RESUMEN
The NMDA receptor (NMDAR) antagonist ketamine has shown great potential as a rapid-acting antidepressant; however, its use is limited by poor oral bioavailability and a side effect profile that necessitates in-clinic dosing. GM-1020 is a novel NMDAR antagonist that was developed to address these limitations of ketamine as a treatment for depression. Here, we present the preclinical characterization of GM-1020 alongside ketamine, for comparison. In vitro, we profiled GM-1020 for binding to NMDAR and functional inhibition using patch-clamp electrophysiology. In vivo, GM-1020 was assessed for antidepressant-like efficacy using the Forced Swim Test (FST) and Chronic Mild Stress (CMS), while motor side effects were assessed in spontaneous locomotor activity and on the rotarod. The pharmacokinetic properties of GM-1020 were profiled across multiple preclinical species. Electroencephalography (EEG) was performed to determine indirect target engagement and provide a potentially translational biomarker. These results demonstrate that GM-1020 is an orally bioavailable NMDAR antagonist with antidepressant-like efficacy at exposures that do not produce unwanted motor effects.
Asunto(s)
Antidepresivos , Receptores de N-Metil-D-Aspartato , Animales , Antidepresivos/administración & dosificación , Antidepresivos/farmacología , Antidepresivos/farmacocinética , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Masculino , Ratas , Ratones , Administración Oral , Ratas Sprague-Dawley , Disponibilidad Biológica , Ketamina/administración & dosificación , Ketamina/farmacología , Depresión/tratamiento farmacológico , Actividad Motora/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ratones Endogámicos C57BL , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Antagonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/farmacocinética , HumanosRESUMEN
Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT2A-Gq/11 and ß-arrestin2 transducers, making their respective roles unclear. To elucidate this, we develop a series of 5-HT2A-selective ligands with varying Gq efficacies, including ß-arrestin-biased ligands. We show that 5-HT2A-Gq but not 5-HT2A-ß-arrestin2 recruitment efficacy predicts psychedelic potential, assessed using head-twitch response (HTR) magnitude in male mice. We further show that disrupting Gq-PLC signaling attenuates the HTR and a threshold level of Gq activation is required to induce psychedelic-like effects, consistent with the fact that certain 5-HT2A partial agonists (e.g., lisuride) are non-psychedelic. Understanding the role of 5-HT2A Gq-efficacy in psychedelic-like psychopharmacology permits rational development of non-psychedelic 5-HT2A agonists. We also demonstrate that ß-arrestin-biased 5-HT2A receptor agonists block psychedelic effects and induce receptor downregulation and tachyphylaxis. Overall, 5-HT2A receptor Gq-signaling can be fine-tuned to generate ligands distinct from classical psychedelics.
Asunto(s)
Alucinógenos , Masculino , Animales , Ratones , Alucinógenos/farmacología , Receptor de Serotonina 5-HT2A , Serotonina , Transducción de Señal , beta-Arrestinas , LigandosRESUMEN
Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT2A-Gq/11 and ß-arrestin2 signaling, making their respective roles unclear. To elucidate this, we developed a series of 5-HT2A-selective ligands with varying Gq efficacies, including ß-arrestin-biased ligands. We show that 5-HT2A-Gq but not 5-HT2A-ß-arrestin2 efficacy predicts psychedelic potential, assessed using head-twitch response (HTR) magnitude in male mice. We further show that disrupting Gq-PLC signaling attenuates the HTR and a threshold level of Gq activation is required to induce psychedelic-like effects, consistent with the fact that certain 5-HT2A partial agonists (e.g., lisuride) are non-psychedelic. Understanding the role of 5-HT2A-Gq efficacy in psychedelic-like psychopharmacology permits rational development of non-psychedelic 5-HT2A agonists. We also demonstrate that ß-arrestin-biased 5-HT2A receptor agonists induce receptor downregulation and tachyphylaxis, and have an anti-psychotic-like behavioral profile. Overall, 5-HT2A receptor signaling can be fine-tuned to generate ligands with properties distinct from classical psychedelics.
