[Neurobiology of addiction]. / Neurobiologie de l'addiction.

Several psychoactive drugs may induce addiction. Despite distinct pharmacological targets, all have the common property to stimulate the brain reward circuitry, which results in an increase of dopamine release in the nucleus accumbens. The stimulation induced by drugs of abuse is much more important in intensity and duration than the stimulation induced by natural rewards. The positive reinforcement resulting from this stimulation promotes repeated drug intake, which induces cellular and molecular adaptations in the brain reward circuit and other regions associated with this circuit. Enduring changes are more particularly observed in regions involved in pleasure, motivation, memory, conditioning, executive functions, judgement and self-control. A tolerance to the reinforcing effects of natural rewards is observed in parallel to a hypersensitivity to the motivational effects of drugs and drug-associated stimuli. Behaviour focuses more and more exclusively on drug research and drug consumption. Drug privation can induce a negative emotional state, withdrawal signs and craving which are key elements of relapse

[Principles of the pharmacological treatment of drug addiction]. / Principes du traitement pharmacologique de l'addiction.

Treatment of addiction is extremely eomplex Identification of neurobiological mechanisms involved in this disease has made it possible to identify interesting pharmacological targets in the reward circuit and regions associated with this circuit. Current treatments are based on interactions with the acute effects of the drug on dopaminergic transmission, on the reactivation of the reward circuit in the absence of drug, on the reduction of withdrawal symptoms, or on inter-Sactions with systems associated with the reward circuit. In these systems, neurotransmitters such as GABA, glutamate and endogenous opioids play a crucial role in the development of addiction. In this article, we focus on the pharmacological management of addiction to alcohol, nicotine and opiates.

[Pharmacological strategies in the modulation of central nervous system activity]. / Stratégies pharmacologiques de modulation de l'activité du système nerveux central.

There are multiple pharmacological targets in the central nervous system. After reviewing the synaptic physiology and the major neurotransmitter molecules, this article describes the main strategies used in neuropharmacology. The concept of specificity in the central nervous system is discussed, and allows a distinction between drugs according to the degree of specificity of their action. A catalogue of pharmacological targets is presented with therapeutic examples, and an emphasis on new agents having an original mechanism of action or acting on new targets.

Characterization of 4-(2-hydroxyphenyl)-1-[2'-[N-(2''-pyridinyl)-p-fluorobenzamido]ethyl]piperazine (p-DMPPF) as a new potent 5-HT1A antagonist.

BACKGROUND AND PURPOSE: The identification of potent and selective radioligands for the mapping of 5-HT receptors is interesting both for clinical and experimental research. The aim of this study was to compare the potency of a new putative 5-HT(1A) receptor antagonist, p-DMPPF, (4-(2-hydroxyphenyl)-1-[2'-[N-(2''-pyridinyl)-p-fluorobenzamido]ethyl]piperazine) with that of the well-known 5-HT(1A) antagonists, WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide) and its fluorobenzoyl analogue, p-MPPF (4-(2-methoxyphenyl)-1-[2'-[N-(2''-pyridinyl)-p-fluorobenzamido]ethyl]piperazine). EXPERIMENTAL APPROACH: Single cell extracellular recordings of dorsal raphe (DR) neurones were performed in rat brain slices. The potency of each compound at antagonizing the effect of the 5-HT(1A) agonist, 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)-tetraline], was quantified using the Schild equation. The pharmacological profile of p-DMPPF was defined using competition binding assays. KEY RESULTS: Consistently with a 5-HT(1A) receptor antagonist profile, incubation of slices with an equimolar (10 nM) concentration of each compound markedly reduced the inhibitory effect of 8-OH-DPAT on the firing rate of DR neurones, causing a significant rightward shift in its concentration-response curve. The rank order of potency of the antagonists was WAY-100635>p-DMPPF>or=p-MPPF. The sensitivity of DR neurones to the inhibitory effect of 8-OH-DPAT was found to be heterogeneous. The binding experiments demonstrated that p-DMPPF is highly selective for 5-HT(1A) receptors, with a K(i) value of 7 nM on these receptors. CONCLUSIONS AND IMPLICATIONS: The potency of the new compound, p-DMPPF, as a 5-HT(1A) antagonist is similar to that of p-MPPF in our electrophysiological assay. Its selectivity towards 5-HT(1A) receptors makes it a good candidate for clinical development.

