RESUMEN
The dopamine D(1) receptor agonist dihydrexidine (DHX) [(±)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a] phenanthridine hydrochloride] has shown efficacy in animal models of Parkinson's disease and improved cerebral blood flow and working memory of schizophrenic patients. Although the discriminative stimulus effects of DHX, an in-vivo predictor of human subjective effect profile, have only been characterized with respect to activity at D(1) receptors, DHX also has significant affinity for D(2) receptors. This study was designed to characterize the role of D(1) and D(2)/D(3) receptors in mediating the discriminative stimulus effects of DHX. Rats were trained to discriminate DHX [3 mg/kg, intraperitoneally (i.p.)] from the vehicle. The selective dopamine D(1) receptor partial agonist SKF 38393 was fully substituted for DHX. The D(1) receptor antagonist SCH 23390 (0.1 mg/kg, s.c.) and the D(3)-selective antagonist U99194 (10 mg/kg, i.p.) significantly attenuated the discriminative stimulus effects of the training dose of DHX by 80 and 60%, respectively, suggesting that both D(1) and D(3) receptors mediate the discriminative stimulus effects of DHX. In contrast, raclopride (1 mg/kg, i.p.) did not significantly alter the discriminative stimulus effects of DHX, indicating a lack of D(2)-mediated effects. The D(2)/D(3) receptor preferring agonists, quinpirole and (+)-PD 128907 were fully substituted, whereas (+)-7-OH-DPAT was partially substituted for DHX. The DHX bound to D(2) receptors with a Ki of 4.3+0.7 nmol/l was compared with 33.7+4.6 nmol/l at D(3) receptors. Determinations of activity at second messenger systems revealed that DHX functioned as a full agonist at D(3) receptors and a partial agonist at D(2) receptors in vitro. These activities at D(2)/D(3) receptors have shown effects in some preclinical models and clinical disease states. Therefore, the prominent in-vivo agonist activity of DHX at both D(1) receptors and D(2)/D(3) receptors should be considered while making predictions of effects in humans.
Asunto(s)
Aprendizaje Discriminativo/efectos de los fármacos , Agonistas de Dopamina/farmacología , Fenantridinas/farmacología , Animales , Antagonistas de Dopamina/farmacología , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/efectos de los fármacos , Receptores de Dopamina D3/metabolismo , Especificidad de la EspecieRESUMEN
One of most formidable problems in the treatment of addiction is the high rate of relapse. The discovery of medicines to help mitigate relapse are aided by animal models that currently involve weeks of training and require surgical preparations and drug delivery devices. The present set of experiments was initiated to investigate a rapid 8-day screening method that utilizes food instead of intravenous drug administration. Male Sprague-Dawley rats were trained in a reinstatement paradigm in which every lever press produced a 45â¯mg food pellet concurrently paired with a light and tone. Behavior was subsequently extinguished with lever responses producing neither food nor food-associated stimuli. Reinstatement of responding was evaluated under conditions in which the first three responses of every 5â¯min time bin produced a food pellet along with food-associated stimuli. The mGlu5 receptor antagonists MPEP and MTEP produced a significant reduction in reinstatement while failing to alter responding where every response produced food. The cannabinoid CB1 receptor antagonist rimonabant and the mGlu2/3 receptor agonist LY379268 also selectively reduced reinstatement. Other compounds including clozapine, d-amphetamine, chlordiazepoxide, ABT-431, naltrexone and citalopram were without effect. The results suggest that relapse-like behavioral effects can be extended to non-pharmacological reinforcers. Drug effects demonstrated both behavioral and pharmacological specificity. The present experimental design thus allows for efficient and rapid assessment of the effects of drugs that might be useful in the treatment of addiction-associated relapse.
