A biorhythmologic approach to evaluating forced swimming as an experimental model of a "depressive" state

Rhythmical structure of forced swimming was studied on rats. Reserpine (1 mg/kg, 24 h before testing), clonidine (150 mkg/kg) and prolonged repeated striatal stimulation induced behavioural depression with reorganization of swimming rhythm and increase of short cycles (less than 6 s) of immobility. After chronic administration of antidepressants (imipramine, amitriptyline, niamid, 10 mg/kg/day, during 14 days), on the contrary, the number of these cycles diminished, while the number of active swimming cycles increased. Chrono-biological "index of depression" is suggested to express more exactly behavioural depression and specific activity of antidepressants than usual registration of immobility time.     

Clinical trials with hypericum extracts in patients with depression--results, comparisons, conclusions for therapy with antidepressant drugs.

By the spring of 2002, results from 34 controlled, double-blind trials of Hypericum extracts in some 3000 patients, predominantly with mild to moderate forms of depression, had been published. An overview is given of the studies conducted since 1990. In the majority of them, the efficacy criterion (primary endpoint) was the score and/or response rate on the Hamilton Rating Scale of Depression (HAMD). In ten studies, based on extracts prepared with 50% or 60% ethanol in water (V/V), the dosages ranged from 300 mg to 1050 mg of extract per day. Five of the ten studies were placebo-controlled and in all five cases, the Hypericum extract was shown to be significantly superior. Results with Hypericum were as good or even better than with imipramine or fluoxetine. In the period since 1990, a total of twelve controlled trials have been published with one particular extract prepared with 80% methanol in water (V/V), of which six were placebo-controlled, two compared Hypericum with imipramine and one each with maprotiline, amitriptyline, sertraline or light therapy. Dosages ranged from 450-1200 mg extract per day. Statistical analysis of the total Hamilton scores showed significant differences between Hypericum extract and placebo in four of the six placebo-controlled studies and a trend in favour of the active treatment in the other two. Of the five comparative trials against four different synthetic antidepressants, amitriptyline was significantly superior to Hypericum after six weeks of therapy, whilst there were no significant differences in treatment outcome between Hypericum and the other synthetics in the remaining four studies. The results of the trials conducted to date show no major differences in efficacy of the alcoholic extracts. Taking all the results into account, it can be assumed that the threshold dose for efficacy against individual symptoms and complaints that occur in the course of the depressive illness could be about 300 mg of extract per day. In the medically supervised treatment of mild to moderate depression, doses of approximately 500-1000 mg of extract per day of these preparations of St. John's Wort are of comparable efficacy to synthetic antidepressants in their normally prescribed dosages.     

A controlled comparison of flupenthixol and amitriptyline in depressed outpatients.

Sixty depressed outpatients were allocated to treatment with either amitriptyline (75-225 mg/day) or flupenthixol (1-5-4-5 mg/day) in flexible dosage for six weeks under double-blind procedures. Various objective and subjective assessments were carried out before and after one, three, and six weeks of treatment. Twenty-three patients completed the course of amitriptyline and 28 the course of flupenthixol. Almost all variables improved significantly over time, irrespective of drug. On most ratings there were no significant differences between the two drugs, but the trends favoured flupenthixol. In particular, flupenthixol lessened anxiety scores more than amitriptyline. Unwanted effects were few and not troublesome except in two patients receiving amitriptyline. Flupenthixol, in low dosage, is a useful alternative antidepressant for depressed outpatients.     

Effect of prolonged 5-hydroxytryptamine uptake inhibition by paroxetine on cortical beta 1 and beta 2-adrenoceptors in rat brain

The effects of prolonged (21 day) oral administration of the antidepressants paroxetine (0.9 to 8.9 mg/kg/day) and amitriptyline (2.7 to 27 mg/kg/day), on rat brain cortical beta 1- and beta 2-adrenoceptor numbers and affinities were investigated using [3H]-CGP 12177. Although amitriptyline, 27 mg/kg, caused a significant (p less than 0.05) 20% reduction in the number of beta 1-adrenoceptors, paroxetine, at doses up to 8.9 mg/kg p.o., did not influence binding of [3H]-CGP 12177 to cortical beta 1- or beta 2-adrenoceptors. This study with paroxetine provides further evidence that the down-regulation of central beta 1-adrenoceptors in rat brain after repeated administration is not a property of all antidepressant drugs.     

