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1.
Psychopharmacology (Berl) ; 231(7): 1277-87, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24221825

RESUMEN

RATIONALE: Although non-medical use of oxycodone continues to be a growing problem in the United States, there are no animal studies examining the effects of long-term oxycodone self-administration (SA). OBJECTIVES: The current study was designed to examine chronic oxycodone SA by mice (14 days), in novel extended (4 h) SA sessions and its effect on selective striatal neurotransmitter receptor mRNA expression. METHODS: Adult male C57/BL6J mice were either allowed to self-administer oxycodone (0.25 mg/kg/infusion, FR1) or served as yoked-saline controls in an extended access paradigm. Mice self-administered oxycodone for 4 h/day for 14 consecutive days. Comparison groups with 14-days exposure to 1-h SA sessions were also studied. Within 1 h of the last extended SA session, mice were sacrificed, dorsal striatum was isolated and selective neurotransmitter receptor mRNA levels were examined. RESULTS: The oxycodone groups poked the active hole significantly more times than the yoked controls. The number of nose pokes at the active hole rose over the 14 days in the oxycodone group with extended access. The expression of 13 neurotransmitter receptor mRNAs was significantly altered in the dorsal striatum, including the gamma-aminobutyric acid (GABA) A receptor beta 2 subunit (Gabrb2) showing experiment-wise significant decrease, as a result of extended oxycodone SA. CONCLUSION: C57BL/6 J mice escalated the amount of oxycodone self-administered across 14 consecutive daily extended sessions, but not 1-h sessions. Decreases in Gabrb2 mRNA levels may underlie escalation of oxycodone intake in the extended access SA sessions.


Asunto(s)
Cuerpo Estriado/metabolismo , Expresión Génica/efectos de los fármacos , Oxicodona/administración & dosificación , Oxicodona/farmacología , Receptores de GABA/genética , Receptores de Neurotransmisores/genética , Animales , Condicionamiento Operante/efectos de los fármacos , Condicionamiento Operante/fisiología , Cuerpo Estriado/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores de GABA/fisiología , Receptores de GABA-A , Autoadministración , Factores de Tiempo
2.
Neuropharmacology ; 67: 259-66, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23164614

RESUMEN

Cocaine addiction is a chronic relapsing disease with periods of chronic escalating self-exposure, separated by periods of abstinence/withdrawal of varying duration. Few studies compare such cycles in preclinical models. This study models an "addiction-like cycle" in mice to determine neurochemical/molecular alterations that underlie the chronic, relapsing nature of this disease. Groups of male C57BL/6J mice received acute cocaine exposure (14-day saline/14-day withdrawal/13-day saline + 1-day cocaine), chronic cocaine exposure (14 day cocaine) or chronic re-exposure (14-day cocaine/14-day withdrawal/14-day cocaine). Escalating-dose binge cocaine (15-30 mg/kg/injection × 3/day, i.p. at hourly intervals) or saline (14-day saline) was administered, modeling initial exposure. In "re-exposure" groups, after a 14-day injection-free period (modeling abstinence/withdrawal), mice that had received cocaine were re-injected with 14-day escalating-dose binge cocaine, whereas controls received saline. Microdialysis was conducted on the 14th day of exposure or re-exposure to determine striatal dopamine content. Messenger RNA levels of preprodynorphin (Pdyn), dopamine D1 (Drd1) and D2 (Drd2) in the caudate putamen were determined by real-time PCR. Basal striatal dopamine levels were lower in mice after 14-day escalating exposure or re-exposure than in those in the acute cocaine group and controls. Pdyn mRNA levels were higher in the cocaine groups than in controls. Long-term adaptation was observed across the stages of this addiction-like cycle, in that the effects of cocaine on dopamine levels were increased after re-exposure compared to exposure. Changes in striatal dopaminergic responses across chronic escalating cocaine exposure and re-exposure are a central feature of the neurobiology of relapsing addictive states.