Asunto(s)
Conducta Adictiva/tratamiento farmacológico , Conducta Adictiva/psicología , Conducta Animal/efectos de los fármacos , Descubrimiento de Drogas/métodos , Modelos Animales , Aminoácidos/administración & dosificación , Aminoácidos/farmacología , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Antagonistas de Receptores de Cannabinoides/administración & dosificación , Antagonistas de Receptores de Cannabinoides/farmacología , Condicionamiento Operante/efectos de los fármacos , Agonistas de Aminoácidos Excitadores/administración & dosificación , Agonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Antagonistas de Aminoácidos Excitadores/farmacología , Extinción Psicológica/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Masculino , Piridinas/administración & dosificación , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Recurrencia , Rimonabant/administración & dosificación , Rimonabant/farmacología , Autoadministración , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Tiazoles/administración & dosificación , Tiazoles/farmacologíaRESUMEN
5-HT7 receptors have been suggested to play a role in the regulation of psychiatric disorders. The experimental literature however is not fully consistent on this possibility. Two selective 5-HT7 receptor antagonists, DR-4004 and SB-269970, were evaluated in mouse models used to detect drugs used to treat anxiety, depression, or schizophrenia. A 5-HT-induced hypothermia assay was used to define the doses of DR-4004 and SB-269970 predicted to impact 5-HT7 receptors in the brain in vivo. 5-HT produced hypothermia in wildtype mice by either i.p. or i.c.v. routes but did not in 5-HT7 receptor knockout mice. 5-HT-induced hypothermia was not attenuated by drugs selectively blocking alpha1 or 5-HT1A receptors. Doses of DR-4004 and SB-269970 that blocked 5-HT-induced hypothermia, did not display significant anxiolytic-like (elevated plus maze; vogel conflict) or antidepressant-like efficacy (tail-suspension test) in mouse models. These compounds did demonstrate some antipsychotic-like properties in the PCP-induced hyperactivity assay and anxiolytic/anti-stress effects in the stress-induced cGMP assay. Negative findings were substantiated by positive control drugs that were active in each assay system. We conclude that 5-HT-induced hypothermia can be used to estimate blockade of central 5-HT7 receptors. Effects of DR-4004 and SB-269970 in animal models are generally consistent with the experimental literature that the evidence is mixed or not robust regarding the potential efficacy of 5-HT7 receptor antagonism in the treatment of anxiety, depression, or schizophrenia.
Asunto(s)
Indoles/farmacología , Fenoles/farmacología , Psicotrópicos/farmacología , Piridinas/farmacología , Receptores de Serotonina , Antagonistas de la Serotonina/farmacología , Sulfonamidas/farmacología , Animales , Trastornos de Ansiedad/tratamiento farmacológico , Trastornos de Ansiedad/metabolismo , Temperatura Corporal/efectos de los fármacos , GMP Cíclico/metabolismo , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Hipotermia/inducido químicamente , Indoles/química , Masculino , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Fenoles/química , Psicotrópicos/química , Piridinas/química , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Antagonistas de la Serotonina/química , Sulfonamidas/químicaRESUMEN
The 5-HT7 receptor is the most recently identified receptor subtype within a family of 5-HT receptors activated by the neurotransmitter serotonin. There has been significant interest in investigating the potential role of this receptor in psychiatric disorders including depression, anxiety, and schizophrenia. Behaviors of 5-HT7 +/+ (wild-type or WT) and 5-HT7 -/- (receptor knockout or KO) mice were compared across 10 different assays (7 for anxiety, 1 for depression, 2 for psychosis) to identify differences that could indicate clinical potential for 5-HT7 receptor antagonism. Evaluation of KO vs. WT mice demonstrated significant differences between the genotypes in the fear conditioning, shock-probe burying, novelty-suppressed feeding, punishment memory, forced swim test, and d-amphetamine hyperactivity assays. There was not consistency in either the direction of behavioral effects across genotypes or across assays. Thus, data from these behavioral assays did not uniformly support the idea that 5-HT7 receptors constitute an important drug target for these psychiatric disorders. The present findings are generally congruent with the mixed results in the literature on the behaviors of 5-HT7 -/-mice and with the data on effects of 5-HT7 receptor antagonists in rodent models that detect activity of anxiolytic, antidepressant, and antipsychotic effects.
Asunto(s)
Ansiedad/tratamiento farmacológico , Depresión/tratamiento farmacológico , Receptores de Serotonina/deficiencia , Esquizofrenia/tratamiento farmacológico , Antagonistas de la Serotonina/uso terapéutico , Animales , Condicionamiento Operante/efectos de los fármacos , Modelos Animales de Enfermedad , Estimulación Eléctrica , Conducta Exploratoria/efectos de los fármacos , Miedo/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Femenino , Fiebre/etiología , Fiebre/terapia , Locomoción/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Noqueados , Castigo , Receptores de Serotonina/genética , Refuerzo en Psicología , Estrés Psicológico/complicaciones , Natación/psicologíaRESUMEN
Cognitive flexibility, the ability to adapt behavior to changing outcomes, is critical to survival. The prefrontal cortex is a key site of cognitive control, and chronic pain is known to lead to significant morphological changes to this brain region. Nevertheless, the effects of chronic pain on cognitive flexibility and learning remain uncertain. We used an instrumental paradigm to assess adaptive learning in an experimental model of chronic pain induced by tight ligation of the spinal nerves L5/6 (spinal nerve ligation model). Naive, sham-operated, and spinal nerve ligation (SNL) rats were trained to perform fixed-ratio, variable-ratio, and contingency-shift behaviors for food reward. Although all groups learned an initial lever-reward contingency, learning was slower in SNL animals in a subsequent choice task that reversed reinforcement contingencies. Temporal analysis of lever-press responses across sessions indicated no apparent deficits in memory consolidation or retrieval. However, analysis of learning within sessions revealed that the lever presses of SNL animals occurred in bursts, followed by delays. Unexpectedly, the degree of bursting correlated positively with learning. Under a variable-ratio probabilistic task, SNL rats chose a less profitable behavioral strategy compared with naive and sham-operated animals. After extinction of behavior for learned preferences, SNL animals reverted to their initially preferred (ie, less profitable) behavioral choice. Our data suggest that in the face of uncertainty, chronic pain drives a preference for familiar associations, consistent with reduced cognitive flexibility. The observed burst-like responding may represent a novel learning strategy in animals with chronic pain.
