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1.
Drug Alcohol Depend ; 130(1-3): 150-7, 2013 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-23200303

RESUMEN

BACKGROUND: Cocaine abuse continues to be a significant public health problem associated with morbidity and mortality. To date, no pharmacotherapeutic approach has proven effective for treating cocaine use disorders. Preclinical and clinical evidence suggests that noradrenergic activity may play a role in mediating some effects of cocaine and may be a rational target for treatment. METHODS: This double blind, placebo-controlled randomized, parallel group, 12-week outpatient clinical trial enrolled cocaine dependent individuals seeking treatment to examine the potential efficacy of the selective norepinephrine reuptake inhibitor, atomoxetine (80 mg/day; p.o.; n = 25), compared to placebo (n = 25). Subjects were initially stratified on cocaine use (< 15 days or ≥ 15 days of the last 30), age and race using urn randomization. Attendance, medication adherence and study compliance were reinforced with contingency management, and weekly counseling was offered. An array of measures (vital signs, laboratory chemistries, cognitive and psychomotor tests, cocaine craving and urine samples for drug testing) was collected throughout the study and at follow-up. RESULTS: Survival analysis revealed no differences in study retention between the two groups, with approximately 56% of subjects completing the 12-week study (Cox analysis χ(2) = .72; p = .40; Hazard Ratio 1.48 [95% CI 0.62-3.39]). GEE analysis of the proportion of urine samples positive for benzoylecgonine, a cocaine metabolite, revealed no differences between the atomoxetine and placebo groups (χ(2) = 0.2, p = .66; OR = 0.89 [95% CI 0.41-1.74]). Atomoxetine was generally well tolerated in this population. CONCLUSIONS: These data provide no support for the utility of atomoxetine in the treatment of cocaine dependence.


Asunto(s)
Trastornos Relacionados con Cocaína/tratamiento farmacológico , Trastornos Relacionados con Cocaína/psicología , Propilaminas/uso terapéutico , Adolescente , Adulto , Clorhidrato de Atomoxetina , Trastornos Relacionados con Cocaína/diagnóstico , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto Joven
2.
Exp Clin Psychopharmacol ; 20(4): 310-7, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22686495

RESUMEN

Oxycodone, an opioid with known abuse liability, is misused by the intranasal route. Our objective was to develop a model of intranasal oxycodone self-administration useful for assessing the relative reinforcing effects of opioids and potential pharmacotherapies for opioid use disorders. Healthy, sporadic intranasal opioid abusers (n = 8; 7 M, 1 F) completed this inpatient 2.5-week, randomized, double-blind, placebo-controlled, crossover study. Each intranasal oxycodone dose (0, 14 & 28 mg) was tested in a separate 3-day block of sessions. The first day of each block was a sample session in which the test dose was given. Two randomized progressive ratio sessions were conducted on the next 2 days: (1) subjects could work for the test dose over 7 trials (1/7th of total dose/trial), and (2) subjects could work for either a portion of the dose (1/7th) or money ($3) over 7 trials. Physiological and subjective measures were collected before and after drug administration for all sessions. Subjects never worked to self-administer placebo regardless of whether money was available. In both self-administration sessions, oxycodone self-administration was dose-dependent. Subjects worked less for drug (28 mg oxycodone) when money was available but only modestly so. Oxycodone dose-dependently increased VAS ratings of positive drug effects (e.g., "like") during sample sessions (p < .05). These reports were positively correlated with self-administration behavior (e.g., "like," r = .65). These data suggest that both procedures are sensitive for detecting the reinforcing properties of intranasal oxycodone and may be used to further explore the characteristics of opioid compounds and potential pharmacotherapies for treatment.


Asunto(s)
Trastornos Relacionados con Opioides/fisiopatología , Oxicodona/administración & dosificación , Administración Intranasal , Método Doble Ciego , Femenino , Humanos , Masculino , Placebos , Autoadministración
3.
Psychopharmacology (Berl) ; 217(4): 485-94, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21559804

