Engaging cervical spinal circuitry with non-invasive spinal stimulation and buspirone to restore hand function in chronic motor complete patients.

The combined effects of cervical electrical stimulation alone or in combination with the monoaminergic agonist buspirone on upper limb motor function were determined in six subjects with motor complete (AIS B) injury at C5 or above and more than one year from time of injury. Voluntary upper limb function was evaluated through measures of controlled hand contraction, handgrip force production, dexterity measures, and validated clinical assessment batteries. Repeated measure analysis of variance was used to evaluate functional metrics, EMG amplitude, and changes in mean grip strength. In aggregate, mean hand strength increased by greater than 300% with transcutaneous electrical stimulation and buspirone while a corresponding clinically significant improvement was observed in upper extremity motor scores and the action research arm test. Some functional improvements persisted for an extended period after the study interventions were discontinued. We demonstrate that, with these novel interventions, cervical spinal circuitry can be neuromodulated to improve volitional control of hand function in tetraplegic subjects. The potential impact of these findings on individuals with upper limb paralysis could be dramatic functionally, psychologically, and economically.

Buspirone treatment of cannabis dependence: A randomized, placebo-controlled trial.

BACKGROUND: The purpose of this study was to evaluate the efficacy of buspirone, a partial 5-HT1A agonist, for treatment of cannabis dependence. METHODS: One hundred seventy-five cannabis-dependent adults were randomized to receive either up to 60mg/day of buspirone (n=88) or placebo (n=87) for 12 weeks combined with a brief motivational enhancement therapy intervention and contingency management to encourage study retention. Cannabis use outcomes were assessed via weekly urine cannabinoid tests. RESULTS: Participants in both groups reported reduced cannabis craving over the course of the study; however, buspirone provided no advantage over placebo in reducing cannabis use. Significant gender by treatment interactions were observed, with women randomized to buspirone having fewer negative urine cannabinoid tests than women randomized to placebo (p=0.007), and men randomized to buspirone having significantly lower creatinine adjusted cannabinoid levels as compared to those randomized to placebo (p=0.023). An evaluation of serotonin allelic variations did not find an association with buspirone treatment response. CONCLUSIONS: Buspirone was not more efficacious than placebo in reducing cannabis use. Important gender differences were noted, with women having worse cannabis use outcomes with buspirone treatment. Considerations for future medication trials in this challenging population are discussed.

The influences of aconitine, an active/toxic alkaloid from aconitum, on the oral pharmacokinetics of CYP3A probe drug buspirone in rats.

Aconitine (AC), an active/toxic alkaloid from Aconitum species, is commonly present in Traditional Chinese Medicine (TCM) prescriptions because of the great effectiveness of Aconitum for the treatment of rheumatoid arthritis, cardiovascular diseases, and tumors in clinic. Buspirone (BP) is a sensitive CYP3A probe drug that is administered through oral/intravenous routes as recommended by the U.S. Food and Drug Administration. This study aims to investigate the influences of AC (0.125 mg/kg, oral) on first-pass (intestinal and hepatic) CYP3A activity by using oral BP as the probe in rats. The pharmacokinetics of oral buspirone hydrochloride at different doses (12.5, 25, and 50 mg/kg) were conducted. The pharmacokinetics of oral BP in rats pretreated with single dose or multiple doses (7-day) of AC were investigated. The plasma concentrations of BP and its major metabolites [1-(2-pyrimidinyl)piperazine (1-PP) and 6'-hydroxybuspirone (6'-OH-BP)] were determined. The formation ratios of 1-PP and 6'-OH-BP from BP (AUC0-∞ of 1-PP/AUC0-∞ of BP and AUC0-∞ of 6'-OH-BP/AUC0-∞ of BP values) showed no alternation when the dose of BP changed. Single dose of AC decreased the AUC0-∞ of BP by 53% but increased the formation ratio of 6'-OH-BP by 74% (P<0.05). Multiple AC exposure increased the AUC0-∞ of BP by 110%, and the formation ratios of 1-PP and 6'-OH-BP from BP were increased by 229% and decreased by 95%, respectively (P<0.05). Conclusively, single/multiple AC exposure did not alter the first-pass CYP3A activity when using oral BP as probe in rats. Nevertheless, multiple AC exposure had markedly changed the production of BP metabolites.

