Eric Dailly

Dopamine, depression and antidepressants

The relationship between depression and dopamine deficiency in the mesolimbic pathway has been hypothesized for many years. The experimental studies with animal models of depression and the human studies implicate the role of the dopamine system in depression. Not only do dopaminergic receptor agonists, but also antagonists such as olanzapine exhibit antidepressant effects associated with standard antidepressants in patients with treatment‐resistant depression. This paradoxical result suggests that further investigations are necessary to understand the role played by dopamine in depression.

Antidepressant-like effects in various mice strains in the tail suspension test.

Several studies have reported rodent strain differences in the response to antidepressants in animal models of depression. The aim of the present study was to investigate the potential contribution of genetic factors to antidepressant response in an animal model of depression: the tail suspension test (TST). For this study four mice strains (Swiss and NMRI, two outbred strains and DBA/2 and C57BL/6J Rj, two inbred strains) were submitted to the TST after acute administration of five antidepressants: the tricyclic antidepressants (TCAs) imipramine and desipramine, the selective serotonin (5-HT) reuptake inhibitors (SSRIs) paroxetine and citalopram and the dopamine reuptake inhibitor bupropion. The C57BL/6J Rj strain had a longer baseline immobility time in comparison to the other strains. All antidepressants studied in this work decreased immobility time in the Swiss and C57BL/6J Rj strains. However, the Swiss strain displayed greater sensitivity to citalopram (from 2mg/kg) and C57BL/6J Rj to paroxetine (from 0.5mg/kg). This latter presented a greater size-effect with citalopram than with other strains and reached more than 60% from 8mg/kg. Moreover the size-effect of desipramine, paroxetine and bupropion in Swiss mice was greater than in the other strains in the TST. The NMRI and DBA/2 mice only responded to 5-HT reuptake inhibitors, both selective (paroxetine, citalopram) or non-selective (imipramine). The NMRI strain was more sensitive to imipramine and presented a size-effect (43% at 8mg/kg) superior to those of other strains. DBA/2 strain was more sensitive to citalopram than paroxetine and imipramine. Our results suggest that response to an antidepressant treatment is under control of genetic factors and that the strain of mouse is an important parameter to consider.

Monoamine metabolism changes following the mouse forced swimming test but not the tail suspension test.

Microdialysis, binding and behavioural studies have shown that the dopaminergic system plays a role in antidepressant treatment. It has been suggested that stress may provoke a modification in dopamine (DA) release in different brain areas and that the forced swimming test (FST), in its own accord as a stressor, may be responsible for this modification. Naive male Swiss mice, receiving saline solution, were used in two animal models of depression, the FST and the tail suspension test (TST). In order to understand the locomotor aspect of each test, groups of mice were studied for effects on locomotor activity. Following each test, mice were killed by cervical dislocation, brains were removed and concentrations of amines in the whole brain were analysed by high‐performance liquid chromatography. DA concentration increased from 5 min of the FST, dihydroxyphénylacetate (DOPAC), from 20 min of FST and serotonin, from 8 min of FST. No modification of noradrenaline was observed during the FST and no modification of the neurotransmitter concentrations was observed during the TST. Following an FST of 2‐min duration, a hypolocomotor effect was observed in the subsequent actimeter test. The same effect was observed after a TST of 8 min and onwards. This study confirms the fact that although these two tests are used to study depression, they involve different neuronal mechanisms.

Specificity and efficacy of noradrenaline, serotonin depletion in discrete brain areas of Swiss mice by neurotoxins

The aim of this work is to define neurotoxins doses to have efficient and specific depletion of noradrenaline (NA), serotonin (5-HT) neurotransmission in cortex, striatum, hippocampus and hypothalamus of Swiss mice after intraperitoneal administration of, respectively, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) and para-chlorophenylalanine methyl ester hydrochloride (PCPA). The neurotransmitters concentrations were determined by high performance liquid chromatography with amperometric detection. The minimal single dose necessary to produce a highly significant decrease of NA levels (p<0.01 in comparison with control group) in hypothalamus (-44%), hippocampus (-91%), striatum (-40%) and cortex (-68%) was 50mg/kg but DA and 5-HT levels were modified, respectively, in hypothalamus and striatum. Three doses of PCPA 300 mg/kg over 3 consecutive days involve a profound depletion of 5-HT transmission in all discrete brain areas but NA and DA levels were also significantly reduced. In conclusion, DSP-4 has a different efficacy in discrete brain areas with a noradrenergic specificity which is not absolute, PCPA has a similar efficacy in all brain areas but is unspecific of 5-HT transmission.

Nicotinic receptors and Alzheimer's disease.

SUMMARY Nicotinic receptors (NRs) belong to the group of polymeric receptors of the cell membrane and are key elements of cholinergic transmission. Numerous subtypes of NRs exist, with the α4β2 and α7 types being encountered most frequently. Deficiencies in NRs seem to play a role in Alzheimers disease, which is characterised by accumulation of senile plaques, mainly composed of β-amyloid peptide (βA). Although the aetiology of this disease is unknown, different pathogenesis hypotheses implicating α7 NRs have been proposed, with the receptors exerting a direct or indirect action on the mechanism of βA toxicity. Allosteric modulators of NRs, such as the cholinesterase inhibitor galantamine, that facilitate the action of acetylcholine on these receptors may provide therapeutic benefits in the areas of cognition, attention and antineurodegenerative activity.

A liquid chromatography-tandem mass spectrometry assay for quantification of nevirapine, indinavir, atazanavir, amprenavir, saquinavir, ritonavir, lopinavir, efavirenz, tipranavir, darunavir and maraviroc in the plasma of patients infected with HIV.