RESUMEN
The 5-HT2A receptor is thought to be the primary target for psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) and other serotonergic hallucinogens (psychedelic drugs). Although a large amount of experimental work has been conducted to characterize the pharmacology of psilocybin and its dephosphorylated metabolite psilocin (4-hydroxy-N,N-dimethyltryptamine), there has been little systematic investigation of the structure-activity relationships (SAR) of 4-substituted tryptamine derivatives. In addition, structural analogs of psilocybin containing a 4-acetoxy group, such as 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT), have appeared as new designer drugs, but almost nothing is known about their pharmacological effects. To address the gap of information, studies were conducted with 17 tryptamines containing a variety of symmetrical and asymmetrical N,N-dialkyl substituents and either a 4-hydroxy or 4-acetoxy group. Calcium mobilization assays were conducted to assess functional activity at human and mouse 5-HT2 subtypes. Head-twitch response (HTR) studies were conducted in C57BL/6J mice to assess 5-HT2A activation in vivo. All of the compounds acted as full or partial agonists at 5-HT2 subtypes, displaying similar potencies at 5-HT2A and 5-HT2B receptors, but some tryptamines with bulkier N-alkyl groups had lower potency at 5-HT2C receptors and higher 5-HT2B receptor efficacy. In addition, O-acetylation reduced the in vitro 5-HT2A potency of 4-hydroxy-N,N-dialkyltryptamines by about 10- to 20-fold but did not alter agonist efficacy. All of the compounds induce head twitches in mice, consistent with an LSD-like behavioral profile. In contrast to the functional data, acetylation of the 4-hydroxy group had little effect on HTR potency, suggesting that O-acetylated tryptamines may be deacetylated in vivo, acting as prodrugs. In summary, the tryptamine derivatives have psilocybin-like pharmacological properties, supporting their classification as psychedelic drugs.
RESUMEN
Lysergic acid diethylamide (LSD) is a prototypical serotonergic psychedelic drug and the subject of many clinical investigations. In recent years, a range of lysergamides has emerged with the production of some being inspired by the existing scientific literature. Others, for example various 1-acyl substituted lysergamides, did not exist before their appearance as research chemicals. 1-Cylopropanoyl-LSD (1CP-LSD) has recently emerged as a new addition to the group of lysergamide-based designer drugs and is believed to be psychoactive in humans. In this investigation, 1CP-LSD was subjected to detailed analytical characterizations including various mass spectrometry (MS) platforms, gas and liquid chromatography, nuclear magnetic resonance spectroscopy, solid phase and GC condensed phase infrared spectroscopy. Analysis by GC-MS also revealed the detection of artificially induced degradation products. Incubation of 1CP-LSD with human serum led to the formation of LSD, indicating that it may act as a prodrug for LSD in vivo, similar to other 1-acyl substituted lysergamides. The analysis of blotters and pellets is also included. 1CP-LSD also induces the head-twitch response (HTR) in C57BL/6 J mice, indicating that it produces an LSD-like behavioural profile. 1CP-LSD induced the HTR with an ED50 = 430.0 nmol/kg which was comparable to 1P-LSD (ED50 = 349.6 nmol/kg) investigated previously. Clinical studies are required to determine the potency and profile of the effects produced by 1CP-LSD in humans.
Asunto(s)
Drogas de Diseño/farmacología , Alucinógenos/farmacología , Dietilamida del Ácido Lisérgico/análogos & derivados , Dietilamida del Ácido Lisérgico/farmacología , Quinolinas/farmacología , Animales , Conducta Animal/efectos de los fármacos , Cromatografía Liquida , Drogas de Diseño/química , Cromatografía de Gases y Espectrometría de Masas , Alucinógenos/sangre , Alucinógenos/química , Dietilamida del Ácido Lisérgico/sangre , Dietilamida del Ácido Lisérgico/química , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos C57BL , Profármacos , Quinolinas/sangre , Quinolinas/química , Espectrofotometría Infrarroja , Espectrometría de Masas en TándemRESUMEN
The 2,5-dimethoxyphenethylamine (2,5-PEA) scaffold is recognized as a motif conferring potent agonist activity at the serotonin 2A receptor (5-HT2AR). The 2,5-dimethoxy motif is present in several classical phenethylamine psychedelics such as 2,4,5- trimethoxyamphetamine (TMA-2), 2,5-dimethoxy-4-methylamphetamine (DOM), 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5- dimethoxy-4-bromoamphetamine (DOB), 2,5-dimethoxy-4-bromophenethylamine (2C-B), and 2,5-dimethoxy-4-iodophenethylamine (2C-I), and it has previously been suggested that this structural motif is essential for 5-HT2AR activation. In the present study, we present data that challenges this assumption. The 2- and 5-desmethoxy derivatives of 2C-B and DOB were synthesized, and their pharmacological profiles were evaluated in vitro at 5-HT2AR and 5-HT2CR in binding and functional assays and in vivo by assessing their induction of the head-twitch response in mice. Elimination of either the 2- or 5-methoxy group leads to a modest drop in binding affinity and functional potency at 5-HT2AR and 5-HT2CR, which was more pronounced upon removal of the 2-methoxy group. However, this trend was not mirrored in vivo, as removal of either methoxy group resulted in significant reduction in the ability of the compounds to induce the head-twitch response in mice. Thus, the 2,5-dimethoxyphenethylamine motif appears to be important for in vivo potency of phenethylamine 5-HT2AR agonists, but this does not correlate to the relative affinity and potency of the ligands at the recombinant 5-HT2AR.