Effects of Venlafaxine and Escitalopram Treatments on NMDA Receptors in the Rat Depression Model

Depression may relate to neurocognitive impairment that results from alteration of N-methyl-D: -aspartate receptor (NMDAR) levels. Venlafaxine and escitalopram are two drugs commonly used to treat depression. The drugs may affect expression of NMDARs, which mediate learning and memory formation. The aim of the study was to examine whether the effects of venlafaxine and escitalopram treatments are associated with NMDARs in a rat model of depression. Forty male Wistar albino rats were randomly divided into four groups (n?=?10) as follows: control group, chronic mild stress group (CMS), venlafaxine (20?mg/kg body weight per day)?+?CMS, and escitalopram (10?mg/kg body weight per day)?+?CMS. After induction of depression, a decrease in the concentration of NR2B was observed; venlafaxine treatment prevented the reduction of NR2B expression. Escitalopram treatment did not effect the reduced levels of NR2B resulting from depression. There was no significant difference in NR2A concentration among groups. The present data support the notion that venlafaxine plays a role in maintaining NR2B receptor in experimental depression. It may be possible that treatment with escitalopram has no effect on NMDARs in experimental depression.     

Randomised controlled trial comparing problem solving treatment with amitriptyline and placebo for major depression in primary care.

OBJECTIVE--To determine whether, in the treatment of major depression in primary care, a brief psychological treatment (problem solving) was (a) as effective as antidepressant drugs and more effective than placebo; (b) feasible in practice; and (c) acceptable to patients. DESIGN--Randomised controlled trial of problem solving treatment, amitriptyline plus standard clinical management, and drug placebo plus standard clinical management. Each treatment was delivered in six sessions over 12 weeks. SETTING--Primary care in Oxfordshire. SUBJECTS--91 patients in primary care who had major depression. MAIN OUTCOME MEASURES--Observer and self reported measures of severity of depression, self reported measure of social outcome, and observer measure of psychological symptoms at six and 12 weeks; self reported measure of patient satisfaction at 12 weeks. Numbers of patients recovered at six and 12 weeks. RESULTS--At six and 12 weeks the difference in score on the Hamilton rating scale for depression between problem solving and placebo treatments was significant (5.3 (95% confidence interval 1.6 to 9.0) and 4.7 (0.4 to 9.0) respectively), but the difference between problem solving and amitriptyline was not significant (1.8 (-1.8 to 5.5) and 0.9 (-3.3 to 5.2) respectively). At 12 weeks 60% (18/30) of patients given problem solving treatment had recovered on the Hamilton scale compared with 52% (16/31) given amitriptyline and 27% (8/30) given placebo. Patients were satisfied with problem solving treatment; all patients who completed treatment (28/30) rated the treatment as helpful or very helpful. The six sessions of problem solving treatment totalled a mean therapy time of 3 1/2 hours. CONCLUSIONS--As a treatment for major depression in primary care, problem solving treatment is effective, feasible, and acceptable to patients.     

Embryotoxicity of oral administered chlorothalonil in mice

BACKGROUND: Chlorothalonil (2,4,5,6-tetrachloroisophthalonitril), the nephrotoxic fungicide, was examined for its potential to produce developmental toxicity in mice after oral administration. METHODS: Pregnant ICR (CD-1) mice were given sublethal doses of 0 (corn oil), 100, 400, and 600 mg/kg/day chlorothalonil by gavage on gestation days (GD) 6-15. RESULTS: Maternal effects in 400 and 600 mg/kg/day dose groups included signs of toxicity such as weakness and depression in the maternal activity, and reduction in body weight and weight gain. No maternal toxicity was apparent in the 100 mg/kg/day dose group. Maternal exposure to chlorothalonil during organogenesis significantly affected the number of live fetuses, early resorption, and mean fetal weight in the 400 and 600 mg/kg/day dose groups. No external, visceral, and skeletal abnormalities were observed among any of the treated groups compared to the control. CONCLUSIONS: On the basis of the present results chlorothalonil can produce clinical signs of toxicity and fetotoxicity without teratogenic effects at 400 and 600 mg/kg/day dose groups.     

