RÉSUMÉ
Fenethylline, also known by the trade name Captagon, is a synthetic psychoactive stimulant that has recently been linked to a substance-use disorder and 'pharmacoterrorism' in the Middle East. Although fenethylline shares a common phenethylamine core with other amphetamine-type stimulants, it also incorporates a covalently linked xanthine moiety into its parent structure. These independently active pharmacophores are liberated during metabolism, resulting in the release of a structurally diverse chemical mixture into the central nervous system. Although the psychoactive properties of fenethylline have been reported to differ from those of other synthetic stimulants, the in vivo chemical complexity it manifests upon ingestion has impeded efforts to unambiguously identify the specific species responsible for these effects. Here we develop a 'dissection through vaccination' approach, called DISSECTIV, to mitigate the psychoactive effects of fenethylline and show that its rapid-onset and distinct psychoactive properties are facilitated by functional synergy between theophylline and amphetamine. Our results demonstrate that incremental vaccination against a single chemical species within a multi-component mixture can be used to uncover emergent properties arising from polypharmacological activity. We anticipate that DISSECTIV will be used to expose unidentified active chemical species and resolve pharmacodynamic interactions within other chemically complex systems, such as those found in counterfeit or illegal drug preparations, post-metabolic tissue samples and natural product extracts.
Sujet(s)
Amfétamine/pharmacologie , Amphétamines/immunologie , Amphétamines/pharmacologie , Stimulants du système nerveux central/antagonistes et inhibiteurs , Stimulants du système nerveux central/pharmacologie , Fractionnement chimique/méthodes , Théophylline/analogues et dérivés , Théophylline/pharmacologie , Vaccins/immunologie , Amfétamine/composition chimique , Amfétamine/immunologie , Amfétamine/métabolisme , Amphétamines/antagonistes et inhibiteurs , Amphétamines/métabolisme , Animaux , Produits biologiques/composition chimique , Produits biologiques/immunologie , Produits biologiques/métabolisme , Produits biologiques/pharmacologie , Stimulants du système nerveux central/immunologie , Stimulants du système nerveux central/métabolisme , Cytochrome P-450 enzyme system/métabolisme , Synergie des médicaments , Haptènes/composition chimique , Haptènes/immunologie , Haptènes/pharmacologie , Hémocyanine/composition chimique , Hémocyanine/immunologie , Substances illicites/composition chimique , Substances illicites/immunologie , Substances illicites/métabolisme , Substances illicites/pharmacologie , Mâle , Souris , Phénéthylamines/analyse , Phénéthylamines/composition chimique , Théophylline/antagonistes et inhibiteurs , Théophylline/composition chimique , Théophylline/immunologie , Théophylline/métabolisme , Vaccins/pharmacologieRÉSUMÉ
Here we report that juxtacellular labeled GABA interneurons in the basolateral amygdaloid nucleus anterior part (BLA) of rats with 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) showed a more burst-firing pattern, while having no change in the firing rate. In sham-operated and the lesioned rats, systemic administration of 5-HT(2A/2C) receptor agonist DOI produced excitation, inhibition and unchanged in the firing rate of the interneurons, and the mean response of DOI was excitatory. However, cumulative dose producing excitation in the lesioned rats was higher than that of sham-operated rats. The local administration of DOI in the BLA also produced three types of responses in two groups of rats. Furthermore, the local administration of DOI excited the interneurons in sham-operated rats, whereas the mean firing rate of the interneurons in the lesioned rats was not affected at the same dose. The excitatory effect of the majority of the interneurons after systemic and local administration of DOI was not reversed by the selective 5-HT(2C) receptor antagonist SB242084, and the inhibitory effect of DOI in all the interneurons examined was reversed by GABA(A) receptor antagonist picrotoxinin. The SNc lesion in rats did not change the density of GAD67/5-HT(2A) receptor co-expressing neurons in the BLA. These results indicate that the SNc lesion changes the firing activity of BLA GABA interneurons. Moreover, DOI regulated the firing activity of the interneurons mainly through activation of 5-HT(2A) receptor, and the lesion led to a decreased response of the interneurons to DOI, which attributes to dysfunction of 5-HT(2A) receptor on these interneurons.