RESUMEN

RATIONALE: Cannabis users display a constellation of withdrawal symptoms upon drug discontinuation, including sleep disturbances, irritability, and possibly memory deficits. In cannabinoid-dependent rodents, the CB(1) antagonist rimonabant precipitates somatic withdrawal and enhances forskolin-stimulated adenylyl cyclase activity in cerebellum, an effect opposite that of acutely administered ∆(9)-tetrahydrocannabinol (THC), the primary constituent in cannabis. OBJECTIVES: Here, we tested whether THC-dependent mice undergoing rimonabant-precipitated withdrawal display short-term spatial memory deficits, as assessed in the Morris water maze. We also evaluated whether rimonabant would precipitate adenylyl cyclase superactivation in hippocampal and cerebellar tissue from THC-dependent mice. RESULTS: Rimonabant significantly impaired spatial memory of THC-dependent mice at lower doses than those necessary to precipitate somatic withdrawal behavior. In contrast, maze performance was near perfect in the cued task, suggesting sensorimotor function and motivational factors were unperturbed by the withdrawal state. Finally, rimonabant increased adenylyl cyclase activity in cerebellar, but not in hippocampal, membranes. CONCLUSIONS: The memory disruptive effects of THC undergo tolerance following repeated dosing, while the withdrawal state leads to a rebound deficit in memory. These results establish spatial memory impairment as a particularly sensitive component of cannabinoid withdrawal, an effect that may be mediated through compensatory changes in the cerebellum.


Asunto(s)
Dronabinol/efectos adversos , Abuso de Marihuana/psicología , Trastornos de la Memoria/inducido químicamente , Memoria a Corto Plazo/efectos de los fármacos , Conducta Espacial/efectos de los fármacos , Síndrome de Abstinencia a Sustancias/psicología , Animales , Relación Dosis-Respuesta a Droga , Dronabinol/antagonistas & inhibidores , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/psicología , Ratones , Ratones Endogámicos C57BL , Piperidinas/farmacología , Pirazoles/farmacología , Rimonabant
4.
Addiction ; 106(8): 1460-73, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21395892

RESUMEN

AIMS: Sublingual buprenorphine and buprenorphine/naloxone are efficacious opioid dependence pharmacotherapies, but there are reports of their diversion and misuse by the intranasal route. The study objectives were to characterize and compare their intranasal pharmacodynamic and pharmacokinetic profiles. DESIGN: A randomized, double-blind, placebo-controlled, cross-over study. SETTING: An in-patient research unit at the University of Kentucky. PARTICIPANTS: Healthy adults (n = 10) abusing, but not physically dependent on, intranasal opioids. MEASUREMENTS: Six sessions (72 hours apart) tested five intranasal doses [0/0, crushed buprenorphine (2, 8 mg), crushed buprenorphine/naloxone (2/0.5, 8/2 mg)] and one intravenous dose (0.8 mg buprenorphine/0.2 mg naloxone for bioavailability assessment). Plasma samples, physiological, subject- and observer-rated measures were collected before and for up to 72 hours after drug administration. FINDINGS: Both formulations produced time- and dose-dependent increases on subjective and physiological mu-opioid agonist effects (e.g. 'liking', miosis). Subjects reported higher subjective ratings and street values for 8 mg compared to 8/2 mg, but these differences were not statistically significant. No significant formulation differences in peak plasma buprenorphine concentration or time-course were observed. Buprenorphine bioavailability was 38-44% and T(max) was 35-40 minutes after all intranasal doses. Naloxone bioavailability was 24% and 30% following 2/0.5 and 8/2 mg, respectively. CONCLUSIONS: It is difficult to determine if observed differences in abuse potential between intranasal buprenorphine and buprenorphine/naloxone are clinically relevant at the doses tested. Greater bioavailability and faster onset of pharmacodynamic effects compared to sublingual administration suggests a motivation for intranasal misuse in non-dependent opioid abusers. However, significant naloxone absorption from intranasal buprenorphine/naloxone administration may deter the likelihood of intranasal misuse of buprenorphine/naloxone, but not buprenorphine, in opioid-dependent individuals.


Asunto(s)
Buprenorfina/farmacocinética , Naloxona/farmacocinética , Antagonistas de Narcóticos/farmacocinética , Trastornos Relacionados con Opioides/metabolismo , Administración Intranasal , Adulto , Análisis de Varianza , Área Bajo la Curva , Disponibilidad Biológica , Buprenorfina/administración & dosificación , Buprenorfina/metabolismo , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Combinación de Medicamentos , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Naloxona/administración & dosificación , Naloxona/metabolismo , Antagonistas de Narcóticos/administración & dosificación , Antagonistas de Narcóticos/metabolismo , Trastornos Relacionados con Opioides/tratamiento farmacológico , Trastornos Relacionados con Opioides/prevención & control , Comprimidos , Factores de Tiempo
5.
Eur J Pharmacol ; 554(2-3): 128-36, 2007 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-17141211