人参总皂苷和远志总苷配伍对小鼠抗抑郁作用

目的确定人参总皂苷（GTS）和远志总苷（PTG）抗抑郁配伍剂量比例,形成参远苷（SGY）制剂,为研制开发抗抑郁新药提供实验数据。方法采用析因设计方法,GTS和PTG均选取25、50、100 mg/kg三个剂量,按照完全随机的两因素3×3实验设计,得到参远苷的9个不同配比组。C57BL/6J小鼠（用于悬尾实验）和ICR小鼠（用于强迫游泳实验）随机分为对照组、阳性药组（10 mg/kg,帕罗西汀用于悬尾实验;阿米替林用于强迫游泳实验）及参远苷的9个不同配比组,共11组。灌胃给药7 d,观察各组对悬尾或强迫游泳实验小鼠不动时间的影响,并通过空场实验观察参远苷各配比对小鼠自主活动的影响。参远苷与单味GTS、PTG的抗抑郁作用比较实验中,C57BL/6J小鼠（用于悬尾实验）和ICR小鼠（用于强迫游泳实验）随机分为对照组、阳性药组（10 mg/kg,帕罗西汀用于悬尾实验;阿米替林用于强迫游泳实验）、参远苷低中高剂量组（37.5、75、150 mg/kg）、GTS和PTG各四个剂量组（均为18.75、37.5、75、150 mg/kg）,共13组。灌胃给药7 d,观察各组对悬尾或强迫游泳实验小鼠不动时间的影响。结果析因设计结果表明,GTS和PTG之间无交互效应。参远苷配比组75 mg/kg（GTS∶PTG为50∶25）及150mg.kg-1（GTS∶PTG为100∶50）显著并稳定缩短悬尾或强迫游泳不动时间（P〈0.05）,得出GTS和PTG的剂量配伍比例为2：1。空场实验结果显示,参远苷各配比对小鼠运动总路程无影响。参远苷与单味GTS、PTG抗抑郁作用比较实验结果显示,GTS 75、150 mg/kg缩短悬尾实验小鼠不动时间（P〈0.01,P〈0.05）,对强迫游泳实验小鼠不动时间无影响。PTG 18.75、37.5 mg/kg缩短强迫游泳实验小鼠不动时间（P〈0.01,P〈0.05）,对悬尾实验小鼠不动时间无影响。参远苷75、150 mg/kg缩短悬尾实验小鼠不动时间（P〈0.05）。同时,参远苷37.5、75 mg/kg缩短强迫游泳实验小鼠不动时间（P〈0.01,P〈0.05）。结论 GTS和PTG以2：1的比例形成的参远苷（SYG）制剂,质量容易控制,作用机制多样,符合抑郁症复杂多样的发病机制,优于单味GTS和PTG,进一步研究之后,有可能成为新型的抗抑郁药物。     

Prenatal bupropion exposure enhances the cocaine reward and stress susceptibility in adult mice

Although a growing body of evidence supports the notion that certain antidepressant treatments in pregnancy produce earlier delivery and minor behavioral teratogenesis in infants, the long-term effects of such treatments in adulthood remain ill-defined. Recently, postnatal exposure to psychotropic drugs was found to affect the emotional development and susceptibility to abused drugs. Thus, this study aimed to examine whether prenatal exposure of four frequently-used antidepressants, bupropion, fluvoxamine, citalopram, and trazodone, altered the responsiveness to stress and cocaine in the adulthood. Dams received daily injection of bupropion (25 or 12.5 mg/kg), citalopram (5 mg/kg), fluvoxamine (10 mg/kg), trazodone (20 mg/kg) or saline throughout their third trimester of gestation, and several birth outcome indices were then examined. Locomotor activity, naive anxiety levels, and the sensitivity to the cocaine reinforcing effects were observed in pups at their day 56-60 post partum. We found that trazodone treatment produced a high mortality rate in pups after weaning. Mice, prenatally treated with bupropion at 25 mg/kg, exhibited lower rearing numbers and ambulatory activity as compared to the saline-treated mice. More importantly, such treatment enhanced the mouse sensitivity to the reinforcing effects of cocaine. Taken together, these results suggest that use of bupropion in the late pregnancy may run a risk of enhancing the offspring's susceptibility to stress and cocaine reward in adulthood.     