Buspirone attenuates tolerance to analgesic effect of morphine in mice with skin cancer.

Adjuvant drugs that can delay tolerance to morphine analgesia may lead to improved management of pain in chronic disease such as cancer. This study was aimed to investigate effect of buspirone, as a partial agonist of 5-HT1A receptor, on tolerance induced to morphine analgesic effect in animals with skin cancer. Study was carried on female Swiss albino mice. For skin tumorigensis, mice were treated with single dose of 7,12-dimethylbenz(a)anthracene (DMBA) and promoted by multiple dose of croton oil. Tolerance to morphine analgesia was induced by daily subcutaneous (sc) injection of morphine (5mg/kg for 30 days) and assayed by using the hot plate method. Results obtained from this study showed that pain threshold in mice with skin cancer were significantly lower. Tolerance to analgesic effect of morphine (5 mg/kg, sc) was appeared at day 15, whereas, in normal and skin tumor bearing mice co-treated daily with morphine (5 mg/kg, sc) and three different intraperitoneal (ip) doses of buspirone (5, 7.5 and 10 mg/kg) tolerance was observed at days 25 and 30. In conclusion our data indicate that concurrent use of morphine with buspirone may produce good cancer pain control and attenuate development of tolerance.

Estrogen prevents 5-HT1A receptor-induced disruptions of prepulse inhibition in healthy women.

The sex steroid hormone, estrogen, has been proposed to be protective against schizophrenia. This study examined the effects of estrogen treatment on modulation of prepulse inhibition (PPI) by the serotonin-1A (5-HT1A) receptor partial agonist, buspirone. PPI is a model of sensorimotor gating, which is deficient in schizophrenia and other mental illnesses. A total of 11 healthy women were tested following four acute treatment conditions: placebo, buspirone (Buspar; 5 mg), estradiol (Estrofem; 2 mg), and combined buspirone and estradiol. Electromyogram activity was measured across three interstimulus intervals (ISI): 30, 60, and 120 ms. There was no significant effect of either drug treatment on startle amplitude or habituation. At 120 ms ISI, buspirone caused a significant disruption of PPI and pretreatment with estrogen prevented this disruption. Estrogen treatment, administered in the appropriate experimental conditions, prevented PPI deficits induced by 5-HT(1A) receptor activation and may therefore also play a protective role in sensorimotor gating deficits in schizophrenia.

Effect of lactic acid and iontophoresis on drug permeation across rabbit ear skin.

The aim of this paper was to explore the efficacy of lactic acid as permeation enhancer for drug molecules across the skin. Three model permeants were chosen: acetaminophen (non-ionized), buspirone hydrochloride (cationic drug) and ibuprofen lysine (anionic drug). We also explored the association of lactic acid and iontophoresis as a means of enhancing drug delivery. Permeation experiments were performed in vitro, using rabbit ear skin as barrier. The results obtained indicate that lactic acid has some effects on model drug permeation across the skin. The effect was more evident with the anionic drug ibuprofen. Cathodal intophoresis increased ibuprofen transport, but when lactic acid was associated with cathodal iontophoresis, a concentration-dependent reduction of ibuprofen iontophoretic flux was observed, probably for the competition by the co-ion. The application of electric current (anodal iontophoresis) to a solution of acetaminophen produced an increase in its transport, due to the presence of an electroosmotic contribution; however, the effect of the association of anodal iontophoresis and lactic acid produced no further enhancement.

Kava-Kava extract LI 150 is as effective as Opipramol and Buspirone in Generalised Anxiety Disorder--an 8-week randomized, double-blind multi-centre clinical trial in 129 out-patients.

