Subacute Administration Research Articles

Experimental basis for the putative role of GluR6/kainate glutamate receptor subunit in Huntington's disease natural history

Age of onset of Huntington's disease (HD) statistically correlates with the length of expanded CAG repeats in the IT15 gene. However, other factors such as polymorphism in the 3′ untranslated region of the GluR6 kainate receptor gene subunit may contribute to variability in the age at onset. To investigate this issue, we studied the motor disorder and related striatal damage induced by 3-nitropropionic acid (3-NP) subacute administration in GluR6 knockout mice (GluR6 −/−) as compared to wild-type mice. In two different age groups (6 months and 1 year), we observed that GluR6 −/− mice did not display more motor impairment nor more striatal histopathological damage than GluR6 +/+ mice, although 1-year-old GluR6 −/− mice displayed reduced activity parameters either at baseline or after 3-NP administration compared to GluR6 +/+. In both age groups, GluR6 −/− mice died earlier and displayed earlier motor symptoms during 3-NP-induced metabolic compromise, suggesting that GluR6-containing kainate receptors may be implicated during neurodegeneration, such as in HD, rather than in the final outcome.

Effects of pycnogenol treatment on oxidative stress in streptozotocin-induced diabetic rats.

Free radicals and oxidative stress have been implicated in the etiology of diabetes and its complications. This in vivo study has examined whether subacute administration of pycnogenol, a French pine bark extract containing procyanidins that have strong antioxidant potential, alters biomarkers of oxidative stress in normal and diabetic rats. Diabetes was induced in female Sprague-Dawley rats by a single injection of streptozotocin (90 mg/kg body weight, ip), resulting (after 30 days) in subnormal body weight, increased serum glucose concentrations, and an increase in liver weight, liver/body weight ratios, total and glycated hemoglobin, and serum aspartate aminotransferase activity. Normal and diabetic rats were treated with pycnogenol (10 mg/kg body weight/day, ip) for 14 days. Pycnogenol treatment significantly reduced blood glucose concentrations in diabetic rats. Biochemical markers for oxidative stress were assessed in the liver, kidney, and heart. Elevated hepatic catalase activity in diabetic rats was restored to normal levels after pycnogenol treatment. Additionally, diabetic rats treated with pycnogenol had significantly elevated levels of reduced glutathione and glutathione redox enzyme activities. The results demonstrate that pycnogenol alters intracellular antioxidant defense mechanisms in streptozotocin-induced diabetic rats.

Effects of flutamide in the rat testis on the expression of occludin, an integral member of the tight junctions

In an effort to uncover the gonadal impairment by the antiandrogen flutamide (FM) in males, the effect of subacute administration of FM on the expression of tight junction (TJ) genes that build the blood–testis barrier (BTB) was investigated in adult rat testis. At 13 weeks old of age male rats were given vehicle (corn oil) or FM (25 mg/kg per day, in corn oil) orally for 6 days. At 8 days (D8) after the first dose, testicular expression of the occludin, claudin-1, and -11 was analyzed by semiquantitative RT-PCR. The testicular weight of the FM-treated rats on D8 was a little but significantly higher than in the control group. On D8 the expression of occludin in the FM-treated animals was significantly decreased but claudin-1 and -11 were not altered significantly. Because FM administration inhibits germ cell differentiation, it is likely that the down-regulated occludin expression in FM-rat testes may be attributed to the alteration in the paracrine interaction between Sertoli cells and germ cells in testis. It also emphasized that FM might have differentially affected the transcription of TJ genes in Sertoli cells building the BTB. These findings provide a rationale for a number of observations on the gonadal impairment by FM in males and suggest that FM is potentially harmful to spermatogenesis by alteration of the BTB.

Neuroprotective effects of (±)-huprine Y on in vitro and in vivo models of excitoxicity damage