Synthesis and biological evaluation of N-methyl-laudanosine iodide analogues as potential SK channel blockers.

Neuronal action potentials are followed by an afterhyperpolarisation (AHP), which is mediated by small conductance Ca2+-activated K+ channels (SK channels or KCa2 channels). This AHP plays an important role in regulating neuronal activity and agents modulating AHP amplitude could have a potential therapeutic interest. It was previously shown that N-methyl-bicuculline iodide blocks SK channels but its GABA) activity represents a serious drawback. In view of the structural analogy between bicuculline and laudanosine 14, several N-quaternary analogues of the latter were developed. It was shown that N-methyl-laudanosine 15 (NML) and N-ethyl-laudanosine 16 induce a reversible and relatively specific blockade of the apamin sensitive AHP in dopaminergic neurones with mean IC50s of 15, and 47 microM, respectively. Laudanosine 14, N-butyl-17 and N-benzyl-18 derivatives were less potent. In order to find pharmacophore elements, modifications were performed at different positions such as C-1, C-6 and C-7. Intracellular recordings on rat midbrain dopaminergic neurones were made in order to evaluate the putative blockade of SK channels by these molecules. Simplified structures such as tetrahydroisoquinoline derivatives with H or Me at C-1 1-6 presented no significant activity at 300 microM. The presence of a 1-(3,4-dimethoxybenzyl) moiety seems an important feature. Indeed, compound 8 showed a blockade of the AHP of only 33% at 300 microM while compound 13 blocked it by 67%, respectively, at the same concentration. Binding experiments were also performed. Binding affinities for SK channels are in good agreement with electrophysiological data. These results indicate that the presence of a charged nitrogen group is an essential point for the affinity on SK channels. Finally, because of the similar activity of both enantiomers of NML 19 and 20, the interaction site may present a symmetrical configuration.

A new approach to the qualitative evaluation of functional disability in dementia.

BACKGROUND: Dementia patients suffer from the progressive deterioration of cognitive and functional abilities. Instrumental disabilities usually appear in the earlier stages of the disease while basic disabilities appear in the more advanced stages. In order to differentiate between mild, moderate and severe patients both instrumental and basic functional disabilities should be taken into account simultaneously. OBJECTIVES: The objective of this study was to find a new method for classifying dementia patients based on their disabilities by using a basic and an instrumental Activities of Daily Living (ADL) scale. METHODS: Functional disability was assessed in a Belgian cohort of dementia patients using the Katz and Lawton Instrumental Activities of Daily Living (IADL) scales. A k-means derived clustering method allocated patients to disability clusters according to their Katz and Lawton scores. In order to validate the classification, we compared socio-demographic, clinical and costs parameters between the groups. RESULTS: The clustering method allocated patients between three clusters: dependent, non-dependent with instrumental functional disability (ND-IFD) and non-dependent. Dependence, as defined by these clusters, significantly correlates with age, residential setting, MMSE, patient's quality of life and costs. CONCLUSION: This new classification of patients suffering from dementia will provide better understanding of functional disabilities and will complement the evaluation of disease severity based on cognitive function.

[The measurement of sense of competence in caregivers of patients with dementia]. / La mesure du sentiment de compétence chez les aidants de patients déments.

BACKGROUND: In the context of a cohort study on the socio-economic consequences of dementia in Belgium, we evaluated the validity, reliability and feasibility of the French version of the Dutch Sense of Competence questionnaire (SCQ), and of its short version (the SSCQ), in caregivers of demented patients The questionnaire was based on Zarit's burden interview and on a theoretical family-crisis model. METHODS: Construct validity was evaluated by factor analysis and by comparison of the results with those of the original SCQ study. Reliability was evaluated by Cronbach's alpha and by item-total correlations. Feasibility was assessed by a standardized index of missing values. RESULTS: The three domains found in the original SCQ were identified by factor analysis: consequences of involvement in care for the personal life of the caregiver, satisfaction with one's own performance as a caregiver and satisfaction with the elderly person as a recipient of care. The mean scores were similar to those in the original study, except for the consequences for personal life. Cronbach's alpha for both the SCQ and the SSCQ exceeded the 0.70 criterion. Two of the 27 items did not meet the item-total correlation criterion; the SSCQ items all met the criterion. The standardised index of missing values was deemed acceptable. CONCLUSIONS: The French versions of the SCQ and the SSCQ are valid and reliable. Like the Dutch version, the French version of the SCQ can be a useful outcome measure for the evaluation of intervention studies and the SSCQ is suitable for the daily practice.