Sujet(s)
Amygdale (système limbique)/effets des médicaments et des substances chimiques , Amygdale (système limbique)/physiologie , Oxidopamine/toxicité , Récepteur de la sérotonine de type 5-HT2A/physiologie , Récepteur de la sérotonine de type 5-HT2C/physiologie , Potentiels d'action/effets des médicaments et des substances chimiques , Potentiels d'action/physiologie , Aminopyridines/pharmacologie , Amphétamines/administration et posologie , Amphétamines/antagonistes et inhibiteurs , Amphétamines/pharmacologie , Amygdale (système limbique)/métabolisme , Animaux , Antagonistes du récepteur GABA-A/pharmacologie , Neurones GABAergiques/effets des médicaments et des substances chimiques , Neurones GABAergiques/physiologie , Glutamate decarboxylase/biosynthèse , Indoles/pharmacologie , Interneurones/effets des médicaments et des substances chimiques , Interneurones/physiologie , Mâle , Microinjections , Oxidopamine/administration et posologie , Picrotoxine/analogues et dérivés , Picrotoxine/pharmacologie , Rats , Récepteur de la sérotonine de type 5-HT2A/biosynthèse , Récepteur de la sérotonine de type 5-HT2A/effets des médicaments et des substances chimiques , Récepteur de la sérotonine de type 5-HT2C/effets des médicaments et des substances chimiques , Agonistes des récepteurs 5-HT2 de la sérotonine/pharmacologie , Antagonistes des récepteurs 5-HT2 de la sérotonine/pharmacologie , Sesterterpènes , Substantia nigra/effets des médicaments et des substances chimiques , Substantia nigra/physiologieRÉSUMÉ
Harmine is a ß-carboline compound that targets glutamatergic, monoaminergic, and GABAergic pathways underlying drug addiction. We compared the efficacy of harmine against different psychoactive drugs using an invertebrate (planarian) assay designed to quantify 'C-shape' responses. Harmine itself (0.01-10 µM) did not produce C-shapes. However, when applied over the same concentration range, harmine significantly inhibited C-shapes elicited by cocaine, with a concentration of 0.1 µM producing almost 90% inhibition. Consistent with its putative actions, harmine produced a similar, though less efficacious, inhibition of C-shapes elicited by the substituted amphetamines methamphetamine and mephedrone (4-methylmethcathinone) but was much less effective against nicotine. When tested in the presence of the glutamate transporter inhibitor dihydrokainate (DHK) (0.1, 1 µM), harmine (0.1 µM) efficacy against cocaine-induced C-shapes was significantly reduced. Harmine also attenuated C-shapes elicited by N-methyl-d-aspartate (NMDA) and by glutamate itself. The present data suggest that harmine displays preferential efficacy against different addictive substances (cocaine>amphetamines>nicotine) and, at least for cocaine, is dependent on the glutamate system.
Sujet(s)
Cocaïne/antagonistes et inhibiteurs , Cocaïne/pharmacologie , Acide glutamique/physiologie , Harmine/pharmacologie , Inhibition psychologique , Psychoanaleptiques/antagonistes et inhibiteurs , Psychoanaleptiques/pharmacologie , Amphétamines/antagonistes et inhibiteurs , Amphétamines/pharmacologie , Animaux , Antagonistes des acides aminés excitateurs/pharmacologie , Acide kaïnique/analogues et dérivés , Acide kaïnique/pharmacologie , Nicotine/pharmacologie , Antagonistes nicotiniques/pharmacologie , PlanairesRÉSUMÉ
Two types of drugs are generally used for treating attention-deficit/hyperactivity disorder or attention-deficit disorder in humans: amphetamines or similar stimulants and the nonamphetamine atomoxetine. We describe the toxicity and treatment of both amphetamines and similar medications and atomoxetine in dogs and cats. Amphetamine intoxication can cause life-threatening stimulatory signs. Treatment is aimed at preventing absorption, controlling the stimulatory signs, and protecting the kidneys; prognosis is generally good. Atomoxetine also has a fast onset of action; stimulatory signs such as hyperactivity and tachycardia are often seen. There are little published data about treatment of atomoxetine toxicity in cats and dogs.
Sujet(s)
Inhibiteurs de la capture adrénergique/intoxication , Maladies des chats/thérapie , Stimulants du système nerveux central/intoxication , Maladies des chiens/thérapie , Inhibiteurs de la capture adrénergique/antagonistes et inhibiteurs , Amphétamines/antagonistes et inhibiteurs , Amphétamines/intoxication , Animaux , Chlorhydrate d'atomoxétine , Trouble déficitaire de l'attention avec hyperactivité/traitement médicamenteux , Maladies des chats/induit chimiquement , Maladies des chats/diagnostic , Chats , Stimulants du système nerveux central/antagonistes et inhibiteurs , Maladies des chiens/induit chimiquement , Maladies des chiens/diagnostic , Chiens , Humains , Centres antipoison/statistiques et données numériques , Propylamines/antagonistes et inhibiteurs , Propylamines/intoxicationRÉSUMÉ
RATIONALE: Overactivation of serotonin (5-hydroxytryptamine, 5-HT)(2A) receptors causes impulsivity and attentional deficits. Since 5-HT(2A) receptors are known to entertain antagonistic interactions with metabotropic glutamate (mGlu)2/3 receptors, this interaction may provide an alternative target for a novel class of antipsychotics. OBJECTIVES/METHODS: The study characterizes interactions between 5-HT(2A) and mGlu2/3 receptors implicated in impulse control. Hooded Lister rats were trained in a 5-choice serial reaction time task (5-CSRTT) and treated with the 5-HT(2A/2C) receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropan hydrochloride (DOI, 0.1 mg/kg) and the mGlu2/3 receptor agonist LY379268 (1 mg/kg). In addition, associated drug-induced changes in neuronal activity were assessed via c-Fos immunoreactivity (Fos IR), and co-localization of c-Fos and GABAergic markers was detected using double immunofluorescence labeling. RESULTS: Systemic DOI caused impulsive overresponding that was attenuated in animals pre-treated with LY379268. LY379268 itself had no significant effect on the rats' performance in the 5-CSRTT. DOI enhanced Fos IR within fronto-cortical and limbic brain structures, and this effect was blocked by LY379268 pre-treatment. Double immunofluorescence labeling showed a specific co-localization of DOI-elicited Fos IR with GABAergic (GAD(67)-positive) cells lacking the calcium-binding protein parvalbumin while LY379268 increased Fos IR in GABAergic and non-GABAergic cells. CONCLUSION: Our results suggest that impulsivity is possibly due to a primary increase in Glu transmission mediated via 5-HT(2A) receptor activation. Thus, mGlu2/3 receptor agonists might have some potential for treating motor impulsivity-related impairments while their cognitive enhancing effects were not confirmed in this study.