We have investigated the neuroprotective effects of (±)-huprine Y on excitotoxic lesions in rat cerebellar granule cells (CGCs). (±)-Huprine Y prevented cell death induced by 100 μM glutamate, as well as, 10 μM MK-801, a NMDA receptor antagonist, in a significant manner. On the other hand, intracellular calcium increase induced by NMDA (200 μM), measured by fura-2 fluorescence, was prevented by (±)-huprine Y with an EC 50 of 12.44 μM, which evidences the modulatory action of this compound on NMDA-induced calcium currents. In vivo, we have studied (±)-huprine Y neuroprotective effects on striatal lesions induced by the subacute administration of the mitochondrial toxin 3-nitropropionic acid (3-NP, 30 mg/kg, ip, for 10 days). We have assessed that both the behavioral and the morphological consequences of the lesion were prevented by pretreatment with (±)-huprine Y (2.5 mg/kg/twice a day, ip). Striatal gliosis induced by 3-NP treatment was prevented by (±)-huprine Y pretreatment, as demonstrated by the attenuation of both the increase in [ 3H]PK 11195 specific binding indicative of microgliosis and the expression of hsp27 kDa, a chaperone expressed mainly in astrocytes. In conclusion, (±)-huprine Y attenuated excitotoxic-induced lesions, both in vitro and in vivo, and further evidence is provided for the potential use of this compound in the prevention of neurodegenerative disorders.

Enhancing action of LSD on neuronal responsiveness to serotonin in a brain structure involved in obsessive-compulsive disorder.

Potent serotonin (5-HT) reuptake inhibitors are the only drugs that consistently exert a therapeutic action in obsessive-compulsive disorder (OCD). Given that some hallucinogens were reported to exert an anti-OCD effect outlasting their psychotomimetic action, possible modifications of neuronal responsiveness to 5-HT by LSD were examined in two rat brain structures: one associated with OCD, the orbitofrontal cortex (OFC), and another linked to depression, the hippocampus. The effects of concurrent microiontophoretic application of LSD and 5-HT were examined on neuronal firing rate in the rat OFC and hippocampus under chloral hydrate anaesthesia. In order to determine whether LSD could also exert a modification of 5-HT neuronal responsiveness upon systemic administration, after a delay when hallucinosis is presumably no longer present, it was given once daily (100 microg/kg i.p.) for 4 d and the experiments were carried out 24 h after the last dose. LSD attenuated the firing activity of OFC neurons, and enhanced the inhibitory effect of 5-HT when concomitantly ejected on the same neurons. In the hippocampus, LSD also decreased firing rate by itself but decreased the inhibitory action of 5-HT. The inhibitory action of 5-HT was significantly greater in the OFC, but smaller in the hippocampus, when examined after subacute systemic administration of LSD. It is postulated that some hallucinogens could have a beneficial action in OCD by enhancing the responsiveness to 5-HT in the OFC, and not necessarily in direct relation to hallucinosis. The latter observation may have theoretical implications for the pharmacotherapy of OCD.

Evaluation of hepatoprotective effect of Gentiana olivieri herbs on subacute administration and isolation of active principle

Hepatoprotective effect of Gentiana olivieri Griseb. (Gentianaceae) flowering herbs on subacute administration were studied using in vivo models in rats. For the activity assessment on carbon tetrachloride-induced hepatic damage following biochemical parameters were evaluated; plasma and hepatic tissue malondialdehyde formation, and liver tissue glutathione level, as well as plasma transaminase enzyme levels (aspartate transferase and alanine transferase). Results of biochemical tests were also confirmed by histopathological examination. Through bioassay-guided fractionation procedures isoorientin, a known C-glycosylflavone, was isolated from the ethyl acetate fraction as the active antihepatotoxic constituent by silica gel column chromatography. Isoorientin exhibited significant hepatoprotective effect at 15 mg/kg b.w. dose.

Alterations of gene expression in adult male rat testis and pituitary shortly after subacute administration of the antiandrogen flutamide.

In the course of profiling alterations of gene expression in the male reproductive system induced by anti-androgenic agents, 28 genes expressed in the testis or pituitary of adult rats were examined shortly after subacute administration of the well-known anti-androgen, flutamide (FM). FM (25 mg/kg/day) was orally administered to male rats for six days. On day 8 (D8) after the first dose of FM, intratesticular testosterone (T) levels had dramatically increased, but daily sperm production on D36 was significantly decreased. The mRNA levels of testicular and pituitary genes on D8 were measured by semiquantitative RT-PCR. Among the six testicular steroidogenic enzyme genes, the mRNAs of the P450 side chain cleavage, P450 17 alpha/C(17-20) lyase, and 3beta-hydroxysteroid dehydrogenase type I (3betaHSD) genes significantly increased, whereas 17beta-hydroxysteroid dehydrogenase type III slightly decreased. Among the three steroid receptors examined, androgen receptor (AR) and glucocorticoid receptor (GR) mRNAs were significantly down-regulated (29% and 35%, respectively) in the testis, but there was no change in estrogen receptor alpha. There were no clear changes in expression of the gonadotropin receptors and Sertoli cell specific genes, but a slight increase was observed in expression of the lactose dehydrogenase-c mRNA, a germ cell specific gene. Among the three immediate early genes, c-myc mRNA was increased approximately 1.4-fold. In the pituitary, on the other hand, mRNAs for LHbeta and FSHbeta subunits and gonadotropin releasing hormone receptor had increased significantly. These results show that subacute FM administration first affected hypothalamus/pituitary hormone gene expression, then altered gonadotropin secretion, and subsequently induced over-expression of testicular steroidogenic enzyme genes. However, the significant up-regulation of 3betaHSD and down-regulation of AR mRNAs, despite the higher level of intratesticular T, might be explained by an antagonistic action of hydroxyflutamide retained in the testis. The profiles of alterations in gene expression observed will provide important information for the screening of adult male animals for anti-androgenic chemicals.