Cognitive impairment, dementia and quality of life in patients and caregivers.

OBJECTIVE: To study the impact of cognitive impairment and severity of dementia on the quality of life (QoL) of patients and their caregivers. DESIGN: Descriptive cross-sectional study within the NAtional Dementia Economic Study. SETTING: 231 general practices and 15 specialist clinics in Belgium. SUBJECTS: 605 patients aged > or = 65 years: 106 referent subjects without cognitive impairment (R), 113 subjects with cognitive impairment and no dementia (CIND), 386 subjects with mild (83), mild/moderate (108), moderate (62) or severe (133) dementia (D1 to D4). OUTCOME MEASURES: QoL of patients: COOP/WONCA charts, Katz's Activities of Daily Living (ADL) scale, Lawton's Instrumental Activities of Daily Living (IADL) scale. QoL of caregivers: COOP/WONCA charts, SF-36 questionnaire, short-form Beck Depression Inventory, Sense of Competence questionnaire (SCQ). MAIN RESULTS: QoL of patients: For R, CIND and D1 to D4 patients, dependence for ADL reached 5%, 6%, 16%, 20%, 48% and 79%, respectively, and mean IADL scores were 5.6, 5.0, 3.4, 2.0, 0.6 and 0.1, respectively. QoL of caregivers: The main impact of caregiving was on mental health, with SF-36 MCS scores of 51.3, 47.7 and 45.4 for R, CIND and all D patients and respectively 32.6%, 31.3% and 42.5% depression prevalence. Sense of competence decreased with severity of patient's cognitive impairment. Caregivers of CIND patients always rated intermediate between R and D1 patients. Caregivers of D3 patients were the most affected ones. CONCLUSION: The data suggest that improving the cognitive status of patients and providing assistance to caregivers would be complementary ways of action to support caregiving of patients living at home.

Modulation of small conductance calcium-activated potassium (SK) channels: a new challenge in medicinal chemistry.

Small conductance calcium-activated potassium (SK) channels are found in many types of neurons as well as in some other cell types. These channels are selective for K(+) and open when intracellular Ca(2+) rises to omega 500 nM. In neurons, this occurs during and after an action potential. Activation of SK channels hyperpolarizes the membrane, thus reducing cell excitability for several tens or hundreds of milliseconds. This phenomenon is called a afterhyperpolarization (AHP). Three subtypes of SK channels (SK1, SK2, SK3) have been cloned and exhibit a differential localization in the brain. SK channels may play a role in physiological and pathological conditions. They may be involved in the control of memory and cognition. Moreover, they are heavily expressed in the basal ganglia (in particular in the substantia nigra, pars compacta) and in the limbic system, suggesting that they may modulate motricity and emotional behaviour. Based on these facts, SK channel subtypes may be a suitable target for developing novel therapeutic agents, but more work is needed to validate these targets. Hence, there is a great need for selective ligands. Moreover, although the risk of peripheral side-effects for SK channel modulators appears to be low, some questions remain to be investigated. Currently, different molecules are known as SK channel modulators. Apamin is a very potent peptidic agent; it produces a strong blockade of these targets which is only very slowly reversible and it has limited selectivity. Dequalinium was found to be an effective blocker. Different chemical modulations on the dequalinium structure led to the discovery of highly potent bis-quinolinium derivatives such as UCL 1684. Other bis-(2-amino-benzimidazole) derivatives are in development. On the other hand, quaternary salts of bicuculline were reported to be effective in inhibiting AHPs. More recent developments on structurally-related molecules revealed that methyl-laudanosine is a new interesting tool for exploring SK channel pharmacology. Finally, a family of compounds has been shown to facilitate SK channel opening. Such compounds may be useful in treating disorders involving neuronal hyperexcitability.

The economic impact of dementia in Belgium: results of the National Dementia Economic Study (NADES).