Sujet(s)
Acides aminés/pharmacologie , Amphétamines/antagonistes et inhibiteurs , Encéphale/physiologie , Composés hétérocycliques bicycliques/pharmacologie , Comportement impulsif/induit chimiquement , Comportement impulsif/traitement médicamenteux , Récepteurs métabotropes au glutamate/agonistes , Acides aminés/usage thérapeutique , Amphétamines/pharmacologie , Animaux , Lignées animales non consanguines , Encéphale/effets des médicaments et des substances chimiques , Composés hétérocycliques bicycliques/usage thérapeutique , Comportement de choix/effets des médicaments et des substances chimiques , Comportement de choix/physiologie , Neurones GABAergiques/effets des médicaments et des substances chimiques , Neurones GABAergiques/physiologie , Gènes fos/physiologie , Comportement impulsif/physiopathologie , Imagerie moléculaire/méthodes , Imagerie moléculaire/psychologie , Rats , Temps de réaction/effets des médicaments et des substances chimiques , Temps de réaction/physiologie , Apprentissage sériel/effets des médicaments et des substances chimiques , Apprentissage sériel/physiologie , Agonistes des récepteurs de la sérotonine/pharmacologie , Agonistes des récepteurs de la sérotonine/physiologieRÉSUMÉ
Serotonin 5-HT(2A) receptor activation improves viability, increases DNA synthesis and activates JAK2-STAT3 and MEK1/2-ERK1/2 signalling pathways in JEG-3 human trophoblast choriocarcinoma cells. The goal of this study was to characterize the signal transduction cascade involved in 5-HT(2A) receptor-induced growth of JEG-3 cells. Selective 5-HT(2A) receptor agonist, DOI, induced JEG-3 cell growth was inhibited by the inhibitor of JAK2 (AG490), MEK1/2 (U0126), phospholipase C-ß (PLC-ß; U73122) and protein kinase C-ß (PKC-ß; Gö6976)), whereas the selective phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002) had no effect. Specific inhibitors of PLC-ß, PKC-ß and Ras (farnesylthiosalicylic acid) inhibit activation of ERK1/2, whereas the PKC-ζ inhibitor GF109203X had no effect. Interestingly, inhibition of JAK2 prevented DOI-induced phosphorylation of ERK1/2 whereas inhibition of ERK1/2 pathway had no effect on DOI-induced activation of STAT3. Taken together, our results demonstrate that both the JAK2-STAT3 and PLC-ß-PKC-ß-Ras-ERK1/2 signalling pathways are involved in the stimulation of JEG-3 cell growth mediated by DOI. Moreover, this study shows that activation of JAK2 by the 5-HT(2A) receptor is essential to activate both STAT3 and ERK1/2 signalling pathways as well as to increase JEG-3 choriocarcinoma cell growth and survival.
Sujet(s)
Kinase Janus-2/métabolisme , Système de signalisation des MAP kinases/effets des médicaments et des substances chimiques , Récepteur de la sérotonine de type 5-HT2A/métabolisme , Facteur de transcription STAT-3/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Amphétamines/antagonistes et inhibiteurs , Butadiènes/pharmacologie , Carbazoles/pharmacologie , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Survie cellulaire/effets des médicaments et des substances chimiques , Choriocarcinome/métabolisme , Oestrènes/pharmacologie , Femelle , Humains , Nitriles/pharmacologie , Phosphatidylinositol 3-kinase/effets des médicaments et des substances chimiques , Phosphatidylinositol 3-kinase/métabolisme , Phospholipase C beta/antagonistes et inhibiteurs , Phosphorylation , Grossesse , Protéine kinase C/antagonistes et inhibiteurs , Protein kinase C beta , Pyrrolidones/pharmacologie , Transduction du signal/physiologie , Tyrphostines/pharmacologieRÉSUMÉ
Acute intermittent hypoxia (AIH) facilitates phrenic motor output by a mechanism that requires spinal serotonin (type 2) receptor activation, NADPH oxidase activity and formation of reactive oxygen species (ROS). Episodic spinal serotonin (5-HT) receptor activation alone, without changes in oxygenation, is sufficient to elicit NADPH oxidase-dependent phrenic motor facilitation (pMF). Here we investigated: (1) whether serotonin 2A and/or 2B (5-HT2A/B) receptors are expressed in identified phrenic motor neurons, and (2) which receptor subtype is capable of eliciting NADPH-oxidase-dependent pMF. In anesthetized, artificially ventilated adult rats, episodic C4 intrathecal injections (3×6 µl injections, 5 min intervals) of a 5-HT2A (DOI) or 5-HT2B (BW723C86) receptor agonist elicited progressive and sustained increases in integrated phrenic nerve burst amplitude (i.e. pMF), an effect lasting at least 90 min post-injection for both receptor subtypes. 5-HT2A and 5-HT2B receptor agonist-induced pMF were both blocked by selective antagonists (ketanserin and SB206553, respectively), but not by antagonists to the other receptor subtype. Single injections of either agonist failed to elicit pMF, demonstrating a need for episodic receptor activation. Phrenic motor neurons retrogradely labeled with cholera toxin B fragment expressed both 5-HT2A and 5-HT2B receptors. Pre-treatment with NADPH oxidase inhibitors (apocynin and diphenylenodium (DPI)) blocked 5-HT2B, but not 5-HT2A-induced pMF. Thus, multiple spinal type 2 serotonin receptors elicit pMF, but they act via distinct mechanisms that differ in their requirement for NADPH oxidase activity.
