Michel Bourin
Université de Nantes, Clinical Pharmacology, Faculty Member
Bipolar disorder is a chronic illness, defined by a succession of depressive and/or manic periods separated by free intervals. Its evolution with aging is marked by a high suicide mortality rate. Bipolar disorders raise the question of... more
Bipolar disorder is a chronic illness, defined by a succession of depressive and/or manic periods separated by free intervals. Its evolution with aging is marked by a high suicide mortality rate. Bipolar disorders raise the question of their evolution when the age of the subject, in particular with regard to their frequency, their clinical characteristics, their prognosis and their management. The evolution of bipolar disorder with aging poses several difficulties in clinical practice due to its underestimated frequency and its misleading presentation and in particular by the presence of sometimes significant cognitive alterations leading sometimes to dementia.
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Research Interests: Psychology, Randomization, Medicine, Humans, Low Dose, and 14 morePlacebo, Female, Male, Reaction Time, Anesthesia, Lorazepam, Sedation, Adult, Analysis of Variance, Reference Values, Clinical Psychopharmacology, Psychomotor Performance, Psychomotor Learning, and Pharmacology and pharmaceutical sciences
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Antidepressants regardless of the mechanism of action can cure only 70% of depressed patients. There is therefore a category of depression that is called resistant. The co-administration of antidepressants of a different nature can... more
Antidepressants regardless of the mechanism of action can cure only 70% of depressed patients. There is therefore a category of depression that is called resistant. The co-administration of antidepressants of a different nature can alleviate this deficit. However, it seems necessary to develop active drugs in the resistant depression to develop animal models or even experimental strategies. The purpose of this chapter is to suggest ways to develop new drugs that may be effective in the treatment of resistant depression. Animal models of depression have been developed with a focus on those likely to demonstrate useful drugs in resistant depression or associations. Genetic or pharmacological leads are also mentioned.
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Alcohol use disorder or alcoholism is characterized by uncontrollable alcohol use and intoxication, as well as a heightened state of anxiety after alcohol withdrawal. Ethanol-associated stimuli also drive the urge to drink by means of... more
Alcohol use disorder or alcoholism is characterized by uncontrollable alcohol use and intoxication, as well as a heightened state of anxiety after alcohol withdrawal. Ethanol-associated stimuli also drive the urge to drink by means of classical conditioning. Alcoholism has been considered a dopamine (DA) dysregulation syndrome that involves the activity of the central amygdala circuitry of anxiety. Cholecystokinin (CCK) is the most abundant neuropeptide in the mammal brain, where it activates two receptors, CCK1 and CCK2. Genetic evidence relates CCK1 receptors to alcoholism in humans. CCK2 activity has been associated with the onset of human anxiety. CCK modulates DA release in the nucleus accumbens (NAc) and it is expressed in the γ-aminobutyric acid (GABA)-expressing basket interneurons in the cerebral cortex. CCK interacts with serotonin (5-HT) neurotransmission through 5-HT3 receptors to regulate mesocorticolimbic pathways and with GABA to attenuate anxiety in the amygdala. Finally, CCK stimulates the release of orexins and oxytocin in the hypothalamus, two relevant hypothalamic neuropeptides involved in signaling satiety for ethanol and well-being respectively. Given the "dimmer-switch" function of endogenous CCK in the neurotransmission by 5-HT, DA, GABA, and glutamate in normal and pathological behaviors (Ballaz and Bourin, 2020), we hypothesize that CCK adjusts functioning of the reward and anxiety circuitries altered by ethanol. This review gathers data supporting this hypothesis, and suggests mechanisms underlying a role for endogenous CCK in alcoholism.