Asunto(s)
Alucinógenos , Receptor de Serotonina 5-HT2A , Animales , Relación Dosis-Respuesta a Droga , Alucinógenos/farmacología , Movimientos de la Cabeza , Ratones , Fenetilaminas/farmacología , Receptor de Serotonina 5-HT2CRESUMEN
A general synthetic method was developed to access known tryptamine natural products present in psilocybin-producing mushrooms. In vitro and in vivo experiments were then conducted to inform speculations on the psychoactive properties, or lack thereof, of the natural products. In animal models, psychedelic activity by baeocystin alone was not evident using the mouse head twitch response assay, despite its putative dephosphorylated metabolite, norpsilocin, possessing potent agonist activity at the 5-HT2A receptor.
Asunto(s)
Alcaloides/química , Alucinógenos/química , Indoles/química , Organofosfatos/química , Compuestos Organofosforados/química , Psilocibina/química , Triptaminas/química , Agaricales , Animales , Ratones , Estructura MolecularRESUMEN
Serotonergic hallucinogens such as lysergic acid diethylamide (LSD) induce head twitches in rodents via 5-HT2A receptor activation. The goal of the present investigation was to determine whether a correlation exists between the potency of hallucinogens in the mouse head-twitch response (HTR) paradigm and their reported potencies in other species, specifically rats and humans. Dose-response experiments were conducted with phenylalkylamine and tryptamine hallucinogens in C57BL/6J mice, enlarging the available pool of HTR potency data to 41 total compounds. For agents where human data are available (n = 36), a strong positive correlation (r = 0.9448) was found between HTR potencies in mice and reported hallucinogenic potencies in humans. HTR potencies were also found to be correlated with published drug discrimination ED50 values for substitution in rats trained with either LSD (r = 0.9484, n = 16) or 2,5-dimethoxy-4-methylamphetamine (r = 0.9564, n = 21). All three of these behavioral effects (HTR in mice, hallucinogen discriminative stimulus effects in rats, and psychedelic effects in humans) have been linked to 5-HT2A receptor activation. We present evidence that hallucinogens induce these three effects with remarkably consistent potencies. In addition to having high construct validity, the HTR assay also appears to show significant predictive validity, confirming its translational relevance for predicting subjective potency of hallucinogens in humans. These findings support the use of the HTR paradigm as a preclinical model of hallucinogen psychopharmacology and in structure-activity relationship studies of hallucinogens. Future investigations with a larger number of test agents will evaluate whether the HTR assay can be used to predict the hallucinogenic potency of 5-HT2A agonists in humans. "This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.