A liquid chromatography-tandem mass spectrometry assay for simultaneous determination of the plasma concentration of 11 antiretroviral agents (nevirapine, indinavir, atazanavir, amprenavir, saquinavir, ritonavir, lopinavir, efavirenz, tipranavir, darunavir and maraviroc) has been developed. Sample pre-treatment is limited to protein precipitation with a mixture of methanol and zinc sulfate. After centrifugation the supernatant is injected in the chromatographic system, which consists of on-line solid phase extraction followed by separation on a phenyl-hexyl column. This method, with its simple sample preparation provides sensitive, accurate and precise quantification of the plasma concentration of antiretroviral drugs and can be used for therapeutic drug monitoring in patients infected with HIV.

A liquid chromatography assay for a quantification of doripenem, ertapenem, imipenem, meropenem concentrations in human plasma: Application to a clinical pharmacokinetic study

A simple chromatographic assay based on ultra high performance liquid chromatography with ultraviolet detection at 295 nm is proposed to determinate simultaneously human plasma concentrations of imipenem, doripenem, meropenem and ertapenem. After deproteinization by acetonitrile, carbapenems are separated on a PentaFluoroPhenyl column with a binary gradient elution. This method is specific, accurate, precise (the intra-day and inter-day imprecision and inaccuracy are lower than 15%), sensitive (the limit of quantitation is equal to 0.50 mg/L for imipenem, doripenem, ertapenem, meropenem) and not time consuming (run time=7 min). An application of this method to measure ertapenem plasma concentrations in burn patients is presented.

Efficacy and Tolerability of a Nucleoside Reverse Transcriptase Inhibitor-sparing Combination of Lopinavir/ritonavir and Efavirenz in Hiv-1-infected Patients

Background:Recommended antiretroviral regimens include a nucleoside reverse transcriptase inhibitor (NRTI) component. Class cross-resistance and mitochondrial toxicity are recognized as problems with this class of antiretrovirals. Methods:In a pilot open-label study, 65 antiretroviral-naive and 21 experienced but nonnucleoside reverse transcriptase inhibitor-naive HIV-1-infected adults were given a combination of lopinavir/ritonavir (533.3/133.3 mg twice daily) and efavirenz (600 mg once daily) for 48 weeks. Results:At baseline, the mean viral load was 4.84 log10 copies/mL and the mean CD4 count was 311 cells/mm3. At week 24, the proportions of patients with a viral load <400 copies/mL were 78% and 93% using an intent-to-treat and on-treatment analysis, respectively. At week 48, proportions were 73% and 97%, respectively. Treatment discontinuation occurred in 21 patients during the 48-week period, with 33% of those attributable to drug-related adverse effects. A viral load >400 copies/mL at week 24 or 48 was associated with nonadherence in 3 patients and virologic failure in 1 patient. After an increase during the first 8 weeks, fasting lipid levels remained stable up to 48 weeks. Conclusion:The lopinavir/ritonavir-efavirenz combination is associated with a high rate of virologic response and should be compared with more classic NRTI-containing regimens in randomized and controlled clinical trials.

Is dopamine a limiting factor of the antidepressant-like effect in the mouse forced swimming test?

To study the role of dopamine (DA) in antidepressant-like effect in the forced swimming test (FST), the relationship between the magnitude of the antidepressant-like effect of drugs [citalopram, fluoxetine, paroxetine (selective serotonin reuptake inhibitors), desipramine (tricyclic antidepressant), maprotiline (tetracyclic antidepressant), bupropion (DA reuptake inhibitor), and tranylcypromine (inhibitor of monoamine oxidase)] and the corresponding concentration of DA in the whole brain of mice was investigated. A trend for an inversely proportional linear relationship [(magnitude of the antidepressant-like effect) = -0.0145 x (concentration of DA in the whole brain) +34.773 (r = 0.276)] was observed between the magnitude of the antidepressant-like effect and the concentrations of DA in the whole brain, but this correlation was not significant. This result suggests that the high concentration of DA in the whole brain could be a limiting factor for the antidepressant-like effect of antidepressants such as tranylcypromine and seems to play a minor role in the antidepressant-like activity of another antidepressant such as bupropion in the FST.

Anxiolytic-like effect of milnacipran in the four-plate test in mice: mechanism of action.

Milnacipran is a serotonin/noradrenaline reuptake inhibitor (SNRI) which has not yet been systematically studied preclinically or clinically for the treatment of anxiety disorders. In the four-plate test (FPT) which is known to predict anxiolytic-like activity in mice, milnacipran (4, 8, 16 and 32 mg/kg) demonstrated strong anti-punishment effects following acute administration. The anxiolytic-like effect of milnacipran was not reversed by the selective GABA(A) receptor antagonist, flumazenil (2 and 4 mg/kg), the selective alpha1-adrenoceptor antagonist, prazosin (0.5 and 2 mg/kg), the selective alpha2-adrenoceptor antagonist, idazoxan (1 and 4 mg/kg) or the selective 5-HT2B receptor antagonist, SB 206553 (0.1 and 1 mg/kg). In contrast, the selective 5-HT2A receptor antagonist, SR 46349B (0.1 and 1 mg/kg), and the non-selective 5-HT2 receptor antagonist, ketanserin (0.125 and 0.5 mg/kg), completely abolished the anxiolytic-like effect of milnacipran in FPT. Neurochemical depletion of NA or 5-HT completely abolished the activity of milnacipran. These results strongly suggest that activation of 5-HT2A receptors is critically involved in the anxiolytic activity of milnacipran. On the other hand the lack of activity of milnacipran after depletion of NA or 5-HT is consistent with milnacipran acting on the locus coeruleus to induce 5-HT release. The present data suggest a strong connection between 5-HT2A receptors and NA neurotransmission.