Asunto(s)
Dolor Crónico/psicología , Cognición/fisiología , Función Ejecutiva/fisiología , Aprendizaje/fisiología , Animales , Dolor Crónico/etiología , Toma de Decisiones/fisiología , Masculino , Traumatismos de los Nervios Periféricos/complicaciones , Traumatismos de los Nervios Periféricos/psicología , Ratas , Ratas Sprague-DawleyRESUMEN
RATIONALE: Associated with frank neuropathology, patients with Alzheimer's disease suffer from a host of neuropsychiatric symptoms that include depression, apathy, agitation, and aggression. Negative allosteric modulators (NAMs) of α5-containing GABAA receptors have been suggested to be a novel target for antidepressant action. We hypothesized that pharmacological modulation of this target would engender increased motivation in stressful environments. METHODS: We utilized electrophysiological recordings from Xenopus oocytes and behavioral measures in mice to address this hypothesis. RESULTS: In the forced-swim assay in mice that detects antidepressant drugs, the α5ß3γ2 GABAΑ receptor NAM, RY-080 produced a marked antidepressant phenotype. Another compound, PWZ-029, was characterized as an α5ß3γ2 receptor NAM of lower intrinsic efficacy in electrophysiological studies in Xenopus oocytes. In contrast to RY-080, PWZ-029 was only moderately active in the forced-swim assay and the α5ß3γ2 receptor antagonist, Xli-093, was not active at all. The effects of RY-080 were prevented by the non-selective benzodiazepine receptor antagonist flumazenil as well as by the selective ligands, PWZ-029 and Xli-093. These findings demonstrate that this effect of RY-080 is driven by negative allosteric modulation of α5ßγ2 GABAA receptors. RY-080 was not active in the tail-suspension test. We also demonstrated a reduction in the age-dependent hyperactivity exhibited by transgenic mice that accumulate pathological tau (rTg4510 mice) by RY-080. The decrease in hyperactivity by RY-080 was selective for the hyperactivity of the rTg4510 mice since the locomotion of control strains of mice were not significantly affected by RY-080. CONCLUSIONS: α5ßγ2 GABAA receptor NAMs might function as a pharmacological treatment for mood, amotivational syndromes, and psychomotor agitation in patients with Alzheimer's and other neurodegenerative disorders.
Asunto(s)
Envejecimiento/efectos de los fármacos , Antidepresivos/farmacología , Agitación Psicomotora/tratamiento farmacológico , Receptores de GABA-A/fisiología , Proteínas tau/antagonistas & inhibidores , Envejecimiento/fisiología , Regulación Alostérica/efectos de los fármacos , Regulación Alostérica/fisiología , Animales , Benzodiazepinas/farmacología , Benzodiazepinas/uso terapéutico , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/psicología , Relación Dosis-Respuesta a Droga , Femenino , Flumazenil/farmacología , Flumazenil/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Agitación Psicomotora/genética , Xenopus laevis , Proteínas tau/genéticaRESUMEN
The 'neurotrophic sesquiterpenes' refer to a group of molecules derived from the Illicium genus of flowering plant. They display neurotrophic effects in cultured neuron preparations and have been suggested to be cognitive enhancers and potential therapeutics for neurodegenerative disorders and dementias. Recent synthetic advances generated sufficient quantities of jiadifenolide for in vivo investigation into its biological effects. Jiadifenolide did not induce convulsions in mice nor did it enhance or diminish convulsions induced by pentylenetetrazole. Other negative allosteric modulators of GABAA receptors, picrotoxin, tetramethylenedisulfotetramine (TETS), and bilobalide all induced convulsions. Either i.p. or i.c.v. dosing generated micromolar plasma and brain levels of jiadifenolide but only small effects on locomotion of mice. However, jiadifenolide decreased d-amphetamine-induced hyperlocomotion in mice, an antipsychotic-like drug effect. Jiadifenolide did not significantly alter body temperature or behavior in the forced-swim test in mice. Molecular simulation data suggested a potential site in the pore/M2 helix region that is at an overlapping, yet lower position than those observed for other 'cage convulsant' compounds such as TETS and picrotoxin. We hypothesize that a position nearer to the entrance of the pore channel may allow for easier displacement of jiadifenolide from its blocking location leading to lower potency and lower side-effect liability. Like jiadifenolide, memantine (Namenda), one of the few drugs used in the symptomatic treatment of dementias, occupies a unique site on the NMDA receptor complex that creates low binding affinity that is associated with its reduced side-effect profile. Given the potential therapeutic applications of jiadifenolide and its relatively inert effects on overt behavior, the possibility of clinical utility for jiadifenolide and related compounds becomes intriguing.
