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1.
Sci Rep ; 14(1): 6646, 2024 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-38503831

RESUMEN

Nicotine use is a leading cause of preventable deaths worldwide, and most of those who attempt to quit will relapse. While electronic cigarettes and other electronic nicotine delivery systems (ENDS) were presented as a safer alternative to traditional cigarettes and promoted as devices to help traditional tobacco smokers reduce or quit smoking, they have instead contributed to increasing nicotine use among youths. Despite this, ENDS also represent a useful tool to create novel preclinical animal models of nicotine exposure that more accurately represent human nicotine use. In this study, we validated a chronic, intermittent, ENDS-based passive vapor exposure model in mice, and then measured changes in multiple behaviors related to nicotine abstinence. First, we performed a behavioral dose curve to investigate the effects of different nicotine inter-vape intervals on various measures including body weight, locomotor activity, and pain hypersensitivity. Next, we performed a pharmacokinetic study to measure plasma levels of nicotine and cotinine following chronic exposure for each inter-vape interval. Finally, we utilized a behavior test battery at a single dosing regimen that produces blood levels equivalent to human smokers in order to characterize the effects of chronic nicotine, vehicle, or passive airflow and identified nicotine-induced impairments in cognitive behavior.


Asunto(s)
Sistemas Electrónicos de Liberación de Nicotina , Nicotina , Adolescente , Masculino , Humanos , Ratones , Animales , Fumar , Cotinina , Gases , Cognición
2.
Res Sq ; 2024 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-38352503

RESUMEN

Nicotine use is a leading cause of preventable deaths worldwide, and most of those who attempt to quit will relapse. While electronic cigarettes and other electronic nicotine delivery systems (ENDS) were presented as a safer alternative to traditional cigarettes and promoted as devices to help traditional tobacco smokers reduce or quit smoking, they have instead contributed to increasing nicotine use among youths. Despite this, ENDS also represent a useful tool to create novel preclinical animal models of nicotine exposure that more accurately represent human nicotine use. In this study, we validated a chronic, intermittent, ENDS-based passive vapor exposure model in mice, and then measured changes in multiple behaviors related to nicotine abstinence. First, we performed a behavioral dose curve to investigate the effects of different nicotine inter-vape intervals on various measures including body weight, locomotor activity, and pain hypersensitivity. Next, we performed a pharmacokinetic study to measure plasma levels of nicotine and cotinine following chronic exposure for each inter-vape interval. Finally, we utilized a behavior test battery at a single dosing regimen that produces blood levels equivalent to human smokers in order to characterize the effects of chronic nicotine, vehicle, or passive airflow and identified nicotine-induced impairments in cognitive behavior.

3.
Addict Biol ; 28(10): e13328, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37753570

RESUMEN

Cocaine predictive cues and contexts exert powerful control over behaviour and can incite cocaine seeking and taking. This type of conditioned behaviour is encoded within striatal circuits, and these circuits and behaviours are, in part, regulated by opioid peptides and receptors expressed in striatal medium spiny neurons. We previously showed that augmenting levels of the opioid peptide enkephalin in the striatum facilitates acquisition of cocaine conditioned place preference (CPP), while opioid receptor antagonists attenuate expression of cocaine CPP. However, whether striatal enkephalin is necessary for acquisition of cocaine CPP and maintenance during extinction remains unknown. To address this, we generated mice with a targeted deletion of enkephalin from dopamine D2-receptor expressing medium spiny neurons and tested them in a cocaine CPP paradigm. Low striatal enkephalin levels did not attenuate acquisition of CPP. However, expression of preference, assessed after acute administration of the opioid receptor antagonist naloxone, was blocked in females, regardless of genotype. When saline was paired with the cocaine context during extinction sessions, females, regardless of genotype, extinguished preference faster than males, and this was prevented by naloxone when paired with the cocaine context. We conclude that while striatal enkephalin is not necessary for acquisition, expression, or extinction of cocaine CPP, expression and extinction of cocaine preference in females is mediated by an opioid peptide other than striatal enkephalin. The unique sensitivity of females to opioid antagonists suggests sex should be a consideration when using these compounds in the treatment of cocaine use disorder.


Asunto(s)
Analgésicos Opioides , Cocaína , Femenino , Masculino , Animales , Ratones , Péptidos Opioides , Naloxona/farmacología , Antagonistas de Narcóticos , Recompensa , Encefalinas/genética , Cocaína/farmacología
4.
Br J Pharmacol ; 180(24): 3130-3145, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37488777