RESUMEN

In previous in vivo voltammetry studies, acute nicotine administration increased striatal dopamine clearance. The current study aimed to determine whether nicotine also increases [(3)H]dopamine uptake across the time course of the previous voltammetry studies and whether dopamine transporter trafficking to the cell surface mediates the nicotine-induced augmentation of dopamine clearance in striatum. Rats were administered nicotine (0.32 mg/kg, s.c.); striatal synaptosomes were obtained 5, 10, 40 or 60 min later. Nicotine increased (25%) the V(max) of [(3)H]dopamine uptake at 10 and 40 min. To determine whether the increase in V(max) was due to an increase in dopamine transporter density, [(3)H]GBR 12935 (1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride) binding was performed using rat striatal membranes; no differences were found between nicotine and saline-control groups at 5, 10 or 40 min post-injection, indicating that nicotine did not increase striatal dopamine transporter density; however, [(3)H]GBR 12935 binding assays determine both cell surface and intracellular dopamine transporter. Changes in cellular dopamine transporter localization in striatum were determined using biotinylation and subfractionation approaches; no differences between nicotine and saline-control groups were observed at 10 and 40 min post-injection. These results suggest that the nicotine-induced increase in dopamine uptake and clearance in striatum may occur via a trafficking-independent mechanism.


Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/fisiología , Nicotina/farmacología , Animales , Unión Competitiva/efectos de los fármacos , Transporte Biológico/fisiología , Western Blotting/métodos , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Cuerpo Estriado/metabolismo , Dopamina/farmacocinética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/análisis , Estimulantes Ganglionares/administración & dosificación , Estimulantes Ganglionares/farmacología , Inyecciones Subcutáneas , Cinética , Masculino , Nicotina/administración & dosificación , Piperazinas/metabolismo , Ratas , Ratas Sprague-Dawley , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Factores de Tiempo , Tritio
6.
Synapse ; 61(3): 157-65, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17146768

RESUMEN

Nornicotine, a tobacco alkaloid and N-demethylated nicotine metabolite, releases DA from superfused rat striatal slices in a mecamylamine-sensitive manner, indicating nicotinic receptor (nAChR) modulation of this response. The current study determined the effect of nornicotine on rat striatal dopamine transporter (DAT) function using in vivo voltammetry. In a dose-related and mecamylamine-sensitive manner, nornicotine (0.35-12.0 mg/kg, s.c.) decreased DA clearance, suggesting that nornicotine inhibits striatal DAT function via a nAChR-mediated mechanism. Furthermore, the nAChRs mediating the nornicotine-induced inhibition of DAT function appear to be different from those activated by nicotine which increases DA clearance. Understanding the actions of nornicotine in brain may have significance for emerging therapeutics and for the management of nicotine dependence.


Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Dopamina/metabolismo , Nicotina/análogos & derivados , Agonistas Nicotínicos/farmacología , Receptores Nicotínicos/efectos de los fármacos , Acetilcolina/metabolismo , Animales , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiopatología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas/fisiología , Insecticidas/farmacología , Masculino , Mecamilamina/farmacología , Tasa de Depuración Metabólica/efectos de los fármacos , Tasa de Depuración Metabólica/fisiología , Nicotina/farmacología , Antagonistas Nicotínicos/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Nicotínicos/metabolismo , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Factores de Tiempo , Tabaquismo/metabolismo , Tabaquismo/fisiopatología
7.
Brain Res Dev Brain Res ; 153(2): 213-23, 2004 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-15527889