Asunto(s)
Convulsivantes/metabolismo , Convulsivantes/farmacología , Progresión de la Enfermedad , Enfermedades Neurodegenerativas/metabolismo , Sesquiterpenos/metabolismo , Sesquiterpenos/farmacología , Animales , Convulsivantes/química , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Ratones , Factores de Crecimiento Nervioso/química , Factores de Crecimiento Nervioso/metabolismo , Factores de Crecimiento Nervioso/farmacología , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Estructura Secundaria de Proteína , Agitación Psicomotora/metabolismo , Sesquiterpenos/químicaRESUMEN
The hypothesis that kainate receptor blockade would be associated with anxiolytic-like effects was tested with a selective ligand, 3S,4aR,6S,8aR-6-((4-carboxyphenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (LY382884). LY382884 selectively binds the GLU(K5) kainate receptor subunit (K(b)=0.6 microM) and has 30 microM or greater affinity for cloned human AMPA receptor subtypes. The anxiolytic potential of LY382884 was tested in rats responding under a Vogel conflict procedure, a pharmacologically validated model for the prediction of antianxiety efficacy in humans. Both the benzodiazepine anxiolytic chlordiazepoxide and LY382884 increased suppressed licking without affecting rates of non-suppressed licking. In contrast, an AMPA receptor selective antagonist, 7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-7-carboxamide, 5-(4-aminophenyl)-8,9-dihydro-N,8-dimethyl-, monohydrochloride (9CI) (GYKI53655), did not increase suppressed responding. The finding that a selective GLU(K5) receptor antagonist produced anxiolytic-like effects in an animal model predictive of efficacy in humans combined with data in the literature on glutamatergic modulation of anxiety suggests that kainate receptor sensitivity to glutamate might be an important mediating event in the pathophysiological expression of anxiety states. The selective targeting of kainate receptors with an antagonist could therefore be a novel pharmacological mechanism to treat anxiety disorders.
Asunto(s)
Ansiolíticos/farmacología , Conducta Animal/efectos de los fármacos , Isoquinolinas/farmacología , Receptores de Ácido Kaínico/fisiología , Animales , Benzodiazepinas/farmacología , Unión Competitiva/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular Transformada , Condicionamiento Operante/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Plasma/efectos de los fármacos , Plasma/metabolismo , Subunidades de Proteína , Ratas , Ratas Sprague-DawleyRESUMEN
The Vogel conflict test has been widely used as a methodology for detecting anxiolytic-like effects of drugs with a broad spectrum of pharmacological activities. Despite widespread acceptance of the Vogel assay as a preclinical predictor of efficacy for anxiolytic-like compounds, detailed parametrics have not been reported on the optimization of this assay to determine how the schedule of reinforcement, the rate of responding and the frequency and temporal distribution of punishing events determine drug effect. The current report documents results of a systematic study of the relationship between number of shocks delivered and efficacy of the prototypical 1,4-benzodiazepine anxiolytic chlordiazepoxide (CDAP) in rats. Under this procedure, water-deprived rats were given access to water and during the later part of this access period, contacts with the drinking tube produced a brief electric shock. CDAP (5-20 mg/kg, i.p.) was first tested under a fixed-ratio 20 response schedule (every 20 th lick produced shock delivered via the sipper tube). CDAP produced dose-dependent increases in punished licking to approximately 275% of control at 20 mg/kg. Increasing the number of shocks during the first ten responses of the punishment component decreased the number of licks made under vehicle control conditions. The frequency of shock delivery produced both quantitative and qualitative changes in the effects of chlordiazepoxide ranging from no effect to 7000% increases in responding. The effects of chlordiazepoxide were dependent both on the control rate of responding and, independently, on the frequency of shock deliveries. Parametric variation under the Vogel conflict test may be useful in comparing the efficacy of novel approaches to the treatment of anxiety disorders.