Sujet(s)
Potentiels d'action/physiologie , NADPH oxidase/physiologie , Nerf phrénique/physiologie , Récepteur de la sérotonine de type 5-HT2A/physiologie , Récepteur de la sérotonine de type 5-HT2B/physiologie , Acétophénones/administration et posologie , Acétophénones/pharmacologie , Potentiels d'action/effets des médicaments et des substances chimiques , Amphétamines/administration et posologie , Amphétamines/antagonistes et inhibiteurs , Amphétamines/pharmacologie , Animaux , Indoles/administration et posologie , Indoles/antagonistes et inhibiteurs , Indoles/pharmacologie , Injections rachidiennes , Kétansérine/administration et posologie , Kétansérine/pharmacologie , Mâle , NADPH oxidase/antagonistes et inhibiteurs , Composés onium/pharmacologie , Nerf phrénique/effets des médicaments et des substances chimiques , Nerf phrénique/enzymologie , Pyridines/pharmacologie , Rats , Rat Sprague-Dawley , Agonistes des récepteurs 5-HT2 de la sérotonine/administration et posologie , Agonistes des récepteurs 5-HT2 de la sérotonine/pharmacologie , Antagonistes des récepteurs 5-HT2 de la sérotonine/administration et posologie , Antagonistes des récepteurs 5-HT2 de la sérotonine/pharmacologie , Thiophènes/administration et posologie , Thiophènes/antagonistes et inhibiteurs , Thiophènes/pharmacologieRÉSUMÉ
Modulation of glutamatergic neurotransmission by metabotropic glutamate2/3 (mGlu2/3) receptor agonists effectively treats seemingly diverse neuropsychiatric illness such as generalized anxiety disorder and schizophrenia. Activation of adenosine A(1) heteroceptors, like mGlu2 autoreceptors, decreases glutamate release in the medial prefrontal cortex (mPFC) and other limbic brain regions. Previously, we have reported electrophysiological, neurochemical and behavioral evidence for interactions between the 5-hydroxytryptamine(2A) (5-HT(2A)) and mGlu2/3 receptors in the mPFC. The present studies were designed to investigate the effects in rats of adenosine A(1) receptor activation/blockade on a behavior modulated by 5-HT(2A) receptor activation/blockade in the mPFC: head shakes induced in the rat by phenethylamine hallucinogens. An adenosine A(1) receptor agonist, N(6)-cyclohexyladenosine (CHA) suppressed head shakes induced by activation of 5-HT(2A) receptors with the phenethylamine hallucinogen (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI). An adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), enhanced DOI-induced head shakes and blocked the suppressant action of an adenosine A(1) receptor agonist on DOI-induced head shakes. Thus, the pattern of activity for an agonist and antagonist at the adenosine A1 receptor with respect to modulating DOI-induced head shakes is similar to the pattern observed with mGlu2/3 receptor agonists and antagonists. These novel observations with an adenosine A(1) receptor agonist suggest that this pharmacological action could contribute to antipsychotic effects in addition to thymoleptic effects.
Sujet(s)
Agonistes du récepteur A1 à l'adénosine , Adénosine/analogues et dérivés , Amphétamines/antagonistes et inhibiteurs , Hallucinogènes/antagonistes et inhibiteurs , Mouvements de la tête/effets des médicaments et des substances chimiques , Agonistes des récepteurs de la sérotonine/toxicité , Adénosine/administration et posologie , Adénosine/pharmacologie , Antagonistes du récepteur A1 à l'adénosine , Amphétamines/administration et posologie , Amphétamines/toxicité , Animaux , Relation dose-effet des médicaments , Acide glutamique/métabolisme , Hallucinogènes/administration et posologie , Hallucinogènes/toxicité , Mouvements de la tête/physiologie , Injections péritoneales , Locomotion/effets des médicaments et des substances chimiques , Mâle , Activité motrice/effets des médicaments et des substances chimiques , Cortex préfrontal/métabolisme , Rats , Rat Sprague-Dawley , Récepteur A1 à l'adénosine/physiologie , Agonistes des récepteurs de la sérotonine/administration et posologie , Xanthines/administration et posologie , Xanthines/pharmacologieRÉSUMÉ
Behavioral and psychological symptoms of dementia (BPSD) are commonly seen in patients with Alzheimer's disease (AD) and other forms of senile dementia. BPSD have a serious impact on the quality of life of dementia patients, as well as their caregivers. However, an effective drug therapy for BPSD has not been established. Recently, the traditional Japanese medicine Yokukansan (YKS, Yi-gan san in Chinese) has been reported to improve BPSD in a randomized, single-blind, placebo-controlled study. Moreover, abnormalities of the serotonin (5-HT) system such as 5-HT2A receptors have been reported to be associated with BPSD of AD patients. In the present study, we investigated the effect of YKS on head-twitch response induced by 2,5-dimethoxy-4-iodoamphetamine (DOI, 5 mg/kg, i.p.) in mice, a behavioral response that is mediated, in part, by 5-HT2A receptors. Acute treatment with YKS (100 and 300 mg/kg, p.o.) had no effect on the DOI-induced head-twitch response, whilst 14 days repeated treatment with YKS (300 mg/kg, p.o.) significantly inhibited this response. Moreover, repeated treatment with YKS (300 mg/kg, p.o.) decreased expression of 5-HT2A receptors in the prefrontal cortex, which is part of the circuitry mediating the head-twitch response. These findings suggest that the inhibition of DOI-induced head-twitch response by YKS may be mediated, in part, by altered expression of 5-HT2A receptors in the prefrontal cortex, which suggests the involvement of the 5-HT system in psychopharmacological effects of YKS.