RESUMEN

BACKGROUND AND PURPOSE: The endocannabinoid (eCB) system plays an important homeostatic role in the regulation of stress circuits and has emerged as a therapeutic target to treat stress disorders and alcohol use disorder (AUD). Extensive research has elucidated a role for the eCB anandamide (AEA), but less is known about 2-arachidonoylglycerol (2-AG) mediated signalling. EXPERIMENTAL APPROACH: We pharmacologically enhanced eCB signalling by inhibiting the 2-AG metabolizing enzyme, monoacylglycerol lipase (MAGL), in male and female Marchigian Sardinian alcohol-preferring (msP) rats, a model of innate alcohol preference and stress hypersensitivity, and in control Wistar rats. We tested the acute effect of the selective MAGL inhibitor MJN110 in alleviating symptoms of alcohol drinking, anxiety, irritability and fear. KEY RESULTS: A single systemic administration of MJN110 increased 2-AG levels in the central amygdala, prelimbic and infralimbic cortex but did not acutely alter alcohol drinking. MAGL inhibition reduced aggressive behaviours in female msPs, and increased defensive behaviours in male msPs, during the irritability test. Moreover, in the novelty-induced hypophagia test, MJN110 selectively enhanced palatable food consumption in females, mitigating stress-induced food suppression. Lastly, msP rats showed increased conditioned fear behaviour compared with Wistar rats, and MJN110 reduced context-associated conditioned fear responses, but not cue-probed fear expression, in male msPs. CONCLUSIONS AND IMPLICATIONS: Acute inhibition of MAGL attenuated some stress-related responses in msP rats but not voluntary alcohol drinking. Our results provide new insights into the sex dimorphism documented in stress-induced responses. Sex-specific eCB-based approaches should be considered in the clinical development of therapeutics.


Asunto(s)
Monoacilglicerol Lipasas , Monoglicéridos , Ratas , Masculino , Femenino , Animales , Ratas Wistar , Etanol/farmacología , Endocannabinoides/metabolismo
5.
Alcohol Res ; 42(1): 09, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35655710

RESUMEN

PURPOSE: The endogenous cannabinoid system is involved in several physiological functions in the central nervous system including the modulation of brain reward circuitry and emotional homeostasis. Substantial evidence implicates brain endocannabinoid signaling in the processing of drug-induced reward states, wherein repeated exposure besets pathological changes in activity that contribute to the progression of alcohol use disorder. This review provides a narrative summary of recent studies exploring the interaction between alcohol exposure and changes in endocannabinoid signaling that may underlie the development of alcohol use disorder. SEARCH METHODS: The authors began with an initial search for review articles to assist in the identification of relevant literature. This was followed by separate searches for primary literature and recent studies. The search terms "alcohol/ethanol" and "endocannabinoids" were applied, along with terms that covered specific objectives in reinforcement and addiction behavior. The content was further refined by excluding articles containing a broad focus on psychiatric disorders, polysubstance abuse, non-cannabinoid signaling lipids, and other criteria. SEARCH RESULTS: The initial search yielded a total of 49 review articles on PubMed, 13 on ScienceDirect, and 17 on Wiley Online, from which the authors garnered information from a total of 16 reviews. In addition to independent searches, this review provides information from a collection of 212 publications, including reviews and original research articles. DISCUSSION AND CONCLUSIONS: The review discusses the effects of alcohol consumption on brain endocannabinoid signaling, including alcohol-based perturbations in endocannabinoid-mediated synaptic transmission, the modulation of alcohol-related behaviors by manipulating signaling elements of the endocannabinoid system, and the influence of dysregulated endocannabinoid function in promoting withdrawal-induced anxiety-like behavior. Notable emphasis is placed on studies exploring the possible therapeutic relevance of bolstering brain endocannabinoid tone at different stages of alcohol use disorder.


Asunto(s)
Alcoholismo , Conducta Adictiva , Alcoholismo/complicaciones , Endocannabinoides , Etanol , Humanos , Recompensa
6.
Biol Psychiatry ; 91(12): 1008-1018, 2022 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-35430085

RESUMEN

BACKGROUND: Alcohol use disorder (AUD) is a leading preventable cause of death. The central amygdala (CeA) is a hub for stress and AUD, while dysfunction of the noradrenaline stress system is implicated in AUD relapse. METHODS: Here, we investigated whether alcohol (ethanol) dependence and protracted withdrawal alter noradrenergic regulation of the amygdala in rodents and humans. Male adult rats were housed under control conditions, subjected to chronic intermittent ethanol vapor exposure to induce dependence, or withdrawn from chronic intermittent ethanol vapor exposure for 2 weeks, and ex vivo electrophysiology, biochemistry (catecholamine quantification by high-performance liquid chromatography), in situ hybridization, and behavioral brain-site specific pharmacology studies were performed. We also used real-time quantitative polymerase chain reaction to assess gene expression of α1B, ß1, and ß2 adrenergic receptors in human postmortem brain tissue from men diagnosed with AUD and matched control subjects. RESULTS: We found that α1 receptors potentiate CeA GABAergic (gamma-aminobutyric acidergic) transmission and drive moderate alcohol intake in control rats. In dependent rats, ß receptors disinhibit a subpopulation of CeA neurons, contributing to their excessive drinking. Withdrawal produces CeA functional recovery with no change in local noradrenaline tissue concentrations, although there are some long-lasting differences in the cellular patterns of adrenergic receptor messenger RNA expression. In addition, postmortem brain analyses reveal increased α1B receptor messenger RNA in the amygdala of humans with AUD. CONCLUSIONS: CeA adrenergic receptors are key neural substrates of AUD. Identification of these novel mechanisms that drive alcohol drinking, particularly during the alcohol-dependent state, supports ongoing new medication development for AUD.