Asunto(s)
Clordiazepóxido/farmacología , Conflicto Psicológico , Hipnóticos y Sedantes/farmacología , Castigo , Animales , Interpretación Estadística de Datos , Relación Dosis-Respuesta a Droga , Electrochoque , Masculino , Ratas , Ratas Sprague-Dawley , Esquema de RefuerzoRESUMEN
6-[(1S)-1-[1-[5-(2-hydroxyethoxy)-2-pyridyl]pyrazol-3-yl]ethyl]-3H-1,3-benzothiazol-2-one (LY3130481 or CERC-611) is a selective antagonist of AMPA receptors containing transmembrane AMPA receptor regulatory protein (TARP) γ-8. This molecule has been characterized as a potent and efficacious anticonvulsant in an array of acute and chronic epilepsy models in rodents. The present set of experiments was designed to assess the effects of LY3130481 on the electroencephelogram (EEG), cognitive function, and neurochemical outflow. LY3130481 disrupted food-maintained responding in rats and spontaneous alternation in a Y-maze in mice. In rat fear conditioning, LY3130481 caused a deficit in trace (hippocampal-dependent), but not in delay fear conditioning. Although these effects on cognitive performances were observed, the known cognitive-impairing anticonvulsant, topiramate, did not always produce deficits under these assay conditions. LY3130481 produced modest increases in wake times in rats. In addition, LY3130481 was able to attenuate some impairing effects of standard antiepileptic drugs. The motor-impairing effects of the lacosamide were attenuated by LY3130481 as was the decrease in non-rapid-eye movement sleep induced by carbamazepine. Evaluation of the effect of LY3130481 on neurotransmitter and metabolite efflux in the rat medial prefrontal cortex, using in vivo microdialysis, revealed significant increases in the pro-cognitive and wake-promoting neurotransmitters, histamine and acetylcholine, as well as in serotonin, telemethylhistamine, 5-HIAA, HVA and MHPG. LY3130481 thus presents a novel behavioral profile that will have to be evaluated in patients to fully appreciate its implications for therapeutics. LY3130481 is currently under clinical development as CERC-611 as an antiepileptic.
Asunto(s)
Anticonvulsivantes/administración & dosificación , Benzotiazoles/administración & dosificación , Canales de Calcio/fisiología , Cognición/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Pirazoles/administración & dosificación , Acetilcolina/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Condicionamiento Clásico/efectos de los fármacos , Electroencefalografía , Miedo/efectos de los fármacos , Fructosa/administración & dosificación , Fructosa/análogos & derivados , Histamina/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Nitrilos , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiología , Piridonas/administración & dosificación , Ratas Sprague-Dawley , Ratas Wistar , Serotonina/metabolismo , Fases del Sueño/efectos de los fármacos , TopiramatoRESUMEN
BACKGROUND & OBJECTIVE: 6-[(1S)-1-[1-[5-(2-hydroxyethoxy)-2-pyridyl]pyrazol-3-yl]ethyl]- 3H-1,3-benzothiazol-2-one (LY3130481 or CERC-611) is a selective antagonist of AMPA receptors containing transmembrane AMPA receptor regulatory protein (TARP) γ-8 that is under development for epilepsy. The present study provided a broad inquiry into its anticonvulsant properties. LY3130481 was anticonvulsant in multiple acute seizure provocation models in mice and rats. In addition, LY3130481 was effective against absence seizures in the GAERS genetic model and in the Frings mouse model. Likewise, LY3130481 attenuated convulsions in mice and rats with long-term induction of seizures (e.g., corneal, pentylenetetrazole, hippocampal, and amygdala kindled seizures). In slices of epileptic human cortex, LY3130481 significantly decreased neuronal firing frequencies. LY3130481 displaced from rat brain a radioligand specific for AMPA receptors associated with TARP γ-8 whereas non-TARP-selective molecules did not. Binding was also observed in hippocampus freshly transected from a patient. RESULTS & CONCLUSION: Taken as a whole, the findings reported here establish the broad anticonvulsant efficacy of LY3130481 indicating that blockade of AMPA receptors associated with TARP γ-8 is sufficient for these protective effects.
Asunto(s)
Benzotiazoles/farmacología , Canales de Calcio/metabolismo , Pirazoles/farmacología , Receptores AMPA/antagonistas & inhibidores , Convulsiones/prevención & control , Animales , Anticonvulsivantes/farmacología , Corteza Cerebral/fisiología , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Neuronas/fisiología , Ensayo de Unión Radioligante , RatasRESUMEN
RATIONALE: The full D1 receptor agonist dihydrexidine (DHX) [(+/-)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine hydrochloride] is under clinical development (DAR-100) for Parkinson's disease and schizophrenia. Despite the clinical development of DHX, very little is known about its discriminative stimulus properties in rats. To more fully characterize the discriminative stimulus properties of DHX, we trained rats to discriminate DHX (3 mg/kg, i.p.) from vehicle. METHODS: Substitution tests in rats discriminating DHX (3 mg/kg, i.p.) from vehicle were performed with structurally distinct D1 receptor agonists with both partial and full intrinsic efficacy. In addition, the peripherally restricted D1 agonist, fenoldopam, was evaluated. RESULTS: SKF 75670A, ABT-431, dinapsoline, SKF 81297, and SKF 82958 all fully substituted in a dose-dependent manner. The rank order of potency for substitution was SKF 82958Asunto(s)