Sujet(s)
Amphétamines/antagonistes et inhibiteurs , Amphétamines/toxicité , Comportement animal/effets des médicaments et des substances chimiques , Démence/induit chimiquement , Démence/psychologie , Médicaments issus de plantes chinoises/pharmacologie , Cortex préfrontal/effets des médicaments et des substances chimiques , Cortex préfrontal/métabolisme , Récepteur de la sérotonine de type 5-HT2A/biosynthèse , Agonistes des récepteurs de la sérotonine/toxicité , Amphétamines/administration et posologie , Animaux , Technique de Western , Catalepsie/induit chimiquement , Catalepsie/psychologie , Relation dose-effet des médicaments , Médicaments issus de plantes chinoises/administration et posologie , Hypothalamus/effets des médicaments et des substances chimiques , Hypothalamus/métabolisme , Mâle , Souris , Microinjections , Activité motrice/effets des médicaments et des substances chimiques , Équilibre postural/effets des médicaments et des substances chimiques , Performance psychomotrice/effets des médicaments et des substances chimiques , Récepteur de la sérotonine de type 5-HT2A/effets des médicaments et des substances chimiques , Agonistes des récepteurs de la sérotonine/administration et posologieRÉSUMÉ
We recently found that rats' ability to discriminate durations of exteroceptive stimuli is disrupted by the non-selective 5-HT receptor agonist quipazine. Ketanserin reversed this effect, suggesting that the effect may be mediated by 5-HT2A receptors. Here, we report that the 5-HT2A/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) also disrupts temporal discrimination, and that this effect can be reversed by ketanserin and the highly selective 5-HT2A receptor antagonist (+/-)2,3-dimethoxyphenyl-1-[2-(4-piperidine)-methanol] (MDL-100907). Twenty rats were trained to discriminate durations in a discrete-trials psychophysical procedure. In each 50-s trial, a light was presented for t seconds, following which two levers (A and B) were presented. A response on A was reinforced if t < 25 s, and a response on B if t > 25 s. Logistic psychometric curves were fitted to the proportional choice of B (%B) for derivation of timing indices [T50: time corresponding to %B = 50; Weber fraction: (T75-T25)/2T50, where T75 and T25 are times corresponding to %B = 75 and 25, respectively]. DOI 0.25 mg kg (subcutaneous) significantly increased the Weber fraction and tended to increase T50. Ketanserin 2 mg kg (subcutaneous) did not alter either parameter, but completely antagonized the effects of DOI. Similarly, MDL-100907 0.5 and 1 mg kg (intraperitoneal) did not affect performance, but completely antagonized the effects of DOI. The results indicate that the mixed 5-HT2A/2C receptor agonist DOI disrupts temporal discrimination via stimulation of 5-HT2A receptors.
Sujet(s)
Amphétamines/pharmacologie , Apprentissage discriminatif/effets des médicaments et des substances chimiques , Fluorobenzènes/pharmacologie , Kétansérine/pharmacologie , Pipéridines/pharmacologie , Récepteur de la sérotonine de type 5-HT2A/effets des médicaments et des substances chimiques , Antisérotonines/pharmacologie , Agonistes des récepteurs de la sérotonine/pharmacologie , Perception du temps/effets des médicaments et des substances chimiques , Amphétamines/antagonistes et inhibiteurs , Animaux , Apprentissage associatif/effets des médicaments et des substances chimiques , Encéphale/effets des médicaments et des substances chimiques , Femelle , Injections péritoneales , Injections sous-cutanées , Psychophysique , Rats , Rat Wistar , Récepteur de la sérotonine de type 5-HT2C/effets des médicaments et des substances chimiquesRÉSUMÉ
The synthesis and pharmacological evaluation of cis- and trans-6-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ols 4a-c and 5a-c and cis- and trans-4-amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ols 4d-f and 5d-f were carried out. Chemo- and stereoselective synthesis of 5a-f was achieved by reduction of corresponding alpha-amino ketones 3a-f with LiAl(t-BuO)3H. cis-4-Amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ol 4d and trans-4-amino-2,3,4,5-tetrahydro-1-benzoxepin-5-ol 5d exhibited marked anorexigenic activity in mice at a dose of LD50 800 and 500 mg/kg and ED50 75 and 55 mg/kg, respectively, while the analog cis-2,3-dihydroxy-6-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol 8 showed typical alpha-sympathomimetic activity.