Asunto(s)
Alcoholismo , Núcleo Amigdalino Central , Consumo de Bebidas Alcohólicas , Animales , Núcleo Amigdalino Central/metabolismo , Etanol/farmacología , Humanos , Masculino , Norepinefrina , ARN Mensajero , Ratas , Receptores Adrenérgicos/metabolismo
7.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-33803557

RESUMEN

Marchigian Sardinian alcohol-preferring (msP) rats serve as a unique model of heightened alcohol preference and anxiety disorders. Their innate enhanced stress and poor stress-coping strategies are driven by a genetic polymorphism of the corticotropin-releasing factor receptor 1 (CRF1) in brain areas involved in glucocorticoid signaling. The activation of glucocorticoid receptors (GRs) regulates the stress response, making GRs a candidate target to treat stress and anxiety. Here, we examined whether mifepristone, a GR antagonist known to reduce alcohol drinking in dependent rats, decreases innate symptoms of anxiety in msPs. Male and female msPs were compared to non-selected Wistar counterparts across three separate behavioral tests. We assessed anxiety-like behavior via the novelty-induced hypophagia (NIH) assay. Since sleep disturbances and hyperarousal are common features of stress-related disorders, we measured sleeping patterns using the comprehensive lab monitoring system (CLAMS) and stress sensitivity using acoustic startle measures. Rats received an acute administration of vehicle or mifepristone (60 mg/kg) 90 min prior to testing on NIH, acoustic startle response, and CLAMS. Our results revealed that both male and female msPs display greater anxiety-like behaviors as well as enhanced acoustic startle responses compared to Wistar counterparts. Male msPs also displayed reduced sleeping bout duration versus Wistars, and female msPs displayed greater acoustic startle responses versus male msPs. Importantly, the enhanced anxiety-like behavior and startle responses were not reduced by mifepristone. Together, these findings suggest that increased expression of stress-related behaviors in msPs are not solely mediated by acute activation of GRs.


Asunto(s)
Ansiedad/patología , Conducta Animal , Mifepristona/farmacología , Receptores de Glucocorticoides/antagonistas & inhibidores , Animales , Ansiedad/complicaciones , Ansiedad/fisiopatología , Nivel de Alerta/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Femenino , Masculino , Ratas Wistar , Receptores de Glucocorticoides/metabolismo , Trastornos del Sueño-Vigilia/complicaciones , Trastornos del Sueño-Vigilia/fisiopatología
8.
Addict Biol ; 26(3): e12978, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33142367

RESUMEN

Genetically-selected Marchigian Sardinian alcohol-preferring (msP) rats display comorbid symptoms of increased alcohol preference and elevated anxiety-like behavior. Heightened stress sensitivity in msPs is influenced by genetic polymorphisms of the corticotropin-releasing factor receptor in the central nucleus of the amygdala (CeA), as well as reduced influence of anti-stress mechanisms that normally constrain the stress response. Given this propensity for stress dysregulation, in this study, we expand on the possibility that msPs may display differences in neuroendocrine processes that normally terminate the stress response. We utilized behavioral, biochemical, and molecular assays to compare basal and restraint stress-induced changes in the hypothalamic-pituitary-adrenal (HPA) axis of male and female msPs relative to their nonselected Wistar counterparts. The results showed that msPs display deficits in marble-burying behavior influenced by environmental factors and procedures that modulate arousal states in a sex-dependent manner. Whereas male msPs display evidence of dysregulated neuroendocrine function (higher adrenocorticotropic hormone levels and subthreshold reductions in corticosterone), females display restraint-induced elevations in corticosterone levels that were persistently higher in msPs. A dexamethasone challenge reduced the circulation of these stress hormones, although the reduction in corticosterone was generally attenuated in msP versus Wistar rats. Finally, we found evidence of diminished stress-induced glucocorticoid receptor (GR) phosphorylation in the hypothalamic paraventricular nucleus of msPs, as well as innate increases in phosphorylated GR levels in the CeA of male msPs. Collectively, these findings suggest that negative feedback processes regulating HPA responsiveness are diminished in msP rats, possibly underlying differences in the expression of anxiety-like behaviors.


Asunto(s)
Glucocorticoides/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Restricción Física , Consumo de Bebidas Alcohólicas/genética , Animales , Ansiedad/genética , Corticosterona/sangre , Retroalimentación Fisiológica , Femenino , Glucocorticoides/genética , Hipotálamo/metabolismo , Masculino , Ratas , Ratas Wistar , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo
9.
eNeuro ; 7(2)2020.
Artículo en Inglés | MEDLINE | ID: mdl-32041742

RESUMEN

The lateral amygdala (LA) serves as the point of entry for sensory information within the amygdala complex, a structure that plays a critical role in emotional processes and has been implicated in alcohol use disorders. Within the amygdala, the corticotropin-releasing factor (CRF) system has been shown to mediate some of the effects of both stress and ethanol, but the effects of ethanol on specific CRF1 receptor circuits in the amygdala have not been fully established. We used male CRF1:GFP reporter mice to characterize CRF1-expressing (CRF1+) and nonexpressing (CRF1-) LA neurons and investigate the effects of acute and chronic ethanol exposure on these populations. The CRF1+ population was found to be composed predominantly of glutamatergic projection neurons with a minority subpopulation of interneurons. CRF1+ neurons exhibited a tonic conductance that was insensitive to acute ethanol. CRF1- neurons did not display a basal tonic conductance, but the application of acute ethanol induced a δ GABAA receptor subunit-dependent tonic conductance and enhanced phasic GABA release onto these cells. Chronic ethanol increased CRF1+ neuronal excitability but did not significantly alter phasic or tonic GABA signaling in either CRF1+ or CRF1- cells. Chronic ethanol and withdrawal also did not alter basal extracellular GABA or glutamate transmitter levels in the LA/BLA and did not alter the sensitivity of GABA or glutamate to acute ethanol-induced increases in transmitter release. Together, these results provide the first characterization of the CRF1+ population of LA neurons and suggest mechanisms for differential acute ethanol sensitivity within this region.