Asunto(s)
Cocaína/administración & dosificación , Cuerpo Estriado/metabolismo , Dinorfinas/metabolismo , Precursores de Proteínas/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Síndrome de Abstinencia a Sustancias/metabolismo , Animales , Trastornos Relacionados con Cocaína/metabolismo , Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Factores de Tiempo
3.
J Clin Invest ; 122(10): 3387-93, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23023708

RESUMEN

Addictive diseases, including addiction to heroin, prescription opioids, or cocaine, pose massive personal and public health costs. Addictions are chronic relapsing diseases of the brain caused by drug-induced direct effects and persisting neuroadaptations at the epigenetic, mRNA, neuropeptide, neurotransmitter, or protein levels. These neuroadaptations, which can be specific to drug type, and their resultant behaviors are modified by various internal and external environmental factors, including stress responsivity, addict mindset, and social setting. Specific gene variants, including variants encoding pharmacological target proteins or genes mediating neuroadaptations, also modify vulnerability at particular stages of addiction. Greater understanding of these interacting factors through laboratory-based and translational studies have the potential to optimize early interventions for the therapy of chronic addictive diseases and to reduce the burden of relapse. Here, we review the molecular neurobiology and genetics of opiate addiction, including heroin and prescription opioids, and cocaine addiction.


Asunto(s)
Trastornos Relacionados con Cocaína/fisiopatología , Trastornos Relacionados con Opioides/fisiopatología , Animales , Ganglios Basales/efectos de los fármacos , Ganglios Basales/fisiopatología , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Trastornos Relacionados con Cocaína/genética , Dopamina/fisiología , Neuronas Dopaminérgicas/fisiología , Regulación de la Expresión Génica/efectos de los fármacos , Predisposición Genética a la Enfermedad , Humanos , Sistema Hipotálamo-Hipofisario/fisiopatología , Sistema Límbico/efectos de los fármacos , Sistema Límbico/fisiopatología , Metadona/uso terapéutico , Ratones , Ratones Noqueados , Neuropéptidos/fisiología , Trastornos Relacionados con Opioides/tratamiento farmacológico , Trastornos Relacionados con Opioides/genética , Farmacogenética , Sistema Hipófiso-Suprarrenal/fisiopatología , Ratas , Receptores Dopaminérgicos/efectos de los fármacos , Receptores Dopaminérgicos/genética , Receptores Dopaminérgicos/fisiología , Receptores Opioides/efectos de los fármacos , Receptores Opioides/fisiología , Receptores Opioides mu/efectos de los fármacos , Receptores Opioides mu/genética , Receptores Opioides mu/fisiología , Recompensa , Estrés Fisiológico , Estrés Psicológico/fisiopatología
4.
Neuropharmacology ; 63(2): 322-9, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22504589

RESUMEN

UNLABELLED: Relapse is a serious problem for the effective treatment of cocaine addiction. RATIONALE: Examining cocaine re-exposure-induced behavioral and neurobiological alterations following chronic escalating-dose binge cocaine administration and withdrawal may provide insight into the neurobiological basis of cocaine relapse. OBJECTIVES: Our goal was to determine how exposure to chronic escalating-dose cocaine affects development of subsequent cocaine-induced conditioned place preference (CPP) and changes in endogenous opioid systems. METHODS: Mice were injected with either escalating-dose binge cocaine (15-30 mg/kg/injection × 3/day) or saline for 14-days and conditioned with 15 mg/kg of cocaine or saline (once per day for 10-days), starting either 1 or 14-days after the last day of binge injections. RESULTS: Mice exposed to chronic escalating cocaine did not develop CPP to cocaine when conditioning commenced on the first day of withdrawal (CPP test on day 10 of withdrawal). By contrast, mice did develop CPP to cocaine when conditioning started on the 14th day of withdrawal (CPP test on day 24 of withdrawal). Furthermore, preproenkephalin (Penk) mRNA levels in caudate putamen were significantly higher in mice that received 14-day withdrawal from escalating-dose binge cocaine before the CPP procedure (tested 24 days post-binge) than those that received 1-day withdrawal (tested 10 days post-binge). CONCLUSIONS: The rewarding effect of cocaine was blunted in early withdrawal from chronic escalating exposure, but recovered in more prolonged withdrawal. Time-dependent elevations in Penk mRNA levels may be part of the underlying mechanisms of this effect.