OBJECTIVES: To estimate costs associated with dementia and its severity and to identify main cost determinants. DESIGN: One-year prospective cohort study. SETTING: 231 general practitioners (GPs) and 15 specialist clinics throughout Belgium. SUBJECTS: 605 patients aged > or = 65 years (219 referent patients, 218 demented patients at home and 168 demented patients in institution). OUTCOME MEASURES: Medical costs (visits to GPs/specialists, physiotherapy, hospitalisation, nursing, incontinence, medication) and non-medical costs (special equipment, services, professional help and caregiving). RESULTS: Total monthly costs amounted to 368.50 Euro dollar for referent patients, 445.56 Euro dollar for demented patients at home and 2301.7 Euro dollar for demented patients in institutions. Highest costs were measured in patients with severe dementia (556.88 Euro dollar at home, 2465.28 Euro dollar in institutions). In demented patients at home, 60% of costs were accounted for by the health system, with hospitalisation and medication being the main cost components (36% and 20%). In demented patients in institution, 46% of the costs were accounted for by the health system, with residential costs and nursing being the main cost components (42% and 32%). In multivariate covariance analysis, the main determinants of costs for demented patients at home were physical dependence and co-morbidity (neoplasm, cardiovascular disease). The adjusted difference between demented and referent patients was 25 Euro dollar per month. CONCLUSIONS: A large fraction of the costs observed in dementia is explained by the association of dementia with physical dependence, co-morbidity and need for caregiving. From an economic point of view, the results support the caring for patients at home.

[Recent progress in the pharmacology of hypnotics and anxiolytics]. / Progrès récents dans la pharmacologie des hypnotiques et anxiolytiques.

Recent studies on the respective contribution of GABAA receptor subunits in the various pharmacological effects of benzodiazepines suggest that the sedative and amnesic properties of diazepam are mediated by enhancement of gabaergic transmission in neurons expressing the alpha 1 subunit while the anxiolytic effect is selectively mediated by alpha 2 subunit. These findings suggest that a separation of the pharmacological properties of benzodiazepines is possible and that drugs with increased clinical specificity could be developed.

[Dementia in Belgium: prevalence in aged patients consulting in general practice]. / La démence en Belgique: taux de prévalence chez les sujets âgés consultant en médecine générale.

Early detection of dementia is an important element for the efficacy of therapies currently proposed to slow down disease progression. This detection mainly relies on general practitioners. In order to estimate the impact of dementia on health services, we have estimated from the data of the NAtional Dementia Economic Study (NADES) the prevalence rate of dementia in patients aged > or = 65 years living at home and consulting in general practice. The study population was based on the sampling of consecutive patients consulting a general practitioner, irrespective of the reason and location of the consultation. The diagnosis of dementia was based on the CAMDEX performed at home in patients presenting > or = 3 warning signs of dementia. The prevalence rate of dementia among 2.234 registered patients living at home was 14.3% (CI95: 12.6-16.0). In age groups 65-74, 75-84 and > or = 85 years, it was 7.0%, 17.5% and 18.5%, respectively, in men, and 6.1%, 15.8% and 25.2%, respectively, in women. The percentage of demented with mild, mild to moderate, moderate and severe dementia was 35.0%, 38.8%, 13.1% and 13.1%, respectively. After adjusting for the age and sex distribution of the Belgian population, the prevalence rate in patients aged > or = 65 years was estimated at 11.3%. A diagnosis of dementia had already been made by a specialist in 41.5% of patients with dementia, with figures of 19.3%, 34.3%, 41.9% and 60.9% according to the severity of disease (mild, mild to moderate, moderate, severe). The onset of first symptoms had preceded the diagnosis by an average of 1 year. Our results show a high prevalence rate of dementia in the elderly living at home consulting in general practice, and less than half of the patients had previously been diagnosed. It is possible that a systematic detection will not be performed as long as specific treatments are not made widely available.

The inclusion of fluoxetine into gamma-cyclodextrin increases its bioavailability: behavioral, electrophysiological and pharmacokinetic studies.