Asunto(s)
Alcoholismo , Etanol , Amígdala del Cerebelo/metabolismo , Animales , Hormona Liberadora de Corticotropina/metabolismo , Etanol/farmacología , Masculino , Ratones , Neuronas/metabolismo , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Ácido gamma-Aminobutírico
10.
Addict Biol ; 25(5): e12813, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-31339221

RESUMEN

Administration of selective serotonin reuptake inhibitors (SSRIs), typically used as antidepressants, induces long-lasting behavioral changes associated with alcohol use disorder (AUD). However, the contribution of SSRI (fluoxetine)-induced alterations in neurobiological processes underlying alcohol relapse such as endocannabinoid and glutamate signaling in the central amygdala (CeA) remains largely unknown. We utilized an integrative approach to study the effects of repeated fluoxetine administration during abstinence on ethanol drinking. Gene expression and biochemical and electrophysiological studies explored the hypothesis that dysregulation in glutamatergic and endocannabinoid mechanisms in the CeA underlie the susceptibility to alcohol relapse. Cessation of daily treatment with fluoxetine (10 mg/kg) during abstinence resulted in a marked increase in ethanol seeking during re-exposure periods. The increase in ethanol self-administration was associated with (a) reductions in levels of the endocannabinoids N-arachidonoylethanolomine and 2-arachidonoylglycerol in the CeA, (b) increased amygdalar gene expression of cannabinoid type-1 receptor (CB1), N-acyl phosphatidylethanolamine phospholipase D (Nape-pld), fatty acid amid hydrolase (Faah), (c) decreased amygdalar gene expression of ionotropic AMPA (GluA2 and GluA4) and metabotropic (mGlu3) glutamate receptors, and (d) increased glutamatergic receptor function. Overall, our data suggest that the administration of the antidepressant fluoxetine during abstinence dysregulates endocannabinoid signaling and glutamatergic receptor function in the amygdala, facts that likely facilitate alcohol drinking behavior during relapse.


Asunto(s)
Alcoholismo/fisiopatología , Núcleo Amigdalino Central/efectos de los fármacos , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Endocannabinoides/metabolismo , Fluoxetina/farmacología , Ácido Glutámico/metabolismo , Animales , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Wistar , Recurrencia , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Transducción de Señal/efectos de los fármacos , Síndrome de Abstinencia a Sustancias/fisiopatología
11.
Proteomes ; 6(4)2018 Dec 09.
Artículo en Inglés | MEDLINE | ID: mdl-30544849

RESUMEN

Drug addiction is a complex disorder driven by dysregulation in molecular signaling across several different brain regions. Limited therapeutic options currently exist for treating drug addiction and related psychiatric disorders in clinical populations, largely due to our incomplete understanding of the molecular pathways that influence addiction pathology. Recent work provides strong evidence that addiction-related behaviors emerge from the convergence of many subtle changes in molecular signaling networks that include neuropeptides (neuropeptidome), protein-protein interactions (interactome) and post-translational modifications such as protein phosphorylation (phosphoproteome). Advancements in mass spectrometry methodology are well positioned to identify these novel molecular underpinnings of addiction and further translate these findings into druggable targets for therapeutic development. In this review, we provide a general perspective of the utility of novel mass spectrometry-based approaches for addressing critical questions in addiction neuroscience, highlighting recent innovative studies that exemplify how functional assessments of the neuroproteome can provide insight into the mechanisms of drug addiction.

12.
Neuropsychopharmacology ; 43(9): 1840-1850, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29748627

RESUMEN

Negative emotional states that are associated with excessive alcohol intake, particularly anxiety-like states, have been linked to opponent processes in the central nucleus of the amygdala (CeA), affecting stress-related transmitters and monoamines. This study extends these observations to include endocannabinoid signaling in alcohol-dependent animals. Rats and mice were exposed to chronic intermittent alcohol with vapor inhalation or liquid diet to induce dependence. In vivo microdialysis was used to estimate interstitial concentrations of endocannabinoids [N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG)] and amino acids (glutamate and GABA) in rat CeA. Additionally, we evaluated the inhibition of endocannabinoids clearance enzymes [monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase] on anxiety-like behavior and alcohol consumption in alcohol-dependent rats and mice. Results revealed that alcohol dependence produced decreases in baseline 2-AG dialysate levels and increases in baseline levels of glutamate and GABA. Acute alcohol abstinence induced an enhancement of these dependence-induced effects and the levels of 2-AG and GABA were restored upon alcohol re-exposure. Additional studies showed that the increased CeA 2-AG levels induced by restraint stress and alcohol self-administration were blunted in alcohol-dependent rats. Pharmacological studies in rats and mice showed that anxiety-like behavior and alcohol consumption were increased in alcohol-dependent animals, and these behavioral effects were attenuated mainly by MAGL inhibitors [MJN110 (10 and 20 mg/kg) in rats and JZL184 (1 and 3 mg/kg) in mice]. The present results suggest a key role for endocannabinoid signaling in motivational neuroadaptations during alcohol dependence, in which a deficiency in CeA 2-AG signaling in alcohol-dependent animals is linked to stress and excessive alcohol consumption.