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Cholecystokinin (CCK), the most abundant brain neuropeptide, is involved in relevant behavioral functions like memory, cognition, and reward through its interactions with the opioid and dopaminergic systems in the limbic system. CCK... more
Cholecystokinin (CCK), the most abundant brain neuropeptide, is involved in relevant behavioral functions like memory, cognition, and reward through its interactions with the opioid and dopaminergic systems in the limbic system. CCK excites neurons by binding two receptors, CCK1 and CCK2, expressed at low and high levels in the brain, respectively. Historically, CCK2 receptors have been related to the induction of panic attacks in humans. Disturbances in brain CCK expression also underlie the physiopathology of schizophrenia, which is attributed to the modulation by CCK1 receptors of the dopamine flux in the basal striatum. Despite this evidence, neither CCK2 receptor antagonists ameliorate human anxiety nor CCK agonists have consistently shown neuroleptic effects in clinical trials. A neglected aspect of the function of brain CCK is its neuromodulatory role in mental disorders. Interestingly, CCK is expressed in pivotal inhibitory interneurons that sculpt cortical dynamics and the ...
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SummaryAs with other drugs it is necessary to look for changes induced by anxiolytics on vital signs, laboratory parameters and adverse events. In return, in a more specific way for anxiolytics, we will look at side effects at the central... more
SummaryAs with other drugs it is necessary to look for changes induced by anxiolytics on vital signs, laboratory parameters and adverse events. In return, in a more specific way for anxiolytics, we will look at side effects at the central nervous system level with psychological and physiological battery tests. We will also assess the safety of use of anxiolytics in certain specific conditions, such as overdose or withdrawal and in certain populations such as the elderly, neonates and children. The assessment of safety and side effects, whatever the drug type studied, must come early in the developing process of a drug (phases I, II and III).
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In this chapter, the authors Michel Bourin and Abdeslam Chagroui argue that the nonmedical use and abuse of prescription drugs is a serious public health problem. The abuse of certain prescription drugs—opioids, central nervous system... more
In this chapter, the authors Michel Bourin and Abdeslam Chagroui argue that the nonmedical use and abuse of prescription drugs is a serious public health problem. The abuse of certain prescription drugs—opioids, central nervous system (CNS) depressants, and stimulants—can lead to a variety of adverse health effects, including addiction. Prescription drug abuse is not a new problem, but one that deserves renewed attention. So medical drugs abuse is the best researched and understood field, with the highest level of regulation. The present chapter covers a wide range of sources of misuses and abuses including licit or illicit drugs as well as food and beverages and pathological behaviors.
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Antagonists of the norepinephrine reuptake and beta-adrenoreceptor agonists are potent, at once, on the three following tests: antagonism of hypothermia induced by reserpine, oxotremorine and apomorphine.... more
Antagonists of the norepinephrine reuptake and beta-adrenoreceptor agonists are potent, at once, on the three following tests: antagonism of hypothermia induced by reserpine, oxotremorine and apomorphine. 2-Carboxy-4-isopropenyl-3-pyrrolidine-acetic acid (kainic acid), which is a powerful stimulant of the neurons and a destroyer of the dopaminergic neurons, has been used in these tests to show if it is possible to antagonize hypothermia induced by different substances. The results obtained show that kainic acid is potent on these three tests, thus providing evidence that it is a stimulant of norepinephrine neurons as well as serotoninergic neurons, even if it is peripherically injected.
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Research Interests: Medicine, Humans, Child, Female, Pubmed, and 6 moreAged, Adult, Dental Care, Antipsychotic agents, Sedative, and Medical prescription
Depression is an incapacitating disease which needs appropriate treatment. This article reviews the pharmacology of antidepressant drugs and the future perspectives of treating mood disorders such as depression. The foremost theory for... more
Depression is an incapacitating disease which needs appropriate treatment. This article reviews the pharmacology of antidepressant drugs and the future perspectives of treating mood disorders such as depression. The foremost theory for explaining the biological basis of depression has been the monoamine hypothesis. Depression is due to a deficiency in one or other biogenic monoamines (serotonin, 5-HT; noradrenaline, NA; dopamine, DA). Antidepressant drugs are therefore classified according to their ability to improve monoaminergic transmission. Since this first theory, other explanations based on abnormal function of monoamine receptors or associated with impaired signalling pathways have been suggested. Notable progress has been accomplished in the treatment of major depressive disorders with new compounds recently discovered (selective serotonin reuptake inhibitors: SSRI; serotonin noradrenaline reuptake inhibitors: SNRI). Behavioural, electrophysiological and microdialysis studie...