A comparative study on the anti-inflammatory, antinociceptive and antipyretic effects of isoquinoline alkaloids from the roots of Turkish Berberis species

Roots and barks of various Berberis species are used as folk remedy for the treatment of various inflammatory diseases such as lumbago, rheumatism and to reduce fever. Six isoquinoline alkaloids namely berberine, berbamine, palmatine, oxyacanthine, magnoflorine, and columbamine were isolated as the main components of alkaloidal fraction from the roots of Turkish Berberis species and effects were studied using various in vivo models in mice. All alkaloids inhibited inflammations in varying degrees, among them berberine, berbamine and palmatine were shown to possess significant and dose-dependent inhibitory activity against serotonin-induced hind paw oedema both on oral and topical applications and acetic acid-induced increase in vascular permeability on oral administration. Moreover, these three alkaloids were also shown to possess dose-dependent antinociceptive activity, which assessed by using the model based on the inhibition of p-benzoquinone-induced writhing movements as well as antipyretic activity on FCA-induced increased rectal temperature on subacute administration. However, all alkaloids induced gastric lesions in varying degrees.

In the rat forced swimming test, chronic but not subacute administration of dual 5-HT/NA antidepressant treatments may produce greater effects than selective drugs

The rat forced swimming test (FST) distinguishes selective serotonin (5-HT) and selective noradrenaline (NA) reuptake-inhibitors, which respectively increase swimming and climbing behaviours. However, NA-system-mediated inhibition of 5-HT-induced swimming prevents dual 5-HT/NA reuptake-inhibition to produce concurrently climbing with swimming. Since adaptative neurochemical processes occur in the treatment of depression, we examined the influence of long-term antidepressant treatment on these interactions. Methods: (1) Selective [fluoxetine: 10 mg/kg; desipramine: 10 mg/kg] and non-selective [milnacipran: 40 mg/kg; mirtazapine: 20 mg/kg] antidepressants were administered subacutely (3inj) and chronically (17inj) over 16 days. (2) A subacute fluoxetine-desipramine combination (10–10 mg/kg) was administered in rats that were pre-treated with chronic-desipramine (10 mg/kg per day, 14 days). (3) NA-system-mediated interactions were further examined by combining the α 2-receptor agonist clonidine (5, 10, 20, 200 μg/kg) with 10 mg/kg fluoxetine. Results: (1) Long-term treatment with either fluoxetine or desipramine does not modify the behavioural response produced by their subacute administration. (2) In contrast, whereas subacute-milnacipran increases climbing solely, chronic-milnacipran produces greater anti-immobility effects and increases both climbing and swimming behaviours. Similarly, the fluoxetine-desipramine combination produces climbing solely, but increases both climbing and swimming behaviours in animals pre-treated with chronic-desipramine. Chronic but not subacute-mirtazapine increases swimming behaviour. (3) clonidine dose-dependently antagonizes fluoxetine-induced anti-immobility effects and swimming behaviour. Conclusions: Chronic enhancement of NA-transmission alters NA-system-mediated inhibition of 5-HT-induced behaviour in the FST, which may involve α 2-receptors.