OBJECTIVE: An 8-week randomized, reference-controlled, double-blind, multi-centre clinical trial investigated Kava-Kava LI 150 in Generalized Anxiety Disorder (GAD; ICD-10: F41.1). METHOD: 129 out-patients received either 400 mg Kava LI 150, 10 mg Buspirone or 100 mg Opipramol daily for 8 weeks. At week 9, subjects were seen to check for symptoms of withdrawal or relapse. Primary outcome measures comprised the HAMA scale and the proportion of responders at week 8. Secondary measures were the Boerner Anxiety Scale (BOEAS), SAS, CGI, a self-rating scale for well-being (Bf-S), a sleep questionnaire (SF-B), a quality-of-life questionnaire (AL) and global judgements by investigator and patients. RESULTS: In 127 patients (ITT) no significant differences could be observed regarding all efficacy and safety measures. About 75% of patients were classified as responders (50% reduction of HAMA score) in each treatment group, about 60% achieved full remission. CONCLUSION: Kava-Kava LI150 is well tolerated and as effective as Buspirone and Opipramol in the acute treatment of out-patients suffering from GAD.

Increase of noradrenaline release in the hypothalamus of freely moving rat by postsynaptic 5-hydroxytryptamine1A receptor activation.

1. 5-Hydroxytryptamine (5-HT) plays a role in the regulation of noradrenergic neurones in the brain, but the precise mechanism of regulation of noradrenaline (NA) release by 5-HT1A receptors has not been defined. The present study describes the effect of a highly potent and selective 5-HT1A receptor agonist, 5-(3-[[(2S)-1,4-benzodioxan-2-ylmethyl)]amino]propoxy)-1,3-b enzodioxole HC1 (MKC-242), on NA release in the hypothalamus using microdialysis in the freely moving rat. 2. Subcutaneous injection of MKC-242 (0.5 mg kg-1) increased extracellular levels of NA and its metabolite, 3-methoxy-4-hydroxyphenylglycol, in the hypothalamus and hippocampus. 3. The 5-HT1A receptor agonists, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (0.2 mg kg-1) and buspirone (3 mg kg-1) mimicked the effect of MKC-242 in increasing NA release in the hypothalamus. 4. The effects of MKC-242 and 8-OH-DPAT in the hypothalamus were antagonized by pretreatment with WAY100135 (10 mg kg-1), a silent 5-HT1A receptor antagonist. 5. Local administration of 8-OH-DPAT (10-100 microM), citalopram (1 microM), a 5-HT reuptake inhibitor, and MDL72222 (10 microM), a 5-HT3 receptor antagonist, into the hypothalamus, had no effect on NA release. 6. Intracerebroventricular injection with 5,7-dihydroxytryptamine caused a marked reduction in brain 5-HT content, but the treatment affected neither basal NA levels nor the MKC-242-induced increase in NA release. 7. The effect of MKC-242 in increasing NA release was not attenuated by repeated treatment with the drug (0.5 mg kg-1, once a day for 2 weeks). 8. The present results suggest that activation of postsynaptic 5-HT1A receptors increases NA release in the hypothalamus.

Pharmacological analysis of fear-potentiated startle.