Asunto(s)
Aprendizaje Discriminativo/efectos de los fármacos , Alucinógenos/administración & dosificación , Movimientos de la Cabeza/efectos de los fármacos , Magnetometría/métodos , Agonistas del Receptor de Serotonina 5-HT2/administración & dosificación , Animales , Aprendizaje Discriminativo/fisiología , Relación Dosis-Respuesta a Droga , Movimientos de la Cabeza/fisiología , Humanos , Magnetometría/instrumentación , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Receptor de Serotonina 5-HT2A/fisiología , Especificidad de la EspecieRESUMEN
The ergoline d-lysergic acid diethylamide (LSD) is one of the most potent psychedelic drugs. 1-Acetyl-LSD (ALD-52), a derivative of LSD containing an acetyl group on the indole nitrogen, also produces psychedelic effects in humans and has about the same potency as LSD. Recently, several other 1-acyl-substitued LSD derivatives, including 1-propanoyl-LSD (1P-LSD) and 1-butanoyl-LSD (1B-LSD), have appeared as designer drugs. Although these compounds are assumed to act as prodrugs for LSD, studies have not specifically tested this prediction. The present investigation was conducted to address the gap of information about the pharmacological effects and mechanism-of-action of 1-acyl-substituted LSD derivatives. Competitive binding studies and calcium mobilization assays were performed to assess the interaction of ALD-52, 1P-LSD, and 1B-LSD with serotonin 5-HT2 receptor subtypes. A receptorome screening was performed with 1B-LSD to assess its binding to other potential targets. Head twitch response (HTR) studies were performed in C57BL/6J mice to assess in vivo activation of 5-HT2A (the receptor thought to be primarily responsible for hallucinogenesis). Finally, liquid chromatography/ion-trap mass spectrometry (LC/MS) was used to quantify plasma levels of LSD in Sprague-Dawley rats treated with ALD-52 and 1P-LSD. 1-Acyl-substitution reduced the affinity of LSD for most monoamine receptors, including 5-HT2A sites, by one to two orders of magnitude. Although LSD acts as an agonist at 5-HT2 subtypes, ALD-52, 1P-LSD and 1B-LSD have weak efficacy or act as antagonists in Ca2+-mobilization assays. Despite the detrimental effect of 1-acyl substitution on 5-HT2A affinity and efficacy, 1-acyl-substitued LSD derivatives induce head twitches in mice with relatively high potency. High levels of LSD were detected in the plasma of rats after subcutaneous administration of ALD-52 and 1P-LSD, demonstrating these compounds are rapidly and efficiently deacylated in vivo. These findings are consistent with the prediction that ALD-52, 1P-LSD and 1B-LSD serve as prodrugs for LSD. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.
Asunto(s)
Alucinógenos/farmacología , Dietilamida del Ácido Lisérgico/análogos & derivados , Dietilamida del Ácido Lisérgico/farmacología , Profármacos/farmacología , Animales , Conducta Animal/efectos de los fármacos , Unión Competitiva/efectos de los fármacos , Biotransformación , Señalización del Calcio/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Alucinógenos/farmacocinética , Dietilamida del Ácido Lisérgico/farmacocinética , Masculino , Ratones , Ratones Endogámicos C57BL , Profármacos/síntesis química , Profármacos/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina 5-HT2/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Antagonistas del Receptor de Serotonina 5-HT2/farmacologíaRESUMEN
Bipolar illness is characterized by periods of "mania" - high energy, irritability, and increased psychomotor activation. While the neurobiological investigation of mania has been limited by the lack of reliable animal models, researchers have recently reported that daily subanesthetic doses of ketamine produce a lithium-reversible increase in rodent locomotor activity. Such studies have typically employed short-term (2â¯week) exposure to daily intraperitoneal-injected lithium and extremely brief (i.e., 5-min) open-field tests of hyperactivity. To increase the translational utility of the model, the effects of 70-days of orally administered lithium were examined on ketamine-induced hyperlocomotion during 30-min test sessions. Rats consumed 2.0â¯mEq/kg lithium chloride (LiCl) presented daily in a high incentive food (10â¯g of peanut butter). Control animals ingested peanut butter infused with an equimolar concentration of sodium chloride (NaCl). After 60â¯days of treatment, a 30-min baseline revealed no differences in the locomotor activity of LiCl and NaCl animals. During the next 10â¯days, animals received single daily supplemental injections of 25â¯mg/kg IP ketamine. A subset of animals was injected daily with saline and served as non-ketamine controls. Behavioral testing on the final two days of treatment confirmed that ketamine administration produced a profound increase in locomotor activity that was significantly attenuated in the LiCl group. Additionally, blood plasma levels of lithium were found to be comparable to low-moderate human therapeutic levels. These data confirm the viability and utility of ketamine-induced hyperlocomotion as a rodent model of mania.