Asunto(s)
Alcoholismo/metabolismo , Alcoholismo/psicología , Ansiedad/metabolismo , Núcleo Amigdalino Central/metabolismo , Endocannabinoides/metabolismo , Amidohidrolasas/antagonistas & inhibidores , Amidohidrolasas/metabolismo , Animales , Ansiedad/inducido químicamente , Núcleo Amigdalino Central/efectos de los fármacos , Depresores del Sistema Nervioso Central/administración & dosificación , Etanol/administración & dosificación , Ácido Glutámico/metabolismo , Masculino , Ratones Endogámicos C57BL , Monoacilglicerol Lipasas/antagonistas & inhibidores , Monoacilglicerol Lipasas/metabolismo , Ratas Wistar , Ácido gamma-Aminobutírico/metabolismo
13.
Addict Biol ; 23(5): 1117-1129, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-28940879

RESUMEN

Repeated cycles of alcohol [ethanol (EtOH)] intoxication and withdrawal dysregulate excitatory glutamatergic systems in the brain and induce neuroadaptations in the medial prefrontal cortex (mPFC) that contribute to cognitive dysfunction. The mPFC is composed of subdivisions that are functionally distinct, with dorsal regions facilitating drug-cue associations and ventral regions modulating new learning in the absence of drug. A key modulator of glutamatergic activity is the holoenzyme calcium/calmodulin-dependent protein kinase II (CaMKII) that phosphorylates ionotropic glutamate receptors. Here, we examined the hypothesis that abstinence from chronic intermittent EtOH (CIE) exposure dysregulates CaMKII activity in the mPFC to impair cognitive flexibility. We used an operant model of strategy set shifting in male Long-Evans rats demonstrating reduced susceptibility to trial omissions during performance in a visual cue-guided task versus albino strains. Relative to naïve controls, rats experiencing approximately 10 days of abstinence from CIE vapor exposure demonstrated impaired performance during a procedural shift from visual cue to spatial location discrimination. Phosphorylation of CaMKII subtype α was upregulated in the dorsal, but not ventral mPFC of CIE-exposed rats, and was positively correlated with perseverative-like responding during the set shift. The findings suggest that abstinence from CIE exposure induces an undercurrent of kinase activity (e.g. CaMKII), which may promote aberrant glutamatergic responses in select regions of the mPFC. Given the role of the mPFC in modulating executive control of behavior, we propose that increased CaMKII subtype α activity reflects a dysregulated 'top-down' circuit that interferes with adaptive behavioral performance under changing environmental demands.


Asunto(s)
Alcoholismo/complicaciones , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Disfunción Cognitiva/etiología , Etanol/farmacología , Corteza Prefrontal/metabolismo , Alcoholismo/genética , Alcoholismo/fisiopatología , Animales , Conducta Animal/efectos de los fármacos , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Depresores del Sistema Nervioso Central/farmacología , Cognición/efectos de los fármacos , Disfunción Cognitiva/fisiopatología , Modelos Animales de Enfermedad , Masculino , Fosforilación , Ratas , Ratas Long-Evans
14.
Addict Biol ; 23(5): 1046-1054, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-28940989

RESUMEN

The aversive effect of nicotine withdrawal is greater in female versus male rats, and we postulate that this sex difference is mediated in the nucleus accumbens (NAc). Nicotine withdrawal induces decreases in NAc dopamine and increases in acetylcholine (ACh) levels in male rats. To our knowledge, these neurochemical markers of nicotine withdrawal have not been compared in female versus male rats. Given the role of amino acids in modulating NAc dopaminergic and cholinergic transmission, concomitant measures of gamma-aminobutyric acid (GABA) and glutamate levels were also compared across sex. Rats received continuous nicotine exposure for 14 days, and then NAc dialysate was collected during baseline and following administration of the nicotinic receptor antagonist mecamylamine to precipitate withdrawal. Chronic nicotine exposure was associated with larger increases in baseline dopamine, GABA and glutamate levels in the NAc of female versus male rats, whereas baseline ACh was only increased in male rats. During withdrawal, both sexes displayed equivalent increases in NAc ACh levels. As expected, male rats displayed decreases in dopamine, coupled with increases in GABA and decreases in glutamate levels, suggesting the possibility of increased inhibitory tone in the NAc during withdrawal. Relative to males, female rats displayed larger decreases in NAc dopamine and related increases in GABAergic transmission. As female rats also showed elevated glutamate levels that persist during withdrawal, it is suggested that sex differences may arise from increased glutamatergic drive of inhibitory tone in the NAc. The findings provide a potential mechanism whereby the aversive effects of nicotine withdrawal are enhanced in female rats.