The inclusion of a drug into cyclodextrin generally results in the modification of its physical and chemical properties and sometimes can increase its oral bioavailability. The aim of this study was to compare the effects of the fluoxetine HCl/gamma-cyclodextrin complex to that of traditional fluoxetine HCl. In the forced swimming test in mice, fluoxetine HCl/gamma-cyclodextrin was more effective than fluoxetine HCl, the ED30s being, respectively, 9.5 and 16.9 mg/kg PO. Both compounds (10 mg/kg PO) were able to reduce the firing rate of dorsal raphe neurons in the rat. However, between-groups comparisons showed no significant differences between fluoxetine HCl treated animals and the vehicle group, while fluoxetine HCl/gamma-cyclodextrin appeared significantly more effective than vehicle from minute 25 of the measurement period. In healthy volunteers, the relative oral bioavailability, calculated as the ratio AUC 0-infinity fluoxetine HCl/gamma-cyclodextrin on AUC 0-infinity fluoxetine HCl (20 mg PO), was equal to 249.9%. The three experiments taken together suggest that the complexation of fluoxetine HCl into gamma-cyclodextrin increases its pharmacological efficacy in animals, this effect being related to an enhancement of its oral bioavailability as demonstrated in human healthy subjects.

Methodological issues in a cost-of-dementia study in Belgium: the NAtional Dementia Economic Study (NADES).

The NAtional Dementia Economic Study (NADES) is an on-going prospective, one-year cohort study developed in Belgium to assess the socio-economic consequences of dementia in a group of patients and their caregivers (n = 400). Comparison is made with a group of subjects with cognitive impairment and no dementia (n = 100) and a group of subjects without any cognitive impairment (n = 100). Recruitment of subjects is based on screening of warning signs of dementia by general practitioners, followed by a Cambridge Mental Disorders of the Elderly Examination (CAMDEX) performed at home. This paper presents an overview of the study protocol and the rationale for basic design options, such as the choice of study population, screening strategy, and methods used for the case validation. It also presents preliminary results on the prevalence of dementia in general practice, the sensitivity and specificity of the warning signs as a screening test of dementia, and the validity of a computerised case ascertainment algorithm based on DSM-III-R criteria.

Effects of JL 3, a putative antidepressant, on rat noradrenergic and serotonergic systems.

Using in vitro electrophysiological procedures, we confirm the inhibitory effect of 10-(4-methylpiperazin-1-yl)pyrido[4,3-b][1, 4]benzothiazepine (JL 3), on dorsal raphe serotonergic (IC(50)=14 microM) and noradrenergic neurons (IC(50)=4.5 microM). The effect on dorsal raphe neurons was reduced by N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl- cyclohexanecarboxamide (WAY-100635), suggesting the importance of 5-HT(1A) receptor stimulation. Yohimbine, and ritanserin, to a lesser extent, blocked the inhibitory effect of JL 3 on locus coeruleus neurons indicating that alpha(2)-adrenoceptors and 5-HT(2A) receptors may be implicated in the effects. Because of its negligible alpha(2)-adrenoceptor affinity, the effect of JL 3 on locus coeruleus neurons, would have to be indirect. JL 3 may interfere with the norepinephrine transporter site (IC(50)=0.34 microM). JL 3 tended to reinforce the hypertensive effect of norepinephrine, while it strongly inhibited the hypertensive effect of tyramine, further indicating an interaction at the norepinephrine transporter site level.

Spontaneous apamin-sensitive hyperpolarizations in dopaminergic neurons of neonatal rats.

Spontaneous apamin-sensitive hyperpolarizations in dopaminergic neurons of neonatal rats. J. Neurophysiol. 80: 3361-3364, 1998. Intracellular recordings from substantia nigra slices revealed the existence of spontaneous hyperpolarizations (amplitude 2-8 mV, duration 100-400 ms) at -60 mV in most dopaminergic neurons of neonatal (9-15 days) but not adult rats. These events were blocked by apamin (300 nM) and bicuculline methochloride (100-300 microM), which blocks apamin-sensitive currents. They were unaffected by the selective gamma-aminobutyric acid-A (GABAA) antagonists SR95531 (100 microM) and picrotoxin (30-50 microM), the GABAB antagonist CGP35348 (300 microM), the D2 antagonist haloperidol (1 microM), and the metabotropic antagonist MCPG (1 mM). The hyperpolarizations were strongly attenuated or abolished when recording electrodes contained 200 mM 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. They were resistant to tetrodotoxin in the majority of the cells. They had some voltage dependency and were in some cases transiently potentiated when cells were briefly depolarized by current injection. We conclude that dopaminergic neurons have developmentally regulated physiological properties. These spontaneous hyperpolarizations might affect the firing rate of these cells, which was found to be lower in neonates than in adults.

A quantitative pharmacological study of the cholinergic depolarization of hippocampal pyramidal cells in rat brain slices.