Asunto(s)
Trastorno Bipolar/tratamiento farmacológico , Modelos Animales de Enfermedad , Ketamina/efectos adversos , Compuestos de Litio/administración & dosificación , Animales , Conducta Animal , Antagonistas de Aminoácidos Excitadores/efectos adversos , Locomoción/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Recent work has implicated the Lateral Habenula (LHb) in the production of anxiogenic and aversive states. It is innervated by all the major monoamine neurotransmitter systems and has projections that have been shown to modulate the activity of both dopaminergic and serotonergic brain regions. Cocaine is a stimulant drug of abuse that potentiates neurotransmission in these monoamine systems and recent research suggests that the drug's behavioral effects may be related in part to its actions within the LHb. The present research was therefore devised to test the hypothesis that alterations in serotonin (5-HT) function within the LHb can affect the behavioral response to cocaine. Male rats were fitted with intracranial guide cannula and trained to traverse a straight alleyway once a day for a 1â¯mg/kg i.v. injection of cocaine. Intra-LHb pretreatment with the 5-HT1B agonist CP 94,253 (0, 0.1, or 0.25⯵g/side) attenuated the development of approach/avoidance "retreat" behaviors known to be a consequence of cocaine's dual rewarding (approach) and anxiogenic (avoidance) properties. This effect was reversed by co-administration of a selective 5-HT1B antagonist, NAS-181 (0.1⯵g/side), demonstrating drug specificity at the 5-HT1B receptor. These data suggest that 5-HT1B signaling within the LHb contributes to the anxiogenic effects of cocaine.
Asunto(s)
Ansiedad/tratamiento farmacológico , Cocaína/administración & dosificación , Inhibidores de Captación de Dopamina/administración & dosificación , Habénula/metabolismo , Receptor de Serotonina 5-HT1B/metabolismo , Análisis de Varianza , Animales , Ansiedad/inducido químicamente , Benzopiranos/farmacología , Cocaína/efectos adversos , Condicionamiento Operante/efectos de los fármacos , Correlación de Datos , Modelos Animales de Enfermedad , Inhibidores de Captación de Dopamina/efectos adversos , Relación Dosis-Respuesta a Droga , Habénula/efectos de los fármacos , Locomoción/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Morfolinas/farmacología , Piridinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Autoadministración , Serotoninérgicos/farmacologíaRESUMEN
Cocaine administration has been shown to produce immediate positive (rewarding) and subsequent negative (anxiogenic) effects in humans and animals. These dual and opposing affective responses have been more difficult to demonstrate with administration of methamphetamine (meth). While animal studies have reliably demonstrated the positive reinforcing effects of the drug, reports of negative aftereffects following acute exposure have been few in number and contradictory in nature. The current research was devised to assess the effects of acute meth using a runway model of self-administration that is uniquely sensitive to both the positive and negative effects of a drug reinforcer in the same animal on the same trial. Male rats were allowed to traverse a straight alley once a day for 16 consecutive days/trials where entry into the goal box resulted in a single IV injection of meth (0.25, 0.5 or 1.0â¯mg/kg/inj.). The chosen doses were confirmed to be psychoactive as they produced dose-dependent increases in motoric/locomotor activation in these same subjects. The results demonstrated a U-shaped dose-response curve for the reinforcing effects of meth in that the intermediate dose group (0.5â¯mg/kg) produced the strongest approach behavior in the runway. Unlike other psychomotor stimulants, like cocaine, animals running for IV meth exhibited no evidence of any significant approach-avoidance behaviors reflective of the drug's negative anxiogenic effects. These results suggest that the abuse potential for meth is likely higher than for other shorter-acting psychomotor stimulants and reaffirms the utility of the runway procedure as a screen for a substance's abuse potential.
Asunto(s)
Conducta Animal , Comportamiento de Búsqueda de Drogas , Metanfetamina/administración & dosificación , Autoadministración , Animales , Infusiones Intravenosas , Locomoción/efectos de los fármacos , Masculino , Metanfetamina/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Recent research has identified the lateral habenula (LHb) as a brain region playing an important role in the production of stressful and anxiogenic states. Additionally, norepinephrine (NE) has long been known to be involved in arousal, stress and anxiety, and NE projections to the LHb have been identified emanating from the locus coeruleus (LC). The current research was devised to test the hypothesis that NE release within the LHb contributes to the occurrence of anxiogenic behaviors. Male rats were implanted with bilateral guide cannula aimed at the LHb and subsequently treated with intracranial (IC) infusions of the selective α2 adrenergic autoreceptor agonist, dexmedetomidine (DEX) (0, 0.5, 1.0⯵g/side), prior to assessment of ambulatory and anxiogenic behavior in tests of spontaneous locomotion, open field behavior, and acoustic startle-response. Results demonstrated that DEX administration significantly reduced the overall locomotor behavior of subjects at both doses indicating that infusion of even small doses of this α2 agonist into the LHb can have profound effects on the subjects' general levels of alertness and activity. DEX was also found to attenuate anxiety as evidenced by a reduction in the magnitude of a startle-response to an acoustic 110â¯dB stimulus. Taken together, these results identify a role for NE release within the LHb in both arousal and anxiety.