RESUMEN

The present study determined if environmental enrichment modifies the effects of prenatal cocaine on open field activity, social interaction and dopamine transporter (DAT) function in the medial prefrontal cortex (mPFC) in rats. Cocaine (40 mg/kg) or saline was administered (s.c.) to pregnant dams from gestation days 8 to 20 (PCOC and PSAL, respectively). At postnatal day 25 (PND 25), female offspring from PCOC and PSAL groups were assigned to the enriched condition (EC; PCOC/EC and PSAL/EC) or impoverished condition (IC; PCOC/IC and PSAL/IC). On PND 60, 90 and 120, locomotor activity, rearing behavior and social interactions were assessed in the open field. On PND 345, rats were anesthetized, challenged with nicotine (0.4 mg/kg), and DAT function in medial prefrontal cortex (mPFC) was assessed using in vivo voltammetry. EC groups displayed decreased locomotor activity across test days, while activity in IC groups did not habituate across days. Generally, PCOC groups displayed more rearing behavior than PSAL groups. During social interaction assessment, IC groups followed their social partner more frequently than EC groups. Moreover, the PCOC/IC group initiated more play solicitations and was engaged in mutual rearing less frequently than PCOC/EC, PSAL/IC and PSAL/EC groups, indicating that epigenetic environmental factors decreased the divergent social behaviors displayed by the PCOC/IC group. Results from in vivo voltammetry experiments demonstrated differences in baseline DAT function in response to environmental enrichment in the prenatal saline groups; however, no effect of prenatal cocaine was observed under baseline conditions. Nicotine challenge unmasked an effect of prenatal cocaine on DA clearance rate in mPFC in the IC groups, which was attenuated by environmental enrichment. Taken together, PCOC/IC rats displayed divergent social interaction and altered DAT function in mPFC, whereas the PCOC/EC group generally was not different from PSAL groups, suggesting that environmental enrichment attenuates the behavioral and neurochemical effects of prenatal cocaine.


Asunto(s)
Conducta Animal/fisiología , Cocaína/toxicidad , Inhibidores de Captación de Dopamina/toxicidad , Ambiente , Glicoproteínas de Membrana/fisiología , Proteínas de Transporte de Membrana/fisiología , Proteínas del Tejido Nervioso/fisiología , Corteza Prefrontal/fisiología , Efectos Tardíos de la Exposición Prenatal , Animales , Conducta Animal/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Dopamina/administración & dosificación , Dopamina/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Electroquímica , Electrofisiología , Femenino , Masculino , Microinyecciones , Nicotina/administración & dosificación , Nicotina/farmacología , Agonistas Nicotínicos/administración & dosificación , Agonistas Nicotínicos/farmacología , Ovariectomía , Corteza Prefrontal/efectos de los fármacos , Embarazo , Ratas , Ratas Long-Evans , Conducta Social
8.
J Pharmacol Exp Ther ; 308(1): 367-77, 2004 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-14563785

RESUMEN

Nicotine activates nicotinic acetylcholine receptors (nAChRs) on dopamine (DA) terminals to evoke DA release, which subsequently is taken back up into the terminal via the DA transporter (DAT). nAChRs may modulate DAT function thereby contributing to the regulation of synaptic DA concentrations. The present study determined the dose-response for nicotine (0.1-0.8 mg/kg, s.c.) to modulate DA clearance in striatum and medial prefrontal cortex (mPFC) using in vivo voltammetry in urethane anesthetized rats and determined if this effect was mediated by nAChRs. Exogenous DA (200 microM) was pressure-ejected at 5-min intervals until reproducible baseline signals were obtained. Subsequently, nicotine or saline was administered, and DA pressure ejection continued at 5-min intervals for 60 min. In both striatum and mPFC, signal amplitude decreased by approximately 20% across the 60-min session in saline-injected rats. A monophasic dose-response curve was found in striatum, with a maximal 50% decrease in signal amplitude after 0.8 mg/kg. In contrast, a U-shaped dose-response curve was found in mPFC, with a maximal 50% decrease in signal amplitude after 0.4 mg/kg. Onset of nicotine response occurred 10 to 15 min after injection in both brain regions; however, the amount of time before maximal response was 45 and 30 min in striatum and mPFC, respectively. Mecamylamine (1.5 mg/kg) completely inhibited the nicotine-induced (0.8 and 0.4 mg/kg) decrease in signal amplitude in striatum and mPFC, respectively, indicating mediation by nAChRs. Thus, nicotine enhances DA clearance in striatum and mPFC in a mecamylamine-sensitive manner, indicating that nAChRs modulate DAT function in these brain regions.


Asunto(s)
Glicoproteínas de Membrana , Proteínas de Transporte de Membrana/metabolismo , Neostriado/metabolismo , Proteínas del Tejido Nervioso , Corteza Prefrontal/metabolismo , Receptores Nicotínicos/metabolismo , Animales , Dopamina/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Masculino , Mecamilamina/farmacología , Tasa de Depuración Metabólica , Nicotina/farmacología , Ratas , Ratas Sprague-Dawley , Receptor Cross-Talk
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