Determination of amitriptyline and some of its metabolites in blood by high-pressure liquid chromatography

Conditions for the determination of amitriptyline and some of its metabolites in serum on a reversed-phase material (C-8) by high-pressure liquid chromatography with UV detection at 254 nm were systematically investigated. The separation of tricyclic antidepressants is best carried out on a phase system consisting of C-8 bonded-phase material as the stationary phase and water—methanol—dichloromethane—propylamine as the mobile phase.The precision and detection limit of the method and the extraction efficiency were established. A chromatogram of a serum extract from a patient treated with amitriptyline is shown. Serum levels of amitriptyline and its four main metabolites (nortriptyline, desmethylnortriptyline, trans-10-hydroxy-amitriptyline and trans-10-hydroxy-nortriptyline) in a patient receiving 150 mg of amitriptyline daily, are reported.     

A Psychiatric and Psychological Study of Amitriptyline (Elavil) as an Antidepressant

The antidepressant effects of amitriptyline (Elavil) were investigated by means of psychiatric assessment and psychological testing of 20 depressed patients who were compared, before and after treatment, with a placebo-treated control group of 14 similar patients. After three weeks on doses of 150 mg. per day, 13 out of 20 of the actively treated group were rated as improved, compared with only three out of 11 of the control group (p < .05). Clinical improvement was associated with changes on some objective tests. No persistent adverse side effects were observed. It was concluded that amitriptyline is an effective antidepressant.     

Relative benefit-risk comparing diclofenac to other traditional non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors in patients with osteoarthritis or rheumatoid arthritis: a network meta-analysis

IntroductionThere is argument over the benefits and risks of drugs for treating chronic musculoskeletal pain. This study compared the efficacy, safety, and tolerability of diclofenac, ibuprofen, naproxen, celecoxib, and etoricoxib for patients with pain caused by osteoarthritis (OA) or rheumatoid arthritis (RA).MethodsA systematic literature review used Medline and EMBASE to identify randomised controlled trials. Efficacy outcomes assessed included: pain relief measured by visual analogue scale (VAS); Western Ontario McMaster Universities Arthritis Index (WOMAC) VAS or WOMAC Likert scale; physical functioning measured by WOMAC VAS or Likert scale; and patient global assessment (PGA) of disease severity measured on VAS or 5-point Likert scale. Safety outcomes included: Antiplatelet Trialists’ Collaboration (APTC), major cardiovascular (CV) and major upper gastrointestinal (GI) events, and withdrawals. Data for each outcome were synthesized by a Bayesian network meta-analysis (NMA). For efficacy assessments, labelled doses for OA treatment were used for the base case while labelled doses for RA treatment were also included in the sensitivity analysis. Pooled data across dose ranges were used for safety.ResultsEfficacy, safety, and tolerability data were found for 146,524 patients in 176 studies included in the NMA. Diclofenac (150 mg/day) was likely to be more effective in alleviating pain than celecoxib (200 mg/day), naproxen (1000 mg/day), and ibuprofen (2400 mg/day), and similar to etoricoxib (60 mg/day); a lower dose of diclofenac (100 mg/day) was comparable to all other treatments in alleviating pain. Improved physical function with diclofenac (100 and 150 mg/day) was mostly comparable to all other treatments. PGA with diclofenac (100 and 150 mg/day) was likely to be more effective or comparable to all other treatments. All active treatments were similar for APTC and major CV events. Major upper GI events with diclofenac were lower compared to naproxen and ibuprofen, comparable to celecoxib, and higher than etoricoxib. Risk of withdrawal with diclofenac was lower compared to ibuprofen, similar to celecoxib and naproxen, and higher than etoricoxib.ConclusionsThe benefit-risk profile of diclofenac was comparable to other treatments used for pain relief in OA and RA; benefits and risks vary in individuals and need consideration when making treatment decisions.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0554-0) contains supplementary material, which is available to authorized users.     

Treatment of massive hypertriglyceridemia resistant to PUFA and fibrates: a possible role for the coenzyme Q10?