Asunto(s)
Ansiedad/metabolismo , Nivel de Alerta/fisiología , Habénula/metabolismo , Norepinefrina/metabolismo , Agonistas alfa-Adrenérgicos/farmacología , Animales , Ansiedad/tratamiento farmacológico , Nivel de Alerta/efectos de los fármacos , Dexmedetomidina/farmacología , Relación Dosis-Respuesta a Droga , Habénula/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Ratas Sprague-Dawley , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiologíaRESUMEN
RATIONALE: Cocaine produces significant aversive/anxiogenic actions whose underlying neurobiology remains unclear. A possible substrate contributing to these actions is the serotonergic (5-HT) pathway projecting from the dorsal raphé (DRN) to regions of the extended amygdala, including the bed nucleus of the stria terminalis (BNST) which have been implicated in the production of anxiogenic states. OBJECTIVES: The present study examined the contribution of 5-HT signaling within the BNST to the anxiogenic effects of cocaine as measured in a runway model of drug self-administration. METHODS: Male Sprague-Dawley rats were fitted with bilateral infusion cannula aimed at the BNST and then trained to traverse a straight alley once a day for a single 1 mg/kg i.v. cocaine infusion delivered upon goal-box entry on each of 16 consecutive days/trials. Intracranial infusions of CP 94,253 (0, 0.25, 0.5, or 1.0 µg/side) were administered to inhibit local 5-HT release via activation of 5-HT1B autoreceptors. To confirm receptor specificity, the effects of this treatment were then challenged by co-administration of the selective 5-HT1B antagonist NAS-181. RESULTS: Intra-BNST infusions of the 5-HT1B autoreceptor agonist attenuated the anxiogenic effects of cocaine as reflected by a decrease in runway approach-avoidance conflict behavior. This effect was reversed by the 5-HT1B antagonist. Neither start latencies (a measure of the subject's motivation to seek cocaine) nor spontaneous locomotor activity (an index of motoric capacity) were altered by either treatment. CONCLUSIONS: Inhibition of 5-HT1B signaling within the BNST selectively attenuated the anxiogenic effects of cocaine, while leaving unaffected the positive incentive properties of the drug.
Asunto(s)
Ansiedad , Autorreceptores/efectos de los fármacos , Cocaína/administración & dosificación , Inhibidores de Captación de Dopamina/administración & dosificación , Receptor de Serotonina 5-HT1B/efectos de los fármacos , Núcleos Septales/efectos de los fármacos , Animales , Benzopiranos/farmacología , Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Locomoción/efectos de los fármacos , Masculino , Morfolinas/farmacología , Motivación , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Autoadministración , Antagonistas del Receptor de Serotonina 5-HT1/farmacologíaRESUMEN
In addition to its initial rewarding effects, cocaine has been shown to produce profound negative/anxiogenic actions. Recent work on the anxiogenic effects of cocaine has examined the role of corticotropin releasing factor (CRF), with particular attention paid to the CRF cell bodies resident to the extended amygdala (i.e., the central nucleus of the amygdala [CeA] and the bed nucleus of the stria terminalis [BNST]) and the interconnections within and projections outside the region (e.g., to the ventral tegmental area [VTA]). In the current study, localized CRF receptor antagonism was produced by intra-BNST, intra-CeA or intra-VTA application of the CRF antagonists, D-Phe CRF(12-41) or astressin-B. The effect of these treatments were examined in a runway model of i.v. cocaine self-administration that has been shown to be sensitive to both the initial rewarding and delayed anxiogenic effects of the drug in the same animal on the same trial. These dual actions of cocaine are reflected in the development of an approach-avoidance conflict ("retreat behaviors") about goal box entry that stems from the mixed associations that subjects form about the goal. CRF antagonism within the VTA, but not the CeA or BNST, significantly reduced the frequency of approach-avoidance retreat behaviors while leaving start latencies (an index of the positive incentive properties of cocaine) unaffected. These results suggest that the critical CRF receptors contributing to the anxiogenic state associated with acute cocaine administration may lie outside the extended amygdala, and likely involve CRF projections to the VTA.