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Bupropion, a novel antidepressant drug, is known to be a moderate hepatic metabolism‐inducer in rodents at high doses but not in young human volunteers. Eleven elderly depressed patients (mean age 76·9 ± 8·7 years) entered in the study... more
Bupropion, a novel antidepressant drug, is known to be a moderate hepatic metabolism‐inducer in rodents at high doses but not in young human volunteers. Eleven elderly depressed patients (mean age 76·9 ± 8·7 years) entered in the study and received 100 mg of bupropion t.i.d. for 28 days. An antipyrine test was performed before and at day 28 of therapy. Antipyrine was taken orally (15 mg/kg) at 8 a.m. and blood samples were drawn at 11 a.m., 2, 5, and 8 p.m. Plasma levels were assayed using a GLC method. Results show a slight but significant increase of apparent clearance (+30 per cent) and decrease in the half‐life (–14 per cent) of antipyrine. Difference between these results and previous results in young volunteers might be explained by the usual decrease of hepatic function described in elderly patients. Bupropion can be considered in elderly people as a slight hepatic enzyme‐inducer.
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Summary— The absorption of sodium valproate was studied in 5 rabbits: Each animal received the drug (70 mg/kg) via 3 routes: intravenous, gastric and duodenal. For the 2 extravascular routes, the absolute bioavailability F, maximal plasma... more
Summary— The absorption of sodium valproate was studied in 5 rabbits: Each animal received the drug (70 mg/kg) via 3 routes: intravenous, gastric and duodenal. For the 2 extravascular routes, the absolute bioavailability F, maximal plasma concentrations Cmax, times to peak Tmax and absorption coefficients Kabs were the same. Absolute bioavailability was always close to unity. This indicated that valproic acid was absorbed from the intestine as well as from the whole gastrointestinal tract. The other pharmacokinetic parameters such as terminal plasma half‐life, total clearance and volume of distribution remained unchanged whatever the route of administration.
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It appears that bipolar patients suffer from cognitive difficulties whereas they are in period of thymic stability. These intercritical cognitive difficulties are fairly stable and their severity is correlated with the functional outcome... more
It appears that bipolar patients suffer from cognitive difficulties whereas they are in period of thymic stability. These intercritical cognitive difficulties are fairly stable and their severity is correlated with the functional outcome of patients. Nevertheless, the profile of cognitive impairment varies significantly from study to study quantitatively and qualitatively. According to the studies, the authors find difficulties in terms of learning, verbal memory, visual memory, working memory, sustained attention, speed of information processing, functions executive. On the other hand, deficits of general intelligence, motor functions, selective attention, and language are not usually found. One of the reasons for the heterogeneity of results is the difficulty of exploring cognition in bipolar disorder. Many factors must be taken into account, such as the presence of residual mood symptoms, the longitudinal history of the disorder (age of onset, number of episodes due, among others...
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Objective: To examine the influence of pre-experimental stress on the anxiogenic-like action of caerulein, an agonist of cholecystokinin (CCK) receptors. Differences in the anxiety levels of rats in summer and winter, and the role of CCK... more
Objective: To examine the influence of pre-experimental stress on the anxiogenic-like action of caerulein, an agonist of cholecystokinin (CCK) receptors. Differences in the anxiety levels of rats in summer and winter, and the role of CCK in these behavioural alterations, were also examined. Design: Prospective animal study. Interventions: Male Wistar rats were injected with the CCK agonist caerulein, or the CCK antagonists L-365,260 or devazepide, after being exposed to pre-experimental stress (handling and isolation). Outcome measures: Performance in the plus-maze model of anxiety; serum levels of prolactin, thyrotropin and growth hormone; brain density and affinity of dopamine D2, serotonin 5-HT2 and CCK receptors. Results: Caerulein (5 micrograms/kg, subcutaneous injection) caused the strongest action in animals brought to the experimental room immediately before the experiment and kept in isolation after the administration of caerulein. Caerulein did not cause any reduction of exploratory activity in rats made familiar with the experimental room and kept in the home-cage after the injection of the CCK agonist. The anti-exploratory action of caerulein in stressed rats was reversed by the CCK antagonist L-365,260 (100 micrograms/kg, intraperitoneal injection), demonstrating the involvement of the CCKB receptor subtype. In addition, seasonal fluctuations occur in the exploratory activity of rats; such activity was much lower in July than in November. The rats displaying the reduced exploratory activity had an increased number of CCK receptors in the frontal cortex and hippocampus. Simultaneously, the density of serotonin 5-HT2 receptors in the frontal cortex, but not that of dopamine D2 receptors in the striatum, was elevated. The blood level of growth hormone was also higher in July. Conclusions: The anti-exploratory action of caerulein appears to be dependent on the pre-experimental stress of rats. Moreover, the seasonal variations of exploratory behaviour of rats are evident in the plus-maze model of anxiety. The reduced exploratory activity in summer appears to be related to the elevated density of CCK and 5-HT2 receptors in the brain.
