Discriminative stimulus properties of cocaine: enhancement by monoamine reuptake blockers. Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. Incidence and risk factors for hyponatraemia following treatment with fluoxetine or paroxetine in elderly people. Rx drugs

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J Pharmacol Exp Ther. 1998 Mar;284(3):1015-25.
Discriminative stimulus properties of cocaine: enhancement by monoamine reuptake blockers.

Kleven MS, Koek W.

Centre de Recherche Pierre Fabre, Castres, France.

In this study we examined the ability of compounds varying in their in vitro potencies as inhibitors of dopamine (DA), norepinephrine (NE) or serotonin (5-HT) reuptake to enhance the discriminative stimulus (DS) effects of cocaine. Compounds were administered in combination with cocaine (2.5 mg/kg i.p.) to rats trained to discriminate a low dose from a high dose of cocaine (2.5 vs. 10 mg/kg i.p.) in a two-lever, FR10 drug discrimination paradigm. All the monoamine reuptake blockers produced high-dose-appropriate responding in a dose-related manner when combined with a low dose of cocaine, but compounds from other pharmacological classes (benztropine, caffeine, diazepam, or 8-hydroxy-2-(di-n-propylamino)tetralin) did not enhance the DS effects of cocaine. Analysis of the relationship between behavioral and in vitro biochemical potencies indicated that inhibition of DA and 5-HT transport is responsible for the cocaine-enhancing effects of the monoamine reuptake blockers we examined. In contrast, NE reuptake apparently does not play a strong role, despite the finding that desipramine, talsupram and nortriptyline enhanced the DS effects of cocaine. However, pretreatment with the alpha-1 adrenergic antagonist prazosin failed to alter completely the ability of desipramine to enhance the DS effects of the low training dose of cocaine, but did produce dose-related decreases in the cocaine-enhancing effects of the beta adrenergic antagonist propranolol (10 mg/kg i.p.). These findings suggested that, under some conditions, NE interactions can modulate the DS effects of cocaine. In all, the results confirm reports that monoamine reuptake blockers enhance the DS effects of cocaine and indicate that 5-HT and DA can effectively modulate the DS effects of cocaine, but suggest that NE interactions may be relatively less important in the rat.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9495862&dopt=Abstract

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Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3239-44.
Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine.

Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E, Guidotti A.

The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois, Chicago, IL 60612, USA.

We recently reported that fluoxetine or paroxetine, two selective serotonin reuptake inhibitors (SSRIs), when administered to rats, increase the brain content of the neurosteroid 3alpha-hydroxy-5alpha-pregnane-20-one (3alpha5alpha-ALLO) without altering the brain content of other neurosteroids. ALLO (3alpha5alpha and 3alpha5beta isomers) binds with high affinity to various gamma-aminobutyric acid (GABA) receptor A subtypes and facilitates the action of GABA at these receptors. We hypothesized that the increase of ALLO brain content induced by treatment with SSRIs could contribute to alleviating the anxiety and dysphoria associated with the symptomatology of major unipolar depression. We measured ALLO content in four cisternal-lumbar fractions of cerebrospinal fluid (CSF) before and 8-10 weeks after treatment with fluoxetine or fluvoxamine in 15 patients with unipolar major depression. The concentration of ALLO ( approximately 40 fmol/ml in each CSF fraction of three control subjects) was about 60% lower in patients with major unipolar depression. However, in the same patients, fluoxetine or fluvoxamine treatment normalized the CSF ALLO content. Moreover, a statistically significant correlation (r = 0.58; P < 0.023; n = 15) existed between symptomatology improvement (Hamilton Rating Scale for Depression scores) and the increase in CSF ALLO after fluoxetine or fluvoxamine treatment. The CSF content of PREG and PROG remained unaltered after treatment and failed to correlate with the SSRI-induced increase of CSF ALLO. The normalization of CSF ALLO content in depressed patients appears to be sufficient to mediate the anxiolytic and antidysphoric actions of fluoxetine or fluvoxamine via its positive allosteric modulation of GABA type A receptors.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9501247&dopt=Abstract

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Br J Clin Pharmacol. 1999 Feb;47(2):211-7.
Incidence and risk factors for hyponatraemia following treatment with fluoxetine or paroxetine in elderly people.

Wilkinson TJ, Begg EJ, Winter AC, Sainsbury R.

Department of Health Care of the Elderly, Princess Margaret Hospital, Christchurch, New Zealand.

AIMS: To establish the incidence, time course and risk factors of hyponatraemia complicating treatment with fluoxetine or paroxetine in an elderly population. METHODS: Retrospective descriptive and case control study in an inpatient/outpatient assessment and rehabilitation service for people aged 65 years and over. Fourteen elderly patients with hyponatraemia complicating treatment with fluoxetine or paroxetine, matched with 56 controls drawn from 845 patients treated with fluoxetine or paroxetine over 3.5 years. No other SSRI antidepressants were used over the study period. RESULTS: The incidence of hyponatraemia was 4.7/1000 people treated/year (6.3/1000 for fluoxetine and 3.5/1000 for paroxetine). Hyponatraemia was detected at a median 13.5 (mean 18.6, range 4-64) days after commencing the drug. Mean (95% confidence intervals) body weights were lower in cases at 53.0 (95% CI 46.5-59.5) kg compared with controls at 64.5 (95% CI 60.1-68.4) kg (P<0.01). 71% of cases were women compared with 45% of controls (P=0.07) but the effect of gender was confounded by body weight. There were trends for cases to be older (odds ratio 1.10: 95% CI 0.99, 1.23) and lighter (odds ratio 0.92, 95% CI 0.86, 0.99). CONCLUSIONS: Approximately 1 in 200 elderly people treated per year with fluoxetine or paroxetine developed complicating hyponatraemia. Low body weight was a particular risk factor. Most cases occurred within 3 weeks of treatment.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10190657&dopt=Abstract

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