Protective effect of docosahexaenoic acid against development of hypertension in young stroke-prone spontaneously hypertensive rats. Focus on the sympathoadrenal system and lipid metabolism

The present study was undertaken to elucidate the effects of acute and subacute administration of docosahexaenoic acid (DHA) on blood pressure in SHRSP between the ages of 6 and 11 weeks. The continuous administration of DHA for 5 weeks in SHRSP significantly inhibited blood pressure rise as compared with levels in non-treated SHRSP. DHA-treated SHRSP showed significantly decreased urinary epinephrine contents as compared with those in non-treated SHRSP. DHA-treated SHRSP produced a significant decrease in adrenal epinephrine concentration as compared with those in non-treated SHRSP at the age of 11 weeks. DHA-treated SHRSP also demonstrated significant decreases in serum triglycerides, LDL and lipid peroxide levels as compared with levels in non-treated SHRSP. However, a single intraperitoneal administration of DHA did not exert any influence on blood pressure in SHRSP at the age of 11 weeks. These findings suggest that the anti-hypertensive effect induced by a 5-week, continuous administration of DHA appears to be associated with the amelioration of increased sympathoadrenal activity and serum lipid derangement during the developmental stage of hypertension in young SHRSP.The present study clarified that a 5-week, continuous administration of DHA had a protective effect against the development of hypertension in SHRSP.

Hexanic Maca extract improves rat sexual performance more effectively than methanolic and chloroformic Maca extracts.

Lepidium meyenii (Maca) is traditionally employed in the Andean region for its supposed properties in improving fertility. The aim of this study was to determine the effect of subacute oral administration of hexanic, methanolic and chloroformic extracts of Maca root on sexual performance in inexperienced male rats. The following sexual performance parameters were evaluated: 1st mount, 1st intromission, ejaculation and post-ejaculatory latencies, intercopulatory interval and copulatory efficacy. All the tested fractions significantly decreased intromission latency and intercopulatory interval and increased intromission frequency and copulatory efficacy (P < 0.05) as compared to controls. Hexanic and methanolic extracts were able to increase mount frequency (MF), while only hexanic fraction significantly improved mount latency (ML) (P=0.038). Globally, only the hexanic fraction significantly improved the majority of the sexual parameters measured. Sub-acute oral administration of hexanic Maca extract improved sexual performance parameters in sexually inexperienced male rats most effectively.

Doxorubicin modulates biological effects of ATP in bone marrow cells in vitro.

ATP activity in mouse bone marrow cells was studied in in vitro experiments. ATP in physiological and supraphysiological concentrations stimulated blebbing of the plasma membrane. Subacute administration of doxorubicin (inductor of oxidative stress) decreased cell sensitivity to ATP, which corresponded to changes in membrane lipid peroxidation.

Anti-inflammatory and anti-ulcer activity of Calligonum comosum in rats

The 10% ethanol extract of the aerial parts of Calligonum comosum (50–400 mg/kg, i.p.) significantly reduced the increase in hind paw oedema induced by carrageenan in rats. Following sub-acute oral administration of the extract (50 and 100 mg/kg, daily for 14 days), a significant anti-inflammatory activity in the cotton pellet model was observed. Pre-treatment with the extract (100, 200 and 400 mg/kg) produced a significant and dose-dependent inhibition to the acute gastric ulcers induced by phenylbutazone, indomethacin, 0.2 N NaOH and 80% ethanol.

Anxiolytic-like effect of saiboku-to, an oriental herbal medicine, on histaminergics-induced anxiety in mice

Effect of saiboku-to, an oriental herbal medicine, on anxiety in mice was investigated using a light/dark test. Anxiogenic- and anxiolytic-like effects were evaluated on the basis of shortened and prolonged time spent in the light zone of the test. Subacute administration (once a day for 7 days) of saiboku-to (0.5–2.0 g/kg, po) induced anxiolytic-like effect. To assess the effect of saiboku-to on brain histaminergic system in a state of anxiety, Compound 48/80 (1.0 μg/2 μl, icv), a non-neuronal mast cell histamine releaser, or thioperamide (10.0 mg/kg, ip), a neuronal histamine releaser possessing the inhibitory effect of histamine H 3 autoreceptors, induced decrease in the time spent in the light zone by co-injection with cimetidine (10.0 μg/2 μl, icv), a H 2 inhibitor, suggesting anxiety-like effect. These histaminergics-induced experimental anxieties were inhibited by pre-treatment with subacute administration of saiboku-to, as well as single treatment with diazepam. The results suggest that saiboku-to exhibits anxiolytic-like effect closely related to histaminergic system in the brain.