Sujet(s)
Anorexigènes/synthèse chimique , Benzocycloheptènes/pharmacologie , Benzoxépinne/pharmacologie , Sympathomimétiques/synthèse chimique , Amphétamines/antagonistes et inhibiteurs , Animaux , Anorexigènes/administration et posologie , Anorexigènes/pharmacologie , Benzocycloheptènes/administration et posologie , Benzocycloheptènes/synthèse chimique , Benzoxépinne/administration et posologie , Benzoxépinne/synthèse chimique , Pression sanguine/effets des médicaments et des substances chimiques , Relation dose-effet des médicaments , Antagonisme des médicaments , Souris , Obésité/traitement médicamenteux , Stéréoisomérie , Sympathomimétiques/administration et posologie , Sympathomimétiques/pharmacologieRÉSUMÉ
RATIONALE: Recently, Delta(9)-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, and synthetic cannabinoid receptor agonists reportedly reduced the head-twitches induced by the 5-HT(2A/2C) receptor agonist 1-(2,5-dimethoxy 4-iodophenyl)-2-amino propane (DOI) in mice, which is mediated via the activation of 5-HT(2A) receptor. However, the effect of endogenous cannabinoid anandamide on the head-twitch response has not been studied. OBJECTIVES: In this study, we investigated the effect of anandamide on the DOI-induced head-twitch response in mice. METHODS: Five minutes after the injection of DOI (5 mg/kg IP), the number of head-twitches was counted for a 5-min period. THC or anandamide was injected IP 60 min or 10 min before the number of head-twitches was counted, respectively. RESULTS: THC and anandamide each reduced the DOI-induced head-twitch response. The inhibition of the DOI-induced head-twitch response by THC was reversed by SR141716A (N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide), a CB(1) receptor antagonist, while the effect of anandamide was not blocked by SR141716A. Cyclooxygenase (COX) inhibitors such as aspirin and indomethacin reversed the inhibition of the DOI-induced head-twitch response by anandamide. On the other hand, COX inhibitors did not affect the inhibition of the DOI-induced head-twitch response by THC. CONCLUSIONS: Taken together, these findings suggest that the endocannabinoid anandamide may inhibit 5-HT(2A) receptor-mediated function via the arachidonic acid cascade, but not via a direct interaction with the CB(1) cannabinoid receptor, and that the mechanism of its action is clearly different from that of THC.
Sujet(s)
Amphétamines/administration et posologie , Amphétamines/antagonistes et inhibiteurs , Acides arachidoniques/pharmacologie , Mouvements de la tête/effets des médicaments et des substances chimiques , Animaux , Relation dose-effet des médicaments , Endocannabinoïdes , Mouvements de la tête/physiologie , Mâle , Souris , Amides gras polyinsaturés N-alkylésRÉSUMÉ
Tourette syndrome (TS) is a neurological disorder characterized by persistent motor and phonic tics. Administration of the selective 5-HT(2A/2C) agonist 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) induces head twitches in mice that have been proposed to model tics seen in TS. Previous studies have demonstrated that nicotine markedly attenuates DOI-induced head twitch response (HTR). This and the reports that nicotine may have clinical efficacy in reducing symptoms of TS suggest possible involvement of the nicotinic cholinergic system in this disorder. Donepezil is an acetylcholinesterase inhibitor approved for use in mild to moderate Alzheimer's disease. The purpose of this study was to investigate whether donepezil might also reduce DOI-induced HTR, and whether its combination with nicotine might result in an additive or synergistic effect. Moreover, to elucidate the possible role of nicotinic receptors in this paradigm, the effects of mecamylamine, a nicotinic antagonist, was also evaluated. Acute and chronic administration of donepezil (0.1 mg/kg) or nicotine (0.5 mg/kg base), significantly reduced DOI-induced HTR. No additive or synergistic effects of donepezil and nicotine were observed. Acute mecamylamine administration (0.5-5.0 mg/kg) dose-dependently inhibited DOI-induced HTR. None of the mecamylamine doses blocked the inhibitory effects of donepezil or nicotine on DOI-induced HTR. These results suggest that donepezil may have therapeutic potential in treating motor tic symptoms of TS. Moreover, the action of donepezil and nicotine may be mediated through the same mechanism.
Sujet(s)
Amphétamines/antagonistes et inhibiteurs , Mouvements de la tête/effets des médicaments et des substances chimiques , Indanes/pharmacologie , Nootropiques/pharmacologie , Pipéridines/pharmacologie , Agonistes des récepteurs de la sérotonine/pharmacologie , Tics/induit chimiquement , Tics/prévention et contrôle , Syndrome de Tourette/traitement médicamenteux , Amphétamines/pharmacologie , Animaux , Donépézil , Synergie des médicaments , Mâle , Mécamylamine/pharmacologie , Souris , Souris de lignée ICR , Nicotine/pharmacologie , Agonistes nicotiniques/pharmacologie , Antagonistes nicotiniques/pharmacologie , Facteurs temps , Syndrome de Tourette/psychologieRÉSUMÉ
YM992 [(S)-2-[[(7-fluoro-4-indanyl)oxy]methyl]morpholine monohydrochloride] is a selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) and a potent 5-HT(2A) antagonist. The aim of the present study was to assess, using in vivo extracellular unitary recordings, the effect of acute and sustained administration of YM992 (40 mg kg(-1) day(-1) s.c., using osmotic minipumps) on the spontaneous firing activity of locus coeruleus (LC) norepinephrine (NE) neurons. Acute intravenous injection of YM992 (4 mg kg(-1)) significantly decreased NE neuron firing activity by 29% and blocked the inhibitory effect of a subsequent injection of the 5-HT(2) agonist DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride]. A 2-day treatment with YM992 decreased the firing rate of NE neurons by 66%, whereas a partial recovery was observed after a 7-day treatment and a complete one after a 21-day treatment. Following the injection of the alpha(2)-adrenoceptor antagonist idazoxan (1 mg kg(-1) i.v.), NE neuron firing was equalized in controls and 2-day YM992-treated rats. This put into evidence an increased degree of activation of alpha(2)-adrenergic autoreceptors in the treated rats. The suppressant effect of the alpha(2)-adrenoceptor agonist clonidine was significantly decreased in long-term YM992-treated rats. The recovery of LC firing activity after long-term YM992 administration could thus be explained by a decreased sensitivity of alpha(2)-adrenergic autoreceptors. Sustained SSRI administration leads to a gradual reduction of the firing activity of NE neurons during long-term administration, whereas YM992 produced opposite effects. The exact basis for the increased synaptic availability of NE by YM992 remains to be elucidated. This NE activity, resulting from 5-HT reuptake inhibition plus 5-HT(2A) receptor antagonism, might confer additional benefits in affective and anxiety disorders.