Aprendizaje Discriminativo/efectos de los fármacos
, Agonistas de Dopamina/farmacología
, Fenantridinas/farmacología
, Receptores de Dopamina D1/agonistas
, Animales
, Masculino
, Ratas
, Ratas Sprague-Dawley
RESUMEN
RATIONALE: Although convergent evidence exists for a role of glutamate in the regulation of anxiety, the involvement of specific glutamate receptor subtypes has yet to be defined. OBJECTIVE: To evaluate the potential for blockade of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptors to produce anxioltyic-like effects with the AMPA/GLU(K5) (kainate) antagonist (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5yl)ethyl]decahydroisoquinoline-3carboxylic acid (LY293558) MATERIALS AND METHODS: Punished responding of rats was used to determine the efficacy of LY293558. Other in vivo and in vitro studies further characterized the specificity of LY293558 for AMPA/kainate receptors. RESULTS: LY293558 had a rank order of potency of GLU(K5) > or = GLU(K5/6) approximately GLU(A2i) approximately GLU(K2/5) approximately GLU(A1i) approximately GLU(A2o) approximately GLU(A3i) approximately GLU(A1o) > or = GLU(A3o) > or = GLU(A4i) approximately GLU(A4o) and >100 microM affinity for rat cortical GABA(A) receptors. Comparison of the blockade of AMPA- vs N-methyl-D-aspartate (NMDA)-induced inward currents demonstrated that LY293558 was five-fold more potent as an antagonist at AMPA vs NMDA receptors in vitro. In keeping with the low affinity of LY293558 for NMDA receptors, LY293558 was not effective in preventing NMDA-induced seizures in mice. LY293558 increased punished responding, a preclinical predictor of anxiolytic efficacy, at a dose that decreased unpunished responding (10 mg/kg, i.p.). Chlordiazepoxide produced comparable increases in both punished and unpunished responding. The NMDA antagonist dizocilpine [(+)-MK-801] also increased both punished and unpunished responding. CONCLUSIONS: These data along with those in the literature suggest that AMPA and/or kainate receptor blockade may be an important component to producing anxiolytic-like effects and may therefore be a target for compounds with efficacy in the therapeutic treatment of anxiety disorders.
Asunto(s)
Ansiolíticos/farmacología , Ácidos Carboxílicos/farmacología , Isoquinolinas/farmacología , Receptores AMPA/antagonistas & inhibidores , Receptores de Ácido Kaínico/antagonistas & inhibidores , Tetrazoles/farmacología , Animales , Células Cultivadas , Clordiazepóxido/farmacología , Condicionamiento Operante/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/efectos de los fármacos , Humanos , Técnicas In Vitro , Masculino , N-Metilaspartato , Neuronas/efectos de los fármacos , Neuronas/fisiología , Técnicas de Placa-Clamp , Subunidades de Proteína/antagonistas & inhibidores , Ratas , Ratas Sprague-Dawley , Receptores AMPA/fisiología , Receptores de Ácido Kaínico/fisiología , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológicoRESUMEN
Rewards influence responses to acute painful stimuli, but the relationship of chronic pain to hedonic or motivational aspects of reward is not well understood. We independently evaluated hedonic qualities of sweet or bitter tastants and motivation to seek food reward in rats with experimental neuropathic pain induced by L5/6 spinal nerve ligation. Hedonic response was measured by implantation of intraoral catheters to allow passive delivery of liquid solutions, and "liking/disliking" responses were scored according to a facial reactivity scale. Spinal nerve ligation rats did not differ from controls in either "liking" or "disliking" reactions to intraoral sucrose or quinine, respectively, at postsurgery day 21, suggesting no differences in perceived hedonic value of sweet or bitter tastants. To assess possible motivational deficits during acute and chronic pain, we used fixed- and progressive-ratio response paradigms of sucrose pellet presentation in rats with transient inflammatory or chronic neuropathic pain. Assessment of response acquisition and break points under the progressive ratio schedule revealed no differences between sham and spinal nerve ligation rats for up to 120 days after injury. However, rats with inflammation showed decrements in lever pressing and break points on days 1 and 2 after complete Freund adjuvant injection that normalized by day 4, consistent with transient ongoing pain. Thus, although acute ongoing inflammatory pain may transiently reduce reward motivation, we did not detect influences of chronic neuropathic pain on hedonic or motivational responses to food rewards. Adaptations that allow normal reward responding to food regardless of chronic pain may be of evolutionary benefit to promote survival.