Behavioral effects of the α 2-adrenoceptor antagonist, atipamezole, after focal cerebral ischemia in rats

The present study characterized the behavioral effects of the selective α 2-adrenoceptor antagonist, atipamezole, in a rat model of focal cerebral ischemia. Atipamezole (1 mg/kg, s.c.) or desipramine (5 mg/kg, i.p.), a noradrenaline reuptake blocker, was administered either as a single injection 2 days after ischemia induction or for 10 days thereafter (subacute administration). A subacute atipamezole treatment given 30 min before behavioral assessment improved performance in the limb-placing test (days 5, 7, 9, and 11) and in the foot-slip test (days 3 and 7), but not in the beam-walking test. There was no difference between experimental groups in behavioral performance following a single administration of atipamezole or following single or subacute administration of desipramine. The drug treatments did not attenuate the impairment of spatial cognitive performance of ischemic rats in the Morris water-maze test. These results suggest that repeated use-dependent release of noradrenaline by atipamezole facilitates the sensorimotor recovery following focal cerebral ischemia in rats.

Evaluation Of The Pharmacological Properties Of Nutmeg Oil In Rats And Mice

The pharmacological properties of nutmeg oil in animal models were investigated. The oil exhibited an anti-inflammatory effect on acute inflammation. An analgesic effect was produced by the oil in the acetic acid-induced writhing model and in the late phase of the formalin-induced licking. The oil showed an antipyretic activity, and antithrombotic and anti-diarrhoeal properties. Sub-acute administration of the oil produced gastric ulcerations. These data indicate that nutmeg oil showed pharmacological activities similar to those of non-steroidal anti-inflammatory drugs, in addition to anti-diarrhoeal activity.

COMPARISON OF NEUROTOXIC EFFECTS AND POTENTIAL RISKS FROM ORAL ADMINISTRATION OR INGESTION OF TRICRESYL PHOSPHATE AND JET ENGINE OIL CONTAINING TRICRESYL PHOSPHATE

Neurotoxicity of tricresyl phosphates (TCPs) and jet engine oil (JEO) containing TCPs were evaluated in studies conducted in both rat and hen. Results for currently produced samples ("conventional" and "low-toxicity") were compared with published findings on older samples to identify compositional changes and relate those changes to neurotoxic potential. Finally, a human risk assessment for exposure by oral ingestion of currently produced TCPs in JEO at 3% (JEO + 3%) was conducted. TCPs and certain other triaryl phosphates administered as single doses inhibited brain neuropathy target esterase (BNTE; neurotoxic esterase) in the rat and the hen (hen 3.25 times as sensitive), and both species were deemed acceptable for initial screening purposes. Neither rat nor hen was sensitive enough to detect statistically significant inhibition of B-NTE after single doses of JEO + 3% "conventional" TCP. Subacute administration of 2 g/kg/d of JEO + 3% "conventional" TCP to the hen produced B-NTE inhibition (32%), which did not result in organophosphorus-induced delayed neurotoxicity (OPIDN). Subchronic administration of JEO + 3% TCP but not JEO + 1% TCP at 2 g/kg/d produced OPIDN. Thus, the threshold for OPIDN was between 20 and 60 mg "conventional" TCP/ kg/d in JEO for 10 wk. The current "conventional" TCPs used in JEO and new "low-toxicity" TCPs now used in some JEO are synthesized from phenolic mixtures having reduced levels of ortho-cresol and ortho-xylenols resulting in TCPs of very high content of meta - and para-substituted phenyl moieties; this change in composition results in lower toxicity. The "conventional" TCPs still retain enough inhibitory activity to produce OPIDN, largely because of the presence of ortho-xylyl moieties; the "low-toxicity" TCPs are largely devoid of ortho substituents and have extremely low potential to cause OPIDN. The TCPs produced in the 1940s and 1950s were more than 400 times as toxic as the "low-toxicity" TCPs produced today. Analysis of the doses required to produce OPIDN in a subchronic hen study suggests that the minimum toxic dose of "conventional" TCP for producing OPIDN in a 70-kg person would be 280 mg/d, and for JEO containing 3% TCP, 9.4 g/d. Food products could be inadvertently contaminated with neat "conventional" TCP but it is unlikely that food such as cooking oil would be contaminated with enough JEO + 3% TCP to cause toxicity. Further, at the dosage required for neurotoxicity, it would be virtually impossible for a person to receive enough JEO + 3% TCP in the normal workplace (or in an aircraft) to cause such toxicity. There is no record of a JEO formulated with the modern "conventional" TCP causing human neurotoxicity.