Asunto(s)
Dopamina/metabolismo , Ácido Glutámico/metabolismo , Núcleo Accumbens/metabolismo , Síndrome de Abstinencia a Sustancias/metabolismo , Tabaquismo/metabolismo , Aminoácidos/metabolismo , Animales , Modelos Animales de Enfermedad , Femenino , Masculino , Mecamilamina/administración & dosificación , Nicotina/metabolismo , Antagonistas Nicotínicos/administración & dosificación , Ratas , Ratas Wistar , Factores Sexuales
15.
J Neurosci ; 37(7): 1853-1861, 2017 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-28202787

RESUMEN

Persons with alcoholism who are abstinent exhibit persistent impairments in the capacity for response inhibition, and this form of impulsivity is significantly associated with heightened relapse risk. Brain-imaging studies implicate aberrant prefrontal cortical function in this behavioral pathology, although the underlying mechanisms are not understood. Here we present evidence that deficient activation of glycine and serine release in the ventral medial prefrontal cortex (vmPFC) contributes to increased motor impulsivity during protracted abstinence from long-term alcohol exposure. Levels of 12 neurotransmitters were monitored in the rat vmPFC during the performance of a challenging variant of the five-choice serial reaction time task (5-CSRTT) in which alcohol-exposed rats exhibit excessive premature responding. Following long-term ethanol exposure, rats showed blunted task-related recruitment of vmPFC glycine and serine release, and the loss of an inverse relationship between levels of these neurotransmitters and premature responding normally evident in alcohol-naive subjects. Intra-vmPFC administration of the glycine transport inhibitor ALX5407 prevented excessive premature responding by alcohol-exposed rats, and this was reliant on NMDA glycine site availability. Alcohol-exposed rats and controls did not differ in their premature responding and glycine and serine levels in vmPFC during the performance of the standard 5-CSRTT. Collectively, these findings provide novel insight into cortical neurochemical mechanisms contributing to increased impulsivity following long-term alcohol exposure and highlight the NMDA receptor coagonist site as a potential therapeutic target for increased impulsivity that may contribute to relapse risk.SIGNIFICANCE STATEMENT Persons with alcoholism demonstrate increased motor impulsivity during abstinence; however, the neuronal mechanisms underlying these behavioral effects remain unknown. Here, we took advantage of an animal model that shows deficiencies in inhibitory control following prolonged alcohol exposure to investigate the neurotransmitters that are potentially responsible for dysregulated motor impulsivity following long-term alcohol exposure. We found that increased motor impulsivity is associated with reduced recruitment of glycine and serine neurotransmitters in the ventromedial prefrontal cortex (vmPFC) cortex in rats following long-term alcohol exposure. Administration of glycine transport inhibitor ALX5407 in the vmPFC alleviated deficits in impulse control.


Asunto(s)
Abstinencia de Alcohol , Consumo de Bebidas Alcohólicas/fisiopatología , Glicina/metabolismo , Conducta Impulsiva/fisiología , Transducción de Señal/fisiología , Animales , Depresores del Sistema Nervioso Central/efectos adversos , Conducta de Elección/efectos de los fármacos , Modelos Animales de Enfermedad , Etanol/efectos adversos , Antagonistas de Aminoácidos Excitadores/farmacología , Transportador 2 de Aminoácidos Excitadores/antagonistas & inhibidores , Masculino , Neurotransmisores/metabolismo , Estimulación Luminosa , Quinolonas/farmacología , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacos , Sarcosina/análogos & derivados , Sarcosina/farmacología , Serina/metabolismo , Serina/farmacología , Transducción de Señal/efectos de los fármacos
16.
Biol Psychiatry ; 82(7): 500-510, 2017 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-28209423

RESUMEN

BACKGROUND: Corticotropin-releasing factor (CRF) mediates anxiogenic responses by activating CRF type 1 (CRF1) receptors in limbic brain regions. Anxiety is further modulated by the endogenous cannabinoid (eCB) system that attenuates the synaptic effects of stress. In the amygdala, acute stress activates the enzymatic clearance of the eCB N-arachidonoylethanolamine via fatty acid amide hydrolase (FAAH), although it is unclear whether chronic dysregulation of CRF systems induces maladaptive changes in amygdalar eCB signaling. Here, we used genetically selected Marchigian Sardinian P (msP) rats carrying an innate overexpression of CRF1 receptors to study the role of constitutive upregulation in CRF systems on amygdalar eCB function and persistent anxiety-like effects. METHODS: We applied behavioral, pharmacological, and biochemical methods to broadly characterize anxiety-like behaviors and amygdalar eCB clearance enzymes in msP versus nonselected Wistar rats. Subsequent studies examined the influence of dysregulated CRF and FAAH systems in altering excitatory transmission in the central amygdala (CeA). RESULTS: msPs display an anxious phenotype accompanied by elevations in amygdalar FAAH activity and reduced dialysate N-arachidonoylethanolamine levels in the CeA. Elevations in CRF-CRF1 signaling dysregulate FAAH activity, and this genotypic difference is normalized with pharmacological blockade of CRF1 receptors. msPs also exhibit elevated baseline glutamatergic transmission in the CeA, and dysregulated CRF-FAAH facilitates stress-induced increases in glutamatergic activity. Treatment with an FAAH inhibitor relieves sensitized glutamatergic responses in msPs and attenuates the anxiety-like phenotype. CONCLUSIONS: Pathological anxiety and stress hypersensitivity are driven by constitutive increases in CRF1 signaling that dysregulate N-arachidonoylethanolamine signaling mechanisms and reduce neuronal inhibitory control of CeA glutamatergic synapses.