Sujet(s)
Neurones/effets des médicaments et des substances chimiques , Norépinéphrine/physiologie , Récepteurs sérotoninergiques/effets des médicaments et des substances chimiques , Inbiteurs sélectifs de la recapture de la sérotonine/pharmacologie , Antisérotonines/pharmacologie , 7-Dipropylamino-5,6,7,8-tétrahydro-1-naphtol/pharmacologie , Agonistes alpha-adrénergiques/pharmacologie , Antagonistes alpha-adrénergiques/pharmacologie , Amphétamines/antagonistes et inhibiteurs , Amphétamines/pharmacologie , Animaux , Clonidine/pharmacologie , Électrophysiologie , Idazoxan/pharmacologie , Mâle , Morpholines/pharmacologie , Rats , Rat Sprague-Dawley , Récepteur de la sérotonine de type 5-HT2A , Agonistes des récepteurs de la sérotonine/pharmacologieRÉSUMÉ
It has been suggested that metabotropic glutamate (mGlu) receptor agonists selective for Group II mGlu receptors may have antipsychotic action. Therefore, we studied whether the effects, which could be related to psychotomimetic action of hallucinogenic drugs, are inhibited by Group II mGlu receptor agonists. The selective mGlu2/3 agonists LY354740 and LY379268 inhibited (+/-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head twitches in mice in a dose-dependent manner. Furthermore, LY379268 suppressed an increase in the frequency of spontaneous excitatory synaptic potentials induced by bath-applied DOI in layer V pyramidal cells recorded in the murine medial frontal cortex. The data indicate that Group II mGlu receptor agonists may counteract the effects of hallucinogenic drugs.
Sujet(s)
Amphétamines/antagonistes et inhibiteurs , Amphétamines/pharmacologie , Comportement animal/effets des médicaments et des substances chimiques , Agonistes des acides aminés excitateurs/pharmacologie , Récepteurs métabotropes au glutamate/agonistes , Agonistes des récepteurs de la sérotonine/pharmacologie , Acides aminés/pharmacologie , Animaux , Composés bicycliques pontés/pharmacologie , Composés hétérocycliques bicycliques/pharmacologie , Électrophysiologie , Potentiels post-synaptiques excitateurs/effets des médicaments et des substances chimiques , Mâle , Souris , Techniques de patch-clamp , Cortex préfrontal/cytologie , Cortex préfrontal/effets des médicaments et des substances chimiques , Cellules pyramidales/effets des médicaments et des substances chimiquesRÉSUMÉ
The feeding effects of 5-hydroxytryptamine (5-HT)(1) and 5-HT(2) receptor agonists injected into the hypothalamic paraventricular nucleus (PVN) immediately prior to PVN administration of neuropeptide Y (NPY) were examined. The impact of these same compounds on NPY-induced alterations in energy metabolism was also assessed in an attempt to characterize further the potential interactive relationship of PVN NPY and 5-HT on feeding and whole body calorimetry. Specifically, several experiments examined the effect of various 5-HT receptor agonists on NPY-stimulated eating and alterations in energy substrate utilization [respiratory quotient (RQ)]. This included the 5-HT(1A) receptor agonist 8-OH-DPAT, the 5-HT(1B/1A) agonist RU 24969, the 5-HT(1D) agonist L-694,247, the 5-HT(2A/2C) agonist DOI, the 5-HT(2B) agonist BW 723C86 and the 5-HT(2C) agonist mCPP. In feeding tests conducted at the onset of the dark cycle, drugs were administered 5 min prior to PVN injection of NPY and food intake was measured 2 h postinjection. The metabolic effects of NPY following a similar pretreatment were monitored using an open-circuit calorimeter measuring the volume of oxygen consumed (VO(2)), carbon dioxide produced (VCO(2)) and RQ (VCO(2)/VO(2)). PVN injection of NPY (100 pmol) potentiated feeding and evoked reliable increases in RQ. Only DOI (2.5--5 nmol) pretreatment antagonized NPY-induced eating and blocked the peptide's effect on energy substrate utilization. Direct PVN pretreatment with spiperone (SPRN), a 5-HT(2A) receptor antagonist, and ketanserin (KTSN), a 5-HT(2A/2C) antagonist, but not SDZ SER 082, a 5-HT(2B/2C) antagonist, or the 5-HT(2C) antagonist RS 102221, blocked the effect of DOI in both feeding and metabolic tests providing additional evidence that activation of PVN 5-HT(2A) receptors inhibits NPY's action on feeding and substrate utilization.