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Various inhibitors of nitric oxide synthase (NOS) have been shown to possess antidepressant- and anxiolytic-like properties in animal models. The aim of this study was to compare the behavioural effects of NOS inhibitor 7-nitroindazole... more
Various inhibitors of nitric oxide synthase (NOS) have been shown to possess antidepressant- and anxiolytic-like properties in animal models. The aim of this study was to compare the behavioural effects of NOS inhibitor 7-nitroindazole (7-NI) with the more selective neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)imidazole (TRIM) in animal models predictive of antidepressant- and anxiolytic-like activity in order to clarify the role of distinct isoforms of NOS in the regulation of depression and anxiety. Both TRIM (50 mg/kg) and 7-NI (50 mg/kg) decreased the immobility time in the forced swimming test. The magnitude of the effect was comparable to that of the tricyclic antidepressant imipramine (15 mg/kg). The antidepressant-like effect of TRIM was counteracted by pretreatment with l-arginine (250 mg/kg). The systemic administration of TRIM (50 mg/kg), but not 7-NI (up to 50 mg/kg) increased the time spent in the light side of the apparatus in the light–dark compartment test. The anxiolytic-like effect of TRIM was antagonised by pretreatment with l-arginine. Both TRIM and 7-NI decreased the locomotion of animals in the open field and caused motor incoordination on rotarod. These motor side effects were more pronounced in the case of 7-NI and were not diminished by pretreatment with l-arginine. We conclude that neuronal NOS seems to play the key role in the antidepressant- and anxiolytic-like effects of NOS inhibitors.
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A new liquid-liquid extraction is described for thiopurine methyl transferase (TPMT, EC 2.1.1.67) activity determination: the use of a pH 9.5 NH4Cl buffer solution, before adding the solvent mixture, allows more rapid extraction, avoiding... more
A new liquid-liquid extraction is described for thiopurine methyl transferase (TPMT, EC 2.1.1.67) activity determination: the use of a pH 9.5 NH4Cl buffer solution, before adding the solvent mixture, allows more rapid extraction, avoiding a centrifugation step, and reduces the global cost of analysis. After the extraction step, 6-methylmercaptopurine, synthesised during the enzymatic reaction, is determined by a liquid chromatographic assay. Analytical performance of the assay was tested on spiked erythrocyte lysates. The linear concentration range was 5-250 ng ml(-1) (r> or =0.997, slope=1.497, intercept=-0.367). The recoveries were 82.8, 89.9 and 82.2% for 75, 125 and 225 ng ml(-1), respectively. The coefficients of variation were < or =6.1% for within-day assay (n=6) and < or =9.5% for between-day assay precision (n=6; 14 days). TPMT activity was determined in a French adult Caucasian population (7 =70). The results ranged from 7.8 to 27.8 nmol h(-1) ml(-1) packed red blood cells and the frequency distribution histogram is similar to that previously published.