Asunto(s)
Alimentos , Motivación/fisiología , Neuralgia/fisiopatología , Neuralgia/psicología , Recompensa , Animales , Condicionamiento Operante/efectos de los fármacos , Condicionamiento Operante/fisiología , Modelos Animales de Enfermedad , Extinción Psicológica/fisiología , Adyuvante de Freund/toxicidad , Masculino , Neuralgia/etiología , Dimensión del Dolor , Ratas , Ratas Sprague-Dawley , Nervios Espinales/lesiones , Sacarosa/administración & dosificación , Gusto/efectos de los fármacos , Factores de TiempoRESUMEN
Pharmacological manipulation of specific neural circuits to optimize therapeutic index is an unrealized goal in neurology and psychiatry. AMPA receptors are important for excitatory synaptic transmission, and their antagonists are antiepileptic. Although efficacious, AMPA-receptor antagonists, including perampanel (Fycompa), the only approved antagonist for epilepsy, induce dizziness and motor impairment. We hypothesized that blockade of forebrain AMPA receptors without blocking cerebellar AMPA receptors would be antiepileptic and devoid of motor impairment. Taking advantage of an AMPA receptor auxiliary protein, TARP γ-8, which is selectively expressed in the forebrain and modulates the pharmacological properties of AMPA receptors, we discovered that LY3130481 selectively antagonized recombinant and native AMPA receptors containing γ-8, but not γ-2 (cerebellum) or other TARP members. Two amino acid residues unique to γ-8 determined this selectivity. We also observed antagonism of AMPA receptors expressed in hippocampal, but not cerebellar, tissue from an patient with epilepsy. Corresponding to this selective activity, LY3130481 prevented multiple seizure types in rats and mice and without motor side effects. These findings demonstrate the first rationally discovered molecule targeting specific neural circuitries for therapeutic advantage.
Asunto(s)
Anticonvulsivantes/farmacología , Benzotiazoles/farmacología , Cerebelo/efectos de los fármacos , Epilepsia/tratamiento farmacológico , Prosencéfalo/efectos de los fármacos , Pirazoles/farmacología , Piridonas/farmacología , Receptores AMPA/antagonistas & inhibidores , Animales , Anticonvulsivantes/efectos adversos , Canales de Calcio/metabolismo , Cerebelo/metabolismo , Convulsivantes/toxicidad , Modelos Animales de Enfermedad , Mareo/inducido químicamente , Epilepsia/inducido químicamente , Ratones , Nitrilos , Pentilenotetrazol/toxicidad , Prosencéfalo/metabolismo , Piridonas/efectos adversos , Ratas , Receptores AMPA/metabolismo , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológicoRESUMEN
Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide whose receptor is designated ORL1 or nociceptin receptor (NOP). We utilized a potent, selective, and orally bioavailable antagonist with documented engagement with NOP receptors in vivo to assess antidepressant- and anxiolytic-related pharmacological effects of NOP receptor blockade along with measures of cognitive and motor impingement. LY2940094 ([2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol) displayed antidepressant-like behavioral effects in the forced-swim test in mice, an effect absent in NOP -/- mice. LY2940094 also augmented the behavioral effect of fluoxetine without changing target occupancies (NOP and serotonin reuptake transporter [SERT]). LY2940094 did not have effects under a differential-reinforcement of low rate schedule. Although anxiolytic-like effects were not observed in some animal models (conditioned suppression, 4-plate test, novelty-suppressed feeding), LY2940094 had effects like that of anxiolytic drugs in three assays: fear-conditioned freezing in mice, stress-induced increases in cerebellar cGMP in mice, and stress-induced hyperthermia in rats. These are the first reports of anxiolytic-like activity with a systemically viable NOP receptor antagonist. LY2940094 did not disrupt performance in either a 5-choice serial reaction time or delayed matching-to-position assay. LY2940094 was also not an activator or suppressor of locomotion in rodents nor did it induce failures of rotarod performance. These data suggest that LY2940094 has unique antidepressant- and anxiolytic-related pharmacological effects in rodents. Clinical proof of concept data on this molecule in depressed patients have been reported elsewhere.
RESUMEN
Transmembrane AMPA receptor regulatory proteins (TARPs) are a family of scaffolding proteins that regulate AMPA receptor trafficking and function. TARP γ-8 is one member of this family and is highly expressed within the hippocampus relative to the cerebellum. A selective TARP γ-8-dependent AMPA receptor antagonist (TDAA) is an innovative approach to modulate AMPA receptors in specific brain regions to potentially increase the therapeutic index relative to known non-TARP-dependent AMPA antagonists. We describe here, for the first time, the discovery of a noncompetitive AMPA receptor antagonist that is dependent on the presence of TARP γ-8. Three major iteration cycles were employed to improve upon potency, CYP1A2-dependent challenges, and in vivo clearance. An optimized molecule, compound (-)-25 (LY3130481), was fully protective against pentylenetetrazole-induced convulsions in rats without the motor impairment associated with non-TARP-dependent AMPA receptor antagonists. Compound (-)-25 could be utilized to provide proof of concept for antiepileptic efficacy with reduced motor side effects in patients.