Asunto(s)
Amidohidrolasas/metabolismo , Amígdala del Cerebelo/metabolismo , Ansiedad/patología , Hormona Liberadora de Corticotropina/metabolismo , Amidohidrolasas/antagonistas & inhibidores , Amígdala del Cerebelo/efectos de los fármacos , Animales , Ansiedad/tratamiento farmacológico , Cannabinoides/metabolismo , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/genética , Conducta Exploratoria/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Neurotransmisores/metabolismo , Técnicas de Placa-Clamp , Piperidinas/farmacología , Piridinas/farmacología , Pirimidinas/farmacología , Ratas , Ratas Mutantes , Receptores de Hormona Liberadora de Corticotropina/genética , Receptores de Hormona Liberadora de Corticotropina/metabolismo
17.
Proc Natl Acad Sci U S A ; 113(4): 1086-91, 2016 Jan 26.
Artículo en Inglés | MEDLINE | ID: mdl-26755579

RESUMEN

Chronic nicotine exposure (CNE) alters synaptic transmission in the ventral tegmental area (VTA) in a manner that enhances dopaminergic signaling and promotes nicotine use. The present experiments identify a correlation between enhanced production of the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) and diminished release of the inhibitory neurotransmitter GABA in the VTA following CNE. To study the functional role of on-demand 2-AG signaling in GABAergic synapses, we used 1,2,3-triazole urea compounds to selectively inhibit 2-AG biosynthesis by diacylglycerol lipase (DAGL). The potency and selectivity of these inhibitors were established in rats in vitro (rat brain proteome), ex vivo (brain slices), and in vivo (intracerebroventricular administration) using activity-based protein profiling and targeted metabolomics analyses. Inhibition of DAGL (2-AG biosynthesis) rescues nicotine-induced VTA GABA signaling following CNE. Conversely, enhancement of 2-AG signaling in naïve rats by inhibiting 2-AG degradation recapitulates the loss of nicotine-induced GABA signaling evident following CNE. DAGL inhibition reduces nicotine self-administration without disrupting operant responding for a nondrug reinforcer or motor activity. Collectively, these findings provide a detailed characterization of selective inhibitors of rat brain DAGL and demonstrate that excessive 2-AG signaling contributes to a loss of inhibitory GABAergic constraint of VTA excitability following CNE.


Asunto(s)
Lipoproteína Lipasa/antagonistas & inhibidores , Nicotina/farmacología , Área Tegmental Ventral/efectos de los fármacos , Animales , Ácidos Araquidónicos/análisis , Ácidos Araquidónicos/antagonistas & inhibidores , Ácidos Araquidónicos/fisiología , Endocannabinoides/análisis , Endocannabinoides/antagonistas & inhibidores , Endocannabinoides/fisiología , Glicéridos/análisis , Glicéridos/antagonistas & inhibidores , Glicéridos/fisiología , Masculino , Ratas , Ratas Wistar , Autoadministración , Área Tegmental Ventral/fisiología , Ácido gamma-Aminobutírico/metabolismo
18.
Addict Biol ; 20(2): 263-74, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24341858

RESUMEN

Impulsivity is a risk factor for alcoholism, and long-term alcohol exposure may further impair impulse control in a manner that propels problematic alcohol use. The present study employed the rat 5-choice serial reaction time task (5-CSRTT) to measure behavioral inhibition and attentional capacity during abstinence from repeated 5-day cycles of alcohol liquid diet consumption. Task performance was not disrupted following the first cycle of alcohol exposure; however, evidence of impaired behavioral inhibition emerged following the third cycle of alcohol exposure. In comparison with controls, alcoholic rats exhibited deficits in inhibitory control during cognitively challenging 5-CSRTT tests employing variable intertrial interval (varITI). This behavioral disruption was not present during early abstinence (3 days) but was evident by 7 days of abstinence and persisted for at least 34 days. Interestingly, renewed alcohol consumption ameliorated these disruptions in impulse control, although deficient behavioral inhibition re-emerged during subsequent abstinence. Indices of increased impulsivity were no longer present in tests conducted after 49 days of abstinence. Alcohol-related impairments in impulse control were not evident in sessions employing highly familiar task parameters regardless of the abstinence period, and control experiments confirmed that performance deficits during the challenge sessions were unlikely to result from alcohol-related disruption in the adaptation to repeated varITI testing. Together, the current findings demonstrate that chronic intermittent alcohol consumption results in decreased behavioral inhibition in rats that is temporally similar to clinical observations of disrupted impulsive control in abstinent alcoholics performing tasks of behavioral inhibition.