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Research Interests: Open Access and Medicine
SummaryThe role of the neuropeptide cholecystokinin in schizophrenia has been widely explored because of its modulating action on midbrain dopamine neurons. The recent discovery of more specific receptor subtype cholecystokinin... more
SummaryThe role of the neuropeptide cholecystokinin in schizophrenia has been widely explored because of its modulating action on midbrain dopamine neurons. The recent discovery of more specific receptor subtype cholecystokinin antagonists should be considered as potential treatment for schizophrenia with fewer side effects. This paper reviews cholecystokinin/dopamine interactions in animal and human studies. Clinical trials with cholecystokinin agonists and antagonists in schizophrenia are updated.
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Norepinephrine (NE)-induced desensitization of the adrenergic receptor pathway may mimic the effects of hypoxia on cardiac adrenoceptors. The mechanisms involved in this desensitization were evaluated in male Wistar rats kept in a... more
Norepinephrine (NE)-induced desensitization of the adrenergic receptor pathway may mimic the effects of hypoxia on cardiac adrenoceptors. The mechanisms involved in this desensitization were evaluated in male Wistar rats kept in a hypobaric chamber (380 Torr) and in rats infused with NE (0.3 mg · kg−1 · h−1) for 21 days. Because NE treatment resulted in left ventricular (LV) hypertrophy, whereas hypoxia resulted in right (RV) hypertrophy, the selective hypertrophic response of hypoxia and NE was also evaluated. In hypoxia, α1-adrenergic receptors (AR) density increased by 35%, only in the LV. In NE, α1-AR density decreased by 43% in the RV. Both hypoxia and NE decreased β-AR density. No difference was found in receptor apparent affinity. Stimulated maximal activity of adenylate cyclase decreased in both ventricles with hypoxia (LV, 41%; RV, 36%) but only in LV with NE infusion (42%). The functional activities of Gi and Gs proteins in cardiac membranes were assessed by incubation wit...
Research Interests: Endocrinology, Biology, Hypoxia, Medicine, Biological Sciences, and 15 moreInternal Medicine, Anoxia, Chronic Disease, Animals, Male, Heart rate, Heart, Myocardium, Adenylate Kinase, Guanosine Triphosphate, Heart Ventricles, Gtp Binding Proteins, Isoproterenol, Medical and Health Sciences, and Cholera toxin
Eleven patients with panic disorder were challenged with cholecystokinin tetrapeptide (CCK-4) on two occasions. The effects of CCK-4 were consistent except symptom onset was more rapid with the second injection. Demonstrating that the... more
Eleven patients with panic disorder were challenged with cholecystokinin tetrapeptide (CCK-4) on two occasions. The effects of CCK-4 were consistent except symptom onset was more rapid with the second injection. Demonstrating that the effects of CCK-4 are reproducible in panic patients opens the doors for studies of the effects of drug treatment on CCK-4-induced panic.
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Efficacy and safety of agomelatine given orally compared to placebo, in addition to a mood stabiliser in bipolar I patients with a current major depressive episode. An eight week randomised, double-blind, controlled, parallel group study followed by a double-blind extension treatment period up to...more
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An isopropyl derivative of barbital (5,5-diethyl-2-(isopropyloxy)pyrimidine-4,6-dione, O2IB) was administered intraperitoneally 30 min before tests in mice. Former experimental investigations have shown that O2IB has an antidepressant... more
An isopropyl derivative of barbital (5,5-diethyl-2-(isopropyloxy)pyrimidine-4,6-dione, O2IB) was administered intraperitoneally 30 min before tests in mice. Former experimental investigations have shown that O2IB has an antidepressant psychopharmacological spectrum. It increases toxicity of yohimbine in mice at 175 mg/kg, antagonises from 50 mg/kg on hypothermia induced by a high dose of apomorphine and is active on the behavioural despair test at 125 mg/kg. These effects are those observed with classical antidepressants. Since phenytoin has an antidepressant profile in mice, carbamazepine is active on manic-depressive illness and beta-mimetic drugs are antidepressants, the question presents itself whether isopropylation or anticonvulsive activity is more important for the antidepressant psychopharmacological spectrum, or whether both are of equal importance.