Asunto(s)
Canales de Calcio/metabolismo , Descubrimiento de Drogas , Receptores AMPA/antagonistas & inhibidores , Ensayos Analíticos de Alto Rendimiento , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Receptores AMPA/metabolismoRESUMEN
Transmembrane AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor regulatory protein (TARP) γ-8 is an auxiliary protein associated with some AMPA receptors. Most strikingly, AMPA receptors associated with this TARP have a relatively high localization in the hippocampus. TARP γ-8 also modifies the pharmacology and trafficking of AMPA receptors. However, to date there is little understanding of the biological significance of this auxiliary protein. In the present set of studies we provide a characterization of the differential pharmacology and behavioral consequences of deletion of TARP γ-8 by comparing the wild type (WT) and γ-8 -/- (knock-out, KO) mouse. KO mice were mildly hyperactive in a locomotor arena but not in other environments compared to WT mice. Additionally, the KO mice demonstrated enhanced locomotor stimulatory effects of both d-amphetamine and phencyclidine. Marble-burying and digging behaviors were dramatically reduced in KO mice. In another assay that can detect anxiety-like phenotypes, the elevated plus maze, no differences were observed in overall movement or open arm entries. In the forced-swim assay, KO mice displayed decreases in immobility time like the antidepressant imipramine and the AMPA receptor potentiator, LY392098. In KO mice, the antidepressant-like effects of LY392098 were prevented whereas the effects of imipramine were unaffected. Convulsions were induced by pentylenetetrazole, N-methyl-D-aspartate, and by kainic acid. However, in KO mice, kainic acid produced less tonic convulsions and lethality. KO mice had reduced levels of norepinephrine in hippocampus and cerebellum but not in hypothalamus or prefrontal cortex, decreased levels of cAMP in hippocampus, and increased levels of acetylcholine in the hypothalamus and prefrontal cortex. KO mice displayed decreased turnover of dopamine and increased histamine turnover in multiple brain areas In contrast, serotonin and its metabolites were not significantly affected by deletion of the γ-8 protein. Of a large panel of plasma lipids, only two monoacylglycerols (1OG and 2OG) were marginally but nonsignificantly altered in WT vs KO mice. Overall, the data suggest genetic inactivation of this specific population of AMPA receptors results in modest changes in behavior characterized by a mild hyperactivity which is condition dependent and a marked reduction in digging and burying behaviors. Despite deletion of TARP γ-8, chemoconvulsants were still active. Consistent with their predicted pharmacological actions, the convulsant effects of kainate and the antidepressant-like effects of an AMPA receptor potentiator (both acting upon AMPA receptors) were reduced or absent in KO mice.
Asunto(s)
Temperatura Corporal/genética , Encéfalo/metabolismo , Canales de Calcio/deficiencia , Hipercinesia/genética , Actividad Motora/genética , Receptores AMPA/metabolismo , Acetilcolina/metabolismo , Anfetaminas/farmacología , Animales , Monoaminas Biogénicas/metabolismo , Canales de Calcio/genética , Estimulantes del Sistema Nervioso Central/farmacología , AMP Cíclico/metabolismo , Antagonistas de Aminoácidos Excitadores/farmacología , Conducta Exploratoria/fisiología , Histamina/metabolismo , Lípidos/sangre , Aprendizaje por Laberinto , Ratones , Ratones Transgénicos , Pentilenotetrazol , Fenciclidina/farmacología , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Convulsiones/genética , Sulfonamidas/farmacología , Natación/psicología , Tiofenos/farmacología , Factores de TiempoRESUMEN
Curcumin, the major constituent of the spice tumeric produces a plethora of biological actions that have translated in vivo into behavioral and neurochemical effects in rodents that are also produced by clinically-used antidepressants. The present study was designed to provide a systematic replication of prior behavioral, pharmacological, and neurochemical experiments. In particular, the ability of curcumin to engender anti-immobility effects in the mouse forced-swim assay was established. Although prior work had shown curcumin to function as an inhibitor of the monoamine metabolizing enzyme, monoamine oxidase (MAO), neither MAOA nor MAOB was inhibitied by curcumin in the present study. Curcumin had also been reported previously to function as a cannabinoid CB1 receptor inverse agonist/antagonist. However, in our hands, curcumin did not potently alter GTP-γ.-35S binding indicative of functional CB1 antagonism (Kb = 2080 nM). Moreover, curcumin was not able to prevent the hypothermic effects of the cannabinoid receptor agonist (-)-cis-3-[2-Hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP 55,940). Nonetheless, the anti-immobility effects of curcumin did not occur in CB1 -/- mice. Finally, a broad array of protein receptors and enzymes were evaluated in vitro for their potential interaction with and/or functional engagement with curcumin. Of the more than 100 targets screened, curcumin had very low potency in most. Of those targets with appreciable activity, curcumin had affinities for the human cloned muscarinic receptor subtypes (Ki = 1.3-3.1 uM). Moreover, the plasma and brain levels of curcumin at behaviorally-active doses were below quantitative limits. Given these findings, it is concluded that the prominent antidepressant-like behavioral effects of curcumin, replicated here and in multiple acute and chronic rodent models detailed in the literature, are the result of as yet undisclosed mechanisms of action. The scientific and patient communities await the full scale clinical evaluation of a sufficiently bioavailable curcumin analog in major depressive disorder.