Asunto(s)
Abstinencia de Alcohol , Intoxicación Alcohólica , Atención , Conducta Impulsiva , Inhibición Psicológica , Animales , Ratas , Ratas Wistar
19.
Dev Neurosci ; 36(3-4): 347-55, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24854235

RESUMEN

Adolescence is a unique period of development characterized by enhanced tobacco use and long-term vulnerability to neurochemical changes produced by adolescent nicotine exposure. In order to understand the underlying mechanisms that contribute to developmental differences in tobacco use, this study compared changes in cholinergic transmission during nicotine exposure and withdrawal in naïve adult rats compared to (1) adolescent rats and (2) adult rats that were pre-exposed to nicotine during adolescence. The first study compared extracellular levels of acetylcholine (ACh) in the nucleus accumbens (NAc) during nicotine exposure and precipitated withdrawal using microdialysis procedures. Adolescent (postnatal day, PND, 28-42) and adult rats (PND60-74) were prepared with osmotic pumps that delivered nicotine for 14 days (adolescents 4.7 mg/kg/day; adults 3.2 mg/kg/day; expressed as base). Another group of adults was exposed to nicotine during adolescence and then again in adulthood (pre-exposed adults) using similar methods. Control rats received a sham surgery. Following 13 days of nicotine exposure, the rats were implanted with microdialysis probes in the NAc. The following day, dialysis samples were collected during baseline and following systemic administration of the nicotinic receptor antagonist mecamylamine (1.5 and 3.0 mg/kg, i.p.) to precipitate withdrawal. A second study compared various metabolic differences in cholinergic transmission using the same treatment procedures as the first study. Following 14 days of nicotine exposure, the NAc was dissected and acetylcholinesterase (AChE) activity was compared across groups. In order to examine potential group differences in nicotine metabolism, blood plasma levels of cotinine (a nicotine metabolite) were also compared following 14 days of nicotine exposure. The results from the first study revealed that nicotine exposure increased baseline ACh levels to a greater extent in adolescent versus adult rats. During nicotine withdrawal, ACh levels in the NAc were increased in a similar manner in adolescent versus adult rats. However, the increase in ACh that was observed in adult rats experiencing nicotine withdrawal was blunted in pre-exposed adults. These neurochemical effects do not appear to be related to nicotine metabolism, as plasma cotinine levels were similar across all groups. The second study revealed that nicotine exposure increased AChE activity in the NAc to a greater extent in adolescent versus adult rats. There was no difference in AChE activity in pre-exposed versus naïve adult rats. In conclusion, our results suggest that nicotine exposure during adolescence enhances baseline ACh in the NAc. However, the finding that ACh levels were similar during withdrawal in adolescent and adult rats suggests that the enhanced vulnerability to tobacco use during adolescence is not related to age differences in withdrawal-induced increases in cholinergic transmission. Our results also suggest that exposure to nicotine during adolescence suppresses withdrawal-induced increases in cholinergic responses during withdrawal. Taken together, this report illustrates important short- and long-term changes within cholinergic systems that may contribute to the enhanced susceptibility to tobacco use during adolescence.


Asunto(s)
Envejecimiento/psicología , Nicotina , Agonistas Nicotínicos , Sistema Nervioso Parasimpático/efectos de los fármacos , Fumar/psicología , Síndrome de Abstinencia a Sustancias/fisiopatología , Transmisión Sináptica/efectos de los fármacos , Acetilcolina/metabolismo , Acetilcolinesterasa/metabolismo , Animales , Cotinina/metabolismo , Masculino , Nicotina/metabolismo , Agonistas Nicotínicos/metabolismo , Núcleo Accumbens/metabolismo , Ratas , Ratas Wistar
20.
Addict Biol ; 19(6): 1006-19, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23834715

RESUMEN

Patients with diabetes display a heightened propensity to use tobacco; however, it is unclear whether they experience enhanced rewarding effects of nicotine. Thus, this study examined the reinforcing effects of nicotine in a rodent model of diabetes involving administration of streptozotocin (STZ), a drug that is toxic to pancreatic insulin-producing cells. The first study compared STZ- and vehicle-treated rats that had 23-hour access to intravenous self-administration (IVSA) of nicotine or saline and concomitant access to food and water. In order to examine the contribution of dopamine to our behavioral effects, dopamine transporter (DAT), D1 and D2 receptor levels were compared in the nucleus accumbens (NAc) following 10 days of nicotine or saline IVSA. Dopamine levels in the NAc were also compared following nicotine administration. Lastly, nicotine metabolism and dose-dependent effects of nicotine IVSA were assessed. The results revealed that STZ-treated rats displayed enhanced nicotine intake and a robust increase in food and water intake relative to controls. Protein analysis revealed an increase in DAT and a decrease in D1 receptor levels in the NAc of STZ- versus vehicle-treated rats regardless of IVSA condition. STZ-treated rats also displayed suppressed NAc dopamine levels during baseline and in response to nicotine. STZ treatment did not alter our assessment of nicotine metabolism. Furthermore, STZ treatment increased nicotine IVSA in a dose-dependent manner. Our findings suggest that STZ-treatment increased the rewarding effects of nicotine. This suggests that strong reinforcing effects of nicotine may contribute to greater tobacco use in patients with diabetes.


Asunto(s)
Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Recompensa , Animales , Glucemia/metabolismo , Condicionamiento Operante/efectos de los fármacos , Diabetes Mellitus Experimental , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Relación Dosis-Respuesta a Droga , Infusiones Intravenosas , Masculino , Nicotina/farmacocinética , Agonistas Nicotínicos/farmacocinética , Núcleo Accumbens/metabolismo , Ratas Wistar , Refuerzo en Psicología , Autoadministración
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