Intracellular recordings were performed in rat brain slices and the pharmacology of the depolarizing effect of cholinomimetic drugs on hippocampus CA1 pyramidal cells was quantitatively investigated. Acetylcholine (ACh) and muscarine induced a concentration-dependent depolarization of these cells. The EC50 values were respectively 159 +/- 54 microM and 0.7 +/- 0.15 microM. Physostigmine (1 microM) or tacrine (1 microM) induced a marked shift in the concentration-response curve for ACh. Both drugs were equipotent in this respect. The EC50 values for ACh became, respectively, 2.4 +/- 1.5 microM and 3 +/- 0.9 microM. The depolarizing effect of ACh was completely blocked by atropine, confirming the involvement of a receptor of the muscarinic type. In order to determine the subtype of muscarinic receptor involved, the EC50 values of muscarine were determined in the presence of atropine (100 nM), pirenzepine (1 microM) or AFDX116 (10 microM). The deduced pKB for the antagonists were, respectively, 8.9, 7.4 and 6.5. Comparison with binding data suggests that M1 receptors play a prominent role in the depolarizing effect of cholinomimetic drugs on CA1 pyramidal cells.

Evidence for a non-GABAergic action of quaternary salts of bicuculline on dopaminergic neurones.

Intracellular recordings were made from neurones, presumed to be dopaminergic, in the rat midbrain slice preparation. Bicuculline methiodide (BMI) and methochloride (BMC) reversibly blocked the slow, apamin-sensitive component of the afterhyperpolarization in these cells. The IC50 for this effect was about 26 microM. In comparison, BMC antagonized the input resistance decrease evoked by muscimol (3 microM) with an IC50 of 7 microM. The base of bicuculline was less potent in blocking the slow afterhyperpolarization. SR95531 (2-[carboxy-3'-propyl]-3-amino-6-paramethoxy-phenyl-pyridaziniu m bromide), another competitive GABA(A) antagonist, and picrotoxin, a non-competitive GABA(A) antagonist, also blocked the action of muscimol (IC50s: 2 and 12 microM respectively), but had no effect on the afterhyperpolarization at a concentration of up to 100 microM. Moreover, 100 microM SR95531 did not affect the blockade of the afterhyperpolarization by BMC. This blockade persisted in the presence of tetrodotoxin and was apparently not due to a reduction of calcium entry, suggesting that it involved a direct action on the channels which mediate this afterhyperpolarization. These results strongly suggest that quaternary salts of bicuculline act on more than one target in the central nervous system. Thus, the involvement of GABA(A) receptors in a given effect cannot be proven solely on the basis of its blockade by these agents.

Effect of potassium channel openers on the firing rate of hippocampal pyramidal cells and A10 dopaminergic neurons in vitro.

The effect of four KATP channel openers (KCOs) on the firing rate of CA1 pyramidal cells and A10 dopaminergic neurons was investigated using extracellular recording techniques in rat brain slices. Pinacidil, lemakalim, diazoxide and a new compound, BPDZ44, had an inhibitory effect on the electrical activity of CA1 pyramidal cells. They all had a similar potency. Only BPDZ44 and diazoxide inhibited the firing rate of A10 dopamine neurons. The sulfonylurea glipizide (1 microM) antagonized the effect of BPDZ44 and diazoxide on A10 neurons but failed to antagonize the effect of KCOs on CA1 pyramidal cells. These results show that differences exist among KCOs in their ability to decrease the electrical activity of various populations of central neurons.

Dibenzoazepine analogues: the electrophysiological properties of JL3, a potential atypical antidepressant.

JL3, 10-(4-methylpiperazin-1-yl)pyrido[4,3-b][1,4]benzothiazepine, has potent antidepressant-like activity in Porsolt's test in mice. Therefore, its influence on the electrical activity of central monoaminergic neurons was investigated in rats anaesthetized with chloral hydrate. JL3 induced a marked decrease of the firing rate of dorsal raphe serotonergic neurons (ID50 = 3.87 +/- 0.57 mg kg-1) and of locus coeruleus noradrenergic neurons (ID50 = 2.63 +/- 0.35 mg kg-1). The drug did not modify the electrical activity of A10 dopaminergic neurons. JL3 does not block amine uptake but it has affinity for 5-HT1A and 5-HT2 receptors. It is speculated that serotonergic mechanisms could play a role in the electrophysiological effects of JL3.