Sujet(s)
Consommation alimentaire/effets des médicaments et des substances chimiques , Métabolisme énergétique/effets des médicaments et des substances chimiques , Neuropeptide Y/pharmacologie , Noyau paraventriculaire de l'hypothalamus/physiologie , Agonistes des récepteurs de la sérotonine/pharmacologie , Sérotonine/physiologie , Amphétamines/antagonistes et inhibiteurs , Amphétamines/pharmacologie , Animaux , Mâle , Neuropeptide Y/antagonistes et inhibiteurs , Consommation d'oxygène/effets des médicaments et des substances chimiques , Rats , Rat Sprague-Dawley , Récepteur de la sérotonine de type 5-HT2C , Récepteurs sérotoninergiques/effets des médicaments et des substances chimiques , Récepteurs de la sérotonine de type 5-HT1 , Antisérotonines/pharmacologie , Activation chimiqueRÉSUMÉ
Serotonin, in addition to dopamine and other factors, is known to participate in the control of prolactin (PRL) and gonadotropins secretion. Isoteoline (IST), a putative serotonin antagonist and dopamine agonist, was studied for its neuroendocrine effects on PRL, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). IST was given intraperitoneally to adult male rats at doses of 0.25, 1 and 4 mg kg(-1)alone and 30 min prior to the injection of three 5-HT agonists with preferential affinity for various receptor subtypes: meta -chlorophenylpiperazine (m CPP) for 5-HT2C; 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) for 5-HT2A and 8-hydroxy-2-(di- n -propylamino)tetralin (8-OH-DPAT) for 5-HT1A. m CPP (2.5 mg kg(-1)), DOI (2.5 mg kg(-1)) and 8-OH-DPAT (1 mg kg(-1)) increased the serum PRL levels to a similar value, without affecting FSH and LH concentrations. IST by itself modified neither PRL nor gonadotropins serum levels. IST antagonized the m CPP-induced elevation in serum PRL, the lowest dose being the most effective. It had no effect on DOI and 8-OH-DPAT-induced increases of PRL levels and produced no significant changes in the gonadotropins levels when used as an antagonist. The results are discussed in terms of the likely involvement of serotonin vs dopamine mechanism in the effect of IST. It is concluded that the inhibition of the m CPP-induced rise of PRL levels by IST confirmed the serotonin antagonistic activity, previously demonstrated for this compound in other studies. The present results are also suggestive of possible selectivity of this antagonism of IST for the 5-HT2C vs 5-HT2A and 5-HT1A receptors, all of which are involved in the control of PRL secretion.
Sujet(s)
7-Dipropylamino-5,6,7,8-tétrahydro-1-naphtol/antagonistes et inhibiteurs , Amphétamines/antagonistes et inhibiteurs , Aporphines/pharmacologie , Pipérazines/antagonistes et inhibiteurs , Prolactine/sang , Antisérotonines/pharmacologie , Animaux , Hormone folliculostimulante/sang , Hormone lutéinisante/sang , Mâle , Rats , Rat WistarRÉSUMÉ
Quinolinic acid, a metabolite of tryptophan in the kynurenine pathway, inhibited the 5-HT(2A/2C) direct agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino propane hydrochloride (DOI) induced head shakes in mice in a dose-dependent manner. This effect was observed 10 min after intracerebroventricular (i.c.v.) administration of 0.0625-1 microg/mouse. 3-Hydroxyanthranilic acid, which is the immediate stable precursor of quinolinic acid in the kynurenine pathway, showed a similar effect 60-120 min after subcutaneous (s.c.) administration, without showing any effect 10 min after i.c.v. administration or 20-40 min after s.c. administration. These observations suggest that quinolinic acid can alter central effects mediated via 5-HT2A receptors.
Sujet(s)
Amphétamines/antagonistes et inhibiteurs , Mouvements de la tête/effets des médicaments et des substances chimiques , Acide quinolinique/pharmacologie , Réflexe/effets des médicaments et des substances chimiques , Agonistes des récepteurs de la sérotonine/pharmacologie , Acide 3-hydroxy-anthranilique/pharmacologie , Amphétamines/pharmacologie , Animaux , Relation dose-effet des médicaments , Injections ventriculaires , Injections sous-cutanées , Cynurénine/métabolisme , Mâle , Souris , Récepteur de la sérotonine de type 5-HT2A , Récepteurs sérotoninergiques/effets des médicaments et des substances chimiquesRÉSUMÉ
The purpose of this study was to determine if (+/-)-1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced wet dog shakes (WDS) required the involvement of nitric oxide synthases (NOS). Systemic administration of the general NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME), but not its d-isomer, and the neuronal NOS (nNOS) inhibitor 7-nitroindazole completely blocked DOI-mediated WDS in a dose dependent manner. The data provides evidence that serotonin 5HT2 receptors are coupled to nNOS activation in the rat brain.
Sujet(s)
Amphétamines/antagonistes et inhibiteurs , Comportement animal/effets des médicaments et des substances chimiques , Antienzymes/pharmacologie , Nitric oxide synthase/antagonistes et inhibiteurs , Agonistes des récepteurs de la sérotonine/toxicité , Amphétamines/toxicité , Animaux , Indazoles/pharmacologie , Isoenzymes/antagonistes et inhibiteurs , Isoenzymes/métabolisme , Mâle , L-NAME/pharmacologie , Nitric oxide synthase type I , Rats , Rat Sprague-DawleyRÉSUMÉ
The 5-HT2A and 5-HT2C antagonists MDL 100,907 and SER-082 were tested with the 5-HT2A/C agonist DOI and the 5-HT1A/2A/2C agonist LSD in the Behavioral Pattern Monitor, which provides multiple measures of locomotor and investigatory activity. Previous investigations have shown that these measures load onto three independent behavioral factors: amount of activity, exploratory behavior, and behavioral organization. Rats pretreated with saline, MDL 100,907 (0.25-2.0 mg/kg), or SER-082 (0.5-1.0 mg/kg) were treated with saline, 0.25 mg/kg DOI, or 60 micrograms/kg LSD. All effects of DOI were blocked by all doses of MDL 100,907, but only by the highest dose of SER-082. While the effects of LSD on activity and exploratory behavior were largely unaffected, either pretreatment antagonized the effects of LSD on behavioral organization. Thus, all of these effects of DOI were attributable to 5-HT2A receptors, whereas the effect of LSD on behavioral organization was influenced by both 5-HT2A and 5-HT2C receptors.