side (black or white) of the CPP apparatus, and 4 saline pairings with the opposite side. Other groups of rats were treated identically except that 30-min prior to placement into the apparatus, these animals received an IP injection of saline or buspirone (a partial 5-HT 1A agonist) at a dose that we have shown to be anxiolytic (2.5 mg/kg IP). Control animals experienced either buspirone or saline pretreatments without cocaine. Our results confirm that animals increase the time spent on the side paired with the immediate effects of cocaine (compared to baseline), but tend to avoid the side paired with effects present 15-min post-injection. Buspirone had no effect on the immediate rewarding properties of cocaine, but completely reversed the negative properties present 15-min post-cocaine. These results are consistent with the view that attenuation of 5-HT neurotransmission (via the autoreceptor agonist properties of buspirone) can reverse the negative impact of IV cocaine.

Lack of deleterious effects of buspirone on cognition in healthy male volunteers

Buspirone is a serotonin 5-HT(1A) receptor agonist licensed for the treatment of anxiety. Other anxiolytic drugs such as benzodiazepines show significant sedative and other unwanted effects on cognition. Studies to date have yet to investigate cognitive effects of buspirone using well-validated computerized tests. The aim of this study was to assess acute subjective and cognitive effects of buspirone in healthy volunteers. Sixty healthy male volunteers received 20 mg buspirone, 30 mg buspirone, or placebo per os in a double-blind parallel groups design (N=20 per group). Subjective ratings (visual analogue scales) were completed at baseline, and at 1.5 and 3.5 hours post-capsule. Cognitive assessment was undertaken between 1.5 and 3.5 hours post-capsule, including tests of memory, executive planning, impulse control, decision making and cognitive flexibility. The 30 mg buspirone group showed significantly higher subjective ratings of contentedness 3.5 hours after capsule relative to placebo. Treatment and placebo groups did not differ significantly on cognitive measures. In contrast to benzodiazepines, the anxiolytic buspirone appears to lack detectable deleterious effects on cognition when administered acutely at clinically meaningful doses. Future research directions are discussed in relation to acute and chronic studies in neuropsychiatric populations.

Effect of buspirone on blood sugar levels in humans

Psychiatric disorders such as depression, schizophrenia and anxiety disorders are seen more common in diabetic patients. The present study investigated the effect of an antianxiety drug, buspirone on blood glucose and plasma insulin level in healthy humans. Twelve healthy adult male volunteers were administered single oral doses of buspirone (10 mg) or placebo, in a randomized, crossover way, followed by oral glucose challenge (75 g in 200 ml) at reported T max of the respective administered drugs. The blood samples were collected as predose, postdose and post oral glucose load at 0.5, 1.0, 1.5, 2.0, 2.5 and 3.0 h. Blood glucose and plasma insulin concentrations were estimated by glucose hexokinase and enzyme linked immunosorbent assay methods respectively. The concentration of blood glucose was significantly ( p <0.05) decreased after oral glucose challenge following administration of buspirone in comparison with placebo. However no significant change was observed in the fasting blood glucose and fasting and oral glucose challenge induced plasma insulin. These results suggest that buspirone may have important risks particularly for diabetics, glucose intolerant and nondiabetics who are on long therapy with buspirone.