OBJECTIVE: To describe the effect of CoQ10 (added to either a fibrate, or PUFA or association of both) in patients affected by massive hypertriglyceridemia (MHTG) resistant to fibrates and PUFA. DESIGN: Open, sequential, comparative intervention study. SETTING: Specialised centres for dyslipidemia management. SUBJECTS: 15 subjects (mean age: 45.1 +/- 12.5 years) affected by MHTG and hyporesponsive to either fibrates, or PUFA, or fibrates-PUFA association, and 15 age-matched subjects regularly responders to PUFA and fenofibrate treatment. INTERVENTIONS: Treatment for periods of 6 weeks each with the following consecutive treatments: CoQ10 150 mg/day, PUFA 3000 mg/day, fenofibrate 200 mg/day, PUFA 3000 mg/day + fenofibrate 200 mg/day, PUFA 3000 mg/day + CoQ10 150 mg/day, fenofibrate 200 mg/day + CoQ10 150 mg/day, and finally, fenofibrate 200 mg/day + PUFA 3000 mg/day + CoQ10 150 mg/day. RESULTS: CoQ10 supplementation improved, in the control group, systolic and diastolic blood pressure, creatinine and Lp(a) plasma levels, both during fenofibrate and/or PUFA treatment. In MHTG group, CoQ10 supplementation significantly improved TG, TC, Lp(a), uric acid and blood pressure during fenofibrate treatment, but only Lp(a) and blood pressure during PUFA treatment. Fenofibrate appeared to have better effect on hsCRP and gamma-GT plasma levels than PUFA. No significant change was observed in any group and under any treatment in regards to homocysteinemia, PAI-1, or t-PA. CONCLUSION: Even though the mechanism of action through which the effects were obtained is yet to be elucidated, adding CoQ10 to fenofibrate could improve the drug's efficacy in MHTG patients not responding to fenofibrate alone.     

Edinburgh primary care depression study: treatment outcome,patient satisfaction,and cost after 16 weeks.

OBJECTIVE--To compare the clinical efficacy, patient satisfaction, and cost of three specialist treatments for depressive illness with routine care by general practitioners in primary care. DESIGN--Prospective, randomised allocation to amitriptyline prescribed by a psychiatrist, cognitive behaviour therapy from a clinical psychologist, counselling and case work by a social worker, or routine care by a general practitioner. SUBJECTS AND SETTING--121 patients aged between 18 and 65 years suffering depressive illness (without psychotic features) meeting the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Third Edition for major depressive episode in 14 primary care practices in southern Edinburgh. MAIN OUTCOME MEASURES--Standard observer rating of depression at outset and after four and 16 weeks. Numbers of patients recovered at four and 16 weeks. Total length and cost of therapist contact. Structured evaluation of treatment by patients at 16 weeks. RESULTS--Marked improvement in depressive symptoms occurred in all treatment groups over 16 weeks. Any clinical advantages of specialist treatments over routine general practitioner care were small, but specialist treatment involved at least four times as much therapist contact and cost at least twice as much as routine general practitioner care. Psychological treatments, especially social work counselling, were most positively evaluated by patients. CONCLUSIONS--The additional costs associated with specialist treatments of new episodes of mild to moderate depressive illness presenting in primary care were not commensurate with their clinical superiority over routine general practitioner care. A proper cost-benefit analysis requires information about the ability of specialist treatment to prevent future episodes of depression.     

Effects of progesterone administered to dairy heifers on sensitivity of corpora lutea to PGF(2)alpha and on plasma LH concentration

To determine whether progesterone facilitates PGF(2)alpha-induced luteolysis prior to day 5 of the estrous cycle, 48 Holstein-Friestian heifers were assigned at random to four treatments: 1) 4 ml corn oil/day + 5 ml Tris-HCl buffer (control); 2) 25 mg prostaglandin F(2)alpha (PGF(2)alpha); 3) 100 mg progesterone/day (progesterone); 4) 100 mg progesterone/day + 25 mg PGF(2)alpha (combined treatment). Progesterone was injected subcutaneously daily from estrus (day 0) through day 3. The PGF(2)alpha was injected intramuscularly on day 3. Estrous cycle lengths were decreased by progesterone: 20.2 +/- 0.56, 19.2 +/- 0.31 (control and PGF(2)alpha); 13.2 +/- 1.40, and 11.7 +/- 1.27 (progesterone and combined). The combination of progesterone and PGF(2)alpha did not shorten the cycle any more than did progesterone alone (interaction, P>0.05). PGF(2)alpha treatment reduced progesterone concentrations on day 6 (P<0.05) and both progesterone and PGF(2)alpha reduced plasma progesterone on day 8 (P<0.01 and P<0.05, respectively). LH was measured in blood samples collected at 10- min intervals for 4 hr on day 4 from three heifers selected at random from each of the four treatment groups. Mean LH concentration for control heifers ranged from 0.35 to 0.63 ng/ml (overall mean, 0.49 ng/ml) and for progesterone-treated heifers ranged from 0.12 to 0.30 ng/ml (overall mean, 0.23 ng/ml). LH concentrations were greater in control heifers (P<0.01). The mean LH pulse rate for control heifers was 2.7 pulses/heifers/4 hr, while that for the progesterone-treated heifers was 1.7 pulses/heifer/4 hr. The mean pulse amplitude for control and progesterone treatments was 0.47 ng/ml and 0.36 ng/ml, respectively. Neither pulse amplitude nor frequency were different between treatment groups.     