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Bromide encephalopathies are frequently reported in Northern America and Great Britain. There is no characteristic clinical pattern, the neurological symptoms are multiple, this is readily explained by the diffusion of bromide ions to all... more
Bromide encephalopathies are frequently reported in Northern America and Great Britain. There is no characteristic clinical pattern, the neurological symptoms are multiple, this is readily explained by the diffusion of bromide ions to all regions in the central nervous system. An accurate history (bromide intake, followed by the slow onset of digestive and neuropsychiatric symptoms) as well as an apparent hyperchloremia are of the greatest aid in suggesting the diagnosis. The incidence of this type of intoxication is greater in women over 50. The association of a salt free diet to bromide therapy favors the onset of clinical symptoms because of the competition between bromide and chloride at the choroid plexus and at the renal tubule.
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The forced swimming test (FST) in mice has failed to predict antidepressant activity for drugs having beta adrenoreceptor agonist activity and for serotonin uptake inhibitors. We investigated the potential for clonidine to render the FST... more
The forced swimming test (FST) in mice has failed to predict antidepressant activity for drugs having beta adrenoreceptor agonist activity and for serotonin uptake inhibitors. We investigated the potential for clonidine to render the FST sensitive to antidepressants by using a behaviorally inactive dose of this agent (0.1 mg/kg). All antidepressants studied (tricyclics, 5-HT uptake inhibitors, iprindole, mianserin, viloxazine, trazodone) showed either activity at lower doses or activity at previously inactive doses. The effect appeared specific because it did not appear with drugs other than antidepressants (diazepam, chlorpromazine, sulpiride, atropine), except for amphetamine and apomorphine which have a strong effect on the dopaminergic system. The use of behaviorally subactive doses of clonidine may thus provide an important means of increasing the sensitivity of the forced swimming test.
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The behavioral and clinical profiles of various benzodiazepines after acute and chronic treatment are not well defined and may differ. The aim of this study was to evaluate the behavioral profiles of alprazolam, bromazepam, diazepam and... more
The behavioral and clinical profiles of various benzodiazepines after acute and chronic treatment are not well defined and may differ. The aim of this study was to evaluate the behavioral profiles of alprazolam, bromazepam, diazepam and lorazepam in mice after single and repeated (every half-life for seven half-lives) administrations using a stimulation-sedation test (actimeter), a myorelaxation test (rotarod), and an anxiolysis test ("four plates"). A dose range from 0.03 to 4 mg/kg was used. A single administration of alprazolam showed stimulating and anxiolytic effects which diminished after repeated administration. Lorezapam's sedative effect diminished but its anxiolytic effect increased upon repeated administration. Except for lorazepam, the myorelaxing effect of all four drugs increased after repeated treatment. These results suggest that the behavioral profile of benzodiazepines may not be identical during acute and chronic treatment. These differences may be p...
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ObjectivesTo apply the negative symptoms (NS) concept used in schizophrenia to patients with AD, to compare the results with the frontal lobe perfusion in ethyl cysteinate dimmer (ECD) single‐photon emission computed tomography (SPECT)... more
ObjectivesTo apply the negative symptoms (NS) concept used in schizophrenia to patients with AD, to compare the results with the frontal lobe perfusion in ethyl cysteinate dimmer (ECD) single‐photon emission computed tomography (SPECT) and with the apolipoprotein E genotype.Method32 patients with a diagnosis of probable AD were assessed by the Positive and Negative Symptoms Scale (PANSS‐N), the Montgomery and Asberg Depression Scale (MADRS), the NeuroPsychiatric Inventory (NPI), and the Mini‐Mental Status Examination (MMSE). Each patient underwent ECD SPECT and APO E genotyping. PANSS‐N, MADRS, NPI, and MMSE were administered to 19 normal elderly control subjects.ResultsThe mean PANSS‐N score for AD patients (20.56, SD: 8, range: 7–40) was significantly higher (p < 0.001) than that of controls (7, SD: 0). MADRS scores were not significantly different (p = 0.75) between AD patients (9.03, SD: 6.14, range: 0–25) and controls (6.2, SD: 3.61, range: 1–15). The NPI apathy score (0–12)...