Lack of deleterious effects of buspirone on cognition in healthy male volunteers

Lack of deleterious effects of buspirone on cognition in healthy male volunteers

Effect of buspirone: An anxiolytic drug on blood glucose in humans

The present study investigated the effect of an antianxiety drug, buspirone on blood glucose and plasma insulin level concerning the role of 5-HT(1A) receptors in blood glucose regulation in healthy humans. Twelve healthy male volunteers were administered single oral doses of buspirone (10 mg) or placebo, in a randomized, crossover way, followed by oral glucose load (75 gm in 200 ml) at reported T(max) i.e. the time of peak plasma concentration of the respective administered drug. The blood samples were collected as predose, postdose and post oral glucose load at 0.5, 1.0, 1.5, 2.0, 2.5 and 3.0 hr to investigate the effect of buspirone or placebo at basal blood glucose and plasma insulin level and after oral glucose load induced (postprandial) blood glucose and plasma insulin level. Blood glucose and plasma insulin concentrations were estimated by glucose hexokinase method and enzyme linked immunosorbent assay (ELISA) method respectively. The concentration of blood glucose was significantly (p<0.05) decreased after oral glucose load following administration of buspirone in comparison with placebo however no significant change was observed in the fasting blood glucose and plasma insulin (fasting and oral glucose load induced) level. In conclusions, the present study findings show that buspirone produced a significant alteration in blood glucose level in healthy humans. In addition, study results also indicate that the involvement of serotonergic (5-HT, receptors) mechanism of blood glucose regulation in humans is different from animals.

The effect of buspirone on normal and hypoarousal-driven abnormal aggression in rats

Aggressiveness is associated with decreased glucocorticoid production, autonomic hypoarousal, and social deficits in antisocial personality disorder and its childhood antecedent conduct disorder. We showed previously that experimentally induced chronic glucocorticoid deficiency leads to abnormal forms of attack, autonomic hypoarousal, and social deficits in rats. We also showed that serotonergic neurotransmission, which downregulates aggressiveness in normal rats appears to lose its aggression-controlling role in glucocorticoid-deficient rats. We suggested that abnormal aggression develops in such rats as a consequence of serotonergic disturbances that result from chronic glucocorticoid deficiency. Here we assessed the effects of the serotonergic anxiolytic buspirone on aggressive behavior in normal and glucocorticoid-deficient rats. Noteworthy, this compound is frequently used in the clinic to control moderate aggression problems. As expected, buspirone dose-dependently reduced the duration of agonistic behaviors in normal rats exposed to resident/intruder conflicts. Similar to earlier experiments, glucocorticoid deficiency dramatically increased the share of attacks directed towards vulnerable body parts of the opponents (head, throat and belly). Surprisingly, 1 and 5 mg/kg buspirone dramatically increased the frequency of biting attacks in glucocorticoid-deficient rats. The share of vulnerable attacks remained as high as in vehicle-treated glucocorticoid-deficient rats. These data show that chronic glucocorticoid deficiency disturbs serotonergic neurotransmission, which reverses the aggression-related effects of the serotonergic agent buspirone. This finding is in line with disparate human findings on the effects of serotonergic agents on aggression in antisocial personality disordered people.

Combined Treatment with Citalopram and Buspirone: Effects on Serotonin 5-HT2Aand 5-HT2CReceptors in the Rat Brain

We wanted to elucidate whether the proposed advantages of citalopram-buspirone combination treatment are related to changes in 5-HT(2A/C) receptor-mediated neurotransmission. The affinity of buspirone to 5-HT2A and 5-HT2C receptors was measured in vitro, and the influence of buspirone on 5-HT2C receptor-mediated phosphoinositide hydrolysis was estimated. Four groups of rats received citalopram (10 mg/kg), buspirone (6 mg/kg), citalopram-buspirone combination, or saline once a day s.c. for 14 days. Treatment effects on 5-HT2A and 5-HT2C receptors were investigated by receptor autoradiography with antagonist and agonist radioligands. Buspirone was found to be a weak 5-HT2C receptor antagonist, with a low affinity for 5-HT2A and 5-HT2C receptors. Repeated buspirone-citalopram combination treatment markedly decreased [3H]ketanserin and [125I]DOI binding to 5-HT2A receptors. Repeated administration of buspirone and buspirone-citalopram combination increased the affinity of [3H]mesulergine toward 5-HT2C receptors, and buspirone-citalopram combination also decreased [125I]DOI binding to 5-HT2C receptors. We suggest that downregulation of brain 5-HT2A receptors and possibly of 5-HT2C receptor agonist sites is involved in the beneficial clinical effects of buspirone-SSRI augmentation treatment. Furthermore, a conversion of brain 5-HT2C receptors from high- to low-affinity state may provide an additional mechanism for the anti-anxiety effects of buspirone.