Controlled trial of trimipramine,monoamine oxidase inhibitors,and combined treatment in depressed outpatients.

A study was carried out in which 135 mildly or moderately depressed outpatients were randomly allocated to one of five groups receiving six weeks'' treatment weith antidepressant drugs. The groups received a tricyclic antidepressant (trimipramine; mean dose 106 mg at night) or a monoamine oxidase inhibitor (MAOI) (phenelzine or isocarboxazid; mean doses 45 and 32 mg/day respectively), or a combination of the two (phenelzine plus trimipramine or isocarboxazid plus trimipramine). Various scales were used to measure depression before and at one, three, and six weeks of treatment, and results were assessed blindly. The tricyclic antidepressant was found to be consistently superior to the MAOIs and the combined treatments. Some differential indicators of response to the various antidepressants were found--for example, patients with initial complaints of dizziness, suicidal ideas, irritability, and insomnia and a longer duration of illness were more likely to respond to trimipramine--but these were of only modest significance. Side effects were not troublesome in any group. It is concluded that neither MAOIs nor MAOIs combined with tricyclic antidepressants are the treatment of first choice in unselected outpatients with mild or moderate depression.     

Incidence and potentiation of external and internal fetal anomalies resulting from chlordiazepoxide and amitriptyline alone and in combination

The teratogenic potential of a combination of chlordiazepoxide (Cdz) and amitriptyline (Amt) was examined with regard to both internal and external anomalies. Timed pregnant golden hamsters were given a single intraperitoneal injection on day 8 of gestation of one of the following: chlordiazepoxide hydrochloride (28.5 mg/kg), amitriptyline hydrochloride (70.3 mg/kg), Cdz-Amt combination (28.5 mg/kg Cdz + 70.3 mg/kg Amt, in order to retain the 1:2.5 dose ratio utilized in a clinically-used preparation of these agents), or saline vehicle (control). Fetuses were recovered on gestation day 15 following maternal sacrifice. Cranial malformations were analyzed in Bouin's-fixed fetuses by making 1-mm coronal sections through each head, whereas visceral anomalies were examined following general dissection of each body. Amt alone produced a significant (P less than 0.05) incidence of bent tail and encephalocele, whereas Cdz significantly (P less than 0.05) altered the male:female ratio of surviving fetuses when compared with saline-injected controls. The Cdz-Amt combination caused significant increases in cranial malformations, open eye, bent tail, abnormal lung, and urogenital anomalies. The teratogenic effects of potentiation between the components of this combination are discussed in terms of external and internal malformations.     

Assessment of female and male fertility in Sprague-Dawley rats administered vorinostat, a histone deacetylase inhibitor