Suppression of carrageenan-induced inflammation in vivo by an extract of the Chinese herbal remedy Tripterygium wilfordii Hook F.

The current studies investigated the effect of subacute administration of an ethyl acetate extract of the Chinese herbal remedy, Tripterygium wilfordii Hook F (TWHF) on the inflammatory response induced by carrageenan in the rat. F344 rats were randomly divided into 3 groups of seven animals. The rats were treated orally for 5 days with either vehicle or an ethyl acetate extract of TWHF at a dose of 270 mg/kg, equivalent to 1/5 of the dose causing death in 50% of the animals. Air pouches were induced subcutaneously on the backs of rats and injected with carrageenan on the last day of treatment. Sixteen hours after carrageenan challenge, the air pouches were removed and analyzed. Student's t-test was employed for statistical analysis. The number of exudate cells and the concentration of PGE2, nitrite and TNF-alpha in the exudate obtained from TWHF-treated animals were significantly reduced (by 69%, 78%, 57% and 77%, respectively) compared to that from vehicle-treated animals. mRNA for cyclooxygenase-2 was markedly suppressed in the air pouch lining tissue of TWHF treated rats (p < 0.001). In contrast, PGE2 content of the kidney and stomach and the production of PGE2, nitrite and TNF-alpha by spleen cells was not affected by treatment with TWHF. These results indicate that TWHF exerts a significant anti-inflammatory activity in vivo.

Glucose tolerance and serum insulin levels in an animal model of obesity induced by sub-acute or chronic administration of antipsychotic drugs

1. 1. To assess the role of insulin in the development of the obesity induced by antipsychotic drugs, a glucose tolerance test was conducted in female rats after 10 or 30 days of sulpiride administration. 2. 2. At day 10, the area under the glucose curve did not differ between sulpiride and vehicle-treated rats, however, the area under the insulin curve was significantly decreased by sulpiride. At day, 30 the insulin response was similar in both groups, but the area under the glucose curve was significantly lower in the sulpiride-treated rats. 3. 3. The results suggest that insulin resistance and hyperinsulinemia are not involved in the development and maintenance of the obesity induced by sulpiride. Contrarily, these findings may be related to an increased insulin sensitivity. 4. 4. The absence of hyperinsulinemia and insulin resistance indicates important differences between primary obesity in humans and rodents and this model of drug-induced excessive weight gain.

Activity and onset of action of reboxetine and effect of combination with sertraline in an animal model of depression

The limitations of antidepressant drugs to treat depression has warranted ongoing research to identify pharmacological agents and strategies which offer a faster onset of action and greater therapeutic efficacy. Noradrenaline and serotonin are widely reported to be involved in the mechanism of action of antidepressants and the recent development of selective reuptake inhibitors of these transmitters has provided the opportunity to determine the effects of targeting these transmitter systems, alone and in combination, in an antidepressant response. The present study investigated the effects of reboxetine, a new antidepressant that selectively inhibits noradrenaline reuptake, sertraline, a selective serotonin reuptake inhibitor and a combination treatment composed of the two drugs in the olfactory bulbectomized (OB) rat model of depression. Sub-acute (2 days) administration of reboxetine (2.5, 5, and 10 mg/kg, i.p.) to sham-operated and OB rats reduced the immobility time in the forced swim test. Repeated (14 days) reboxetine (10 mg/kg) treatment attenuated the OB-related behavioural hyperactivity in the `open-field' test. Examination of the onset of the antidepressant effect in the `open-field' test demonstrated that reboxetine (10 mg/kg), sertraline (5 mg/kg) and the combination reduced the behavioural hyperactivity after 14 days but not before this following 3, 7 or 10 days of treatment. Reduced 5-hydroxyindoleacetic acid (5-HIAA) concentrations in amygdaloid cortex of both sham and OB rats following sertraline and combination treatments are likely to be related to acute pharmacological effects on the reuptake of 5-hydroxytryptamine (5-HT). Attenuation of the hypothermia induced by 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT, 0.05 mg/kg s.c.) and clonidine (0.1 mg/kg s.c.) occurred in the reboxetine and sertraline combination treated groups following both 7 and 14 days administration indicating changes to 5-HT 1A receptor and α 2-adrenoceptor sensitivity. The results indicate that changes to 8-OH-DPAT and clonidine-induced responses occur quicker with the combination treatment than with either reboxetine or sertraline treatments alone.