1. The potentiated startle paradigm measures conditioned fear by an increase in the amplitude of a simple reflex (the acoustic startle reflex) in the presence of a cue previously paired with shock. This paradigm offers a number of advantages as an alternative to most animal tests of fear or anxiety because it involves no operant and is reflected by an enhancement rather than a suppression of ongoing behavior. 2. A variety of drugs which block anxiety in people block fear-potentiated startle in rats. Although the 5-HT1A agonist buspirone is especially effective in blocking fear-potentiated startle, more selective 5-HT1A agonists have been less consistently effective. However, when these drugs are combined with only partially effective doses of the D1 antagonist, SCH23390, a full blockade of fear-potentiated startle is achieved. Hence, synergistic actions appear to occur between serotonin and dopamine in modulating the expression of fear-potentiated startle. 3. In addition to pharmacological studies, physiological studies are being used to define the neural pathways necessary for a visual conditioned stimulus to alter the acoustic startle reflex. The current working hypothesis is that the conditioned stimulus activates the central nucleus of the amygdala through a pathway involving the lateral geniculate nucleus, perirhinal cortex, and lateral and basolateral amygdaloid nuclei. The central nucleus of the amygdala then projects directly to the acoustic startle pathway so as to modulate the startle response. Chemical or electrolytic lesions of either the central nucleus or the lateral and basolateral nuclei of the amygdala block the expression of fear-potentiated startle. These latter amygdaloid nuclei may actually be the site of plasticity for fear conditioning, because local infusion of the NMDA antagonist AP5 blocks the acquisition but not the expression of fear-potentiated startle. 4. Finally, we have begun to investigate brain systems that might be involved in the inhibition of fear. Local infusion of AP5 into the amygdala was found to block the acquisition of experimental extinction, a prototypical method for reducing fear. We have also established a reliable procedure for producing conditioned inhibition of fear-potentiated startle and hope to eventually understand the neural systems involved in this phenomenon.

5-HT1A agonists and dopamine: the effects of 8-OH-DPAT and buspirone on brain-stimulation reward.

Two specific 5-HT1A agonists, 8-OH-DPAT (0-300 micrograms/kg), and buspirone (0-3.0 mg/kg), were tested on variable-interval, threshold-current self-stimulation of rat lateral hypothalamus. Buspirone produced a prolonged monotonic depression of responding, whereas the effects of 8-OH-DPAT were biphasic: 3.0 micrograms/kg produced a sustained enhancement of responding while higher doses (100-300 micrograms/kg) produced a relatively short-lasting depression. This biphasic pattern parallels previously reported effects of 8-OH-DPAT on food intake and on various other behaviours. Threshold-current self-stimulation is highly sensitive to alterations in dopaminergic transmission but relatively insensitive to changes in 5-HT. Thus the facilitatory effect of low-dose 8-OH-DPAT seems most plausibly interpreted in terms of enhanced dopaminergic transmission. This could be brought about by 5HT1A autoreceptor-mediated inhibiton of 5-HT release and consequent disinhibition of dopaminergic transmission. Depression of self-stimulation by higher doses of 8-OH-DPAT may reflect the activity of 8-OH-DPAT at postsynaptic 5-HT receptors, with consequent inhibition of DA transmission. Suppression of responding after buspirone at all doses tested may reflect the action of this compound as a partial agonist at postsynaptic 5-HT receptors, and/or its effects on other systems.

5-hydroxytryptamine1A agonists. A new therapeutic principle for stroke treatment.

We conducted the present study to investigate the effects of 5-hydroxytryptamine agonists on brain morphology after the induction of focal cerebral ischemia by permanent occlusion of the left middle cerebral artery in rats and mice. Forty-eight hours after vessel occlusion, the damage was quantified in rats by planimetry and subsequent integration on cresyl violet-stained serial sections and in mice by planimetric analysis of the damaged cortical surface after counterstaining with carbon black. All 5-HT1A agonists investigated substantially decreased cortical infarct size in the rat focal ischemia model (p less than 0.05). Drugs were applied 30 minutes before the induction of ischemia, and efficacy was demonstrated for 8-OH-DPAT (1 mg/kg s.c.), buspirone (10 mg/kg i.p.), gepirone (10 mg/kg i.p.), ipsapirone (10 or 30 mg/kg i.p.), and Bay R 1531 (1 mg/kg i.p.). The most pronounced effects were seen with the higher dose of ipsapirone and Bay R 1531, both compounds reducing cortical infarct size by more than 60%. Except for 8-OH-DPAT, the 5-HT1A agonists also caused a reduction in total infarct volumes. In a separate series, ipsapirone (30 mg/kg i.p.), applied 1 hour after vessel occlusion, led to a reduction in cortical and total infarct volumes by about 50% compared with corresponding controls (p less than 0.05). In neither series was striatal damage influenced. We tested the compounds in the mouse ischemia model over a broad dose range.(ABSTRACT TRUNCATED AT 250 WORDS)