BACKGROUND: Histone deacetylase (HDAC) inhibitors have been shown to mediate the regulation of gene expression, induce cell growth, cell differentiation, and apoptosis of tumor cells. These compounds are now marketed or are in clinical development. One such HDAC inhibitor, vorinostat (suberoylanilide hydroxamic acid [SAHA], Zolinza), was assessed for its potential effects on fertility in Sprague–Dawley rats. METHODS: Female rats were administered oral dose levels of 0 (vehicle only), 15, 50, or 150 mg/kg/day of vorinostat for 14 days before cohabitation, during cohabitation, and through Gestation Day (GD) 7. In a separate study, male rats were administered oral dose levels of 0 (vehicle only), 20, 50, or 150 mg/kg/day for 10 weeks before cohabitation, during cohabitation, and until the day before scheduled sacrifice (approximately 14 weeks total). In both studies, % peri‐implantation loss and % postimplantation loss were evaluated on GD 15–17. Testicular weight and histomorphology, cauda epididymal sperm count, and sperm motility were evaluated in the male rat study at termination. RESULTS: There were treatment‐related decreases in body weight gain at 150 mg/kg/day in both studies. There were no effects on mating or fertility indices in either study. In the female study there were increased numbers of corpora lutea in all drug‐treated groups (only 1 or 2 affected dams in low and mid‐dose groups), and a marked increase in percent postimplantation loss only in the high‐dose group. No treatment‐related effects were observed on litter or sperm parameters of the male study. CONCLUSIONS: Vorinostat had no effects on mating or fertility in rats up to 150 mg/kg/day. There were no indications of reproductive toxicity in drug‐treated male rats. Increases in corpora lutea or resorptions were observed in treated female rats. Birth Defects Res (Part B) 80:1–8, 2007. © 2007 Wiley‐Liss, Inc.     

Behavioural alterations in rats induced by single prenatal exposure of haloperidol

Haloperidol (50 mg/kg, i.p.) treatment was given once to two different groups of pregnant Charles Foster rats on gestational day 9 and 14, these being respectively the critical periods of neural morphogenesis and rapid neural cell proliferation in this species. Pregnant control rats were similarly treated with equal volume of vehicle. The pups born were subjected to open-field exploratory behaviour and elevated plus-maze behaviour tests of anxiety and learned helplessness test of depression at 9 weeks of age. The results indicate that prenatal haloperidol treatment on gestational day 14 induces a significant increase in open-field ambulation and faecal droppings whereas haloperidol treatment on gestational day 9 caused significantly decreased rearing and unaltered ambulation in rat offsprings. Rat offsprings treated with haloperidol on gestational day 9 and 14 also displayed significant anxiogenic behaviour pattern on elevated plus-maze. Significantly increased number of escape failures were observed in learned helplessness tests indicating presence of depression in haloperidol treated rat offsprings. These behavioural alterations were found to be more marked in rat offsprings treated with haloperidol on gestational day 14. The results suggest that prenatal single exposure of high dose of haloperidol during critical period of neural cell proliferation leaves a lasting imprint on offsprings resulting in abnormal emotional state.     

Effects of cocaine on conflict behavior in the rat

The present studies examined the effects of acute cocaine administration, chronic cocaine administration and cocaine withdrawal on behavior in the Conditioned Suppression of Drinking (CSD) conflict paradigm, an animal model for the study of anxiety. In daily 10-minute sessions, water deprived rats were trained to drink from a tube that was occasionally electrified (0.25 mA), electrification being signalled by a tone. Within 3-4 weeks, control (i.e., non-drug) CSD behavior stabilized (30-50 shocks and 10-12 ml/session) and drug studies were initiated. Acute administration of cocaine (30-min pretreatment) produced a selective pro-conflict effect only at a dose of 10 mg/kg cocaine, with lower doses (2.5, 5 mg/kg) exerting no effect on CSD behavior and a higher dose (20 mg/kg) depressing both punished and unpunished responding. In a second experiment, cocaine (10 mg/kg, IP, 2/day) or saline was administered to separate groups of subjects for 7 weeks. In this chronic treatment study, CSD testing was conducted 12 hours after each evening cocaine administration. Although it had no effect on CSD behavior during the first week of treatment, this chronic cocaine administration produced a significant and selective pro-conflict effect which was stable during the period from Weeks 2-7. In a final experiment, a high dose of cocaine (20 mg/kg, 3/day) or saline was given to separate groups of subjects for 2 weeks and the behavioral effects of these treatments and their subsequent termination were examined. In this study, CSD testing was conducted 8 hours after each evening cocaine treatment. During the first week of high dose cocaine treatment, a decrease in punished responding was observed; this parameter returned to baseline levels by Week 2. Discontinuation of this high dose chronic cocaine treatment resulted in a selective decrease in punished responding. This pro-conflict effect was greatest at 3 days, and lasted for 6 days after the last cocaine dose. These data are consistent with clinical findings demonstrating the anxiogenic effects of both acute and chronic cocaine treatment as well as cocaine withdrawal and suggest that conflict paradigms such as the CSD may be useful for the study of cocaine-induced anxiety states.