Asunto(s)
Cocaína/administración & dosificación , Condicionamiento Operante/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Inhibidores de Captación de Dopamina/administración & dosificación , Encefalinas/metabolismo , Precursores de Proteínas/metabolismo , Síndrome de Abstinencia a Sustancias/metabolismo , Animales , Aprendizaje por Asociación/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Cuerpo Estriado/metabolismo , Esquema de Medicación , Encefalinas/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Precursores de Proteínas/genética , ARN Mensajero/metabolismo
5.
Brain Res ; 1345: 206-12, 2010 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-20478275

RESUMEN

Using real time qPCR, we examined the expression of mRNAs for the five somatostatin receptors (SSTRs) in the caudate putamen of male C57BL/6J and 129P3/J mice. Animals were exposed to multiple injections of heroin, or saline, in the setting of a conditioned place preference study. The relative expression levels of the five SSTR mRNAs differed between the two strains. In both strains, SSTR-1 mRNA was expressed at the highest levels and SSTR-5 at the lowest. Interestingly, in 129P3/J mice SSTR-3 mRNA was not detected in the caudate putamen. We confirmed this finding in the frontal cortex, hypothalamus, nucleus accumbens and a region containing the substantia nigra and ventral tegmental area. We also found strain differences in the mRNA levels of SSTR-2 and -4. Intermittent heroin administration had a dose-dependent effect on the levels of SSTR-1 and -3 mRNAs. These results demonstrate strain differences in the expression of specific mRNAs and a heroin-induced dose-dependent elevation of SSTR-1 and -3 mRNAs in the mouse caudate putamen.


Asunto(s)
Heroína/farmacología , Narcóticos/farmacología , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Receptores de Somatostatina/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Núcleo Caudado/efectos de los fármacos , Núcleo Caudado/metabolismo , Condicionamiento Clásico/efectos de los fármacos , Condicionamiento Clásico/fisiología , Relación Dosis-Respuesta a Droga , Heroína/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Narcóticos/administración & dosificación , Putamen/efectos de los fármacos , Putamen/metabolismo , ARN Mensajero/metabolismo , Distribución Aleatoria , Percepción Espacial/efectos de los fármacos , Percepción Espacial/fisiología , Especificidad de la Especie
6.
Neuropsychopharmacology ; 34(4): 912-22, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18784649

RESUMEN

Nonmedical use of the prescription opioid analgesic oxycodone is a major problem in the United States, particularly among adolescents and young adults. This study characterized self-administration of oxycodone by adolescent and adult mice, and how this affects striatal dopamine levels. Male C57BL/6J mice (4 or 10 weeks old) were allowed to acquire oxycodone self-administration (0.25 mg/kg per infusion) for 9 days, and then tested with varying doses of oxycodone (0, 0.125, 0.25, 0.5, and 0.75 mg/kg per infusion). On completion of the self-administration study, a guide cannula was implanted into the striatum of these mice. Six days later, microdialysis was conducted on the freely moving mouse. After collection of baseline samples, oxycodone was administered i.p. (1.25, 2.5, and 5.0 mg/kg) and samples were collected for 1 h after each dose. Adult mice self-administered significantly more oxycodone across the doses tested. After 1 week, basal striatal dopamine levels were lower in mice of both ages that had self-administered oxycodone than in yoked saline controls. Oxycodone challenge increased striatal dopamine levels in a dose-dependent manner in both age groups. Of interest, the lowest dose of oxycodone led to increased striatal dopamine levels in the mice that had self-administered oxycodone during adolescence but not those that self-administered it as adults. The lower number of infusions of oxycodone self-administered by adolescent mice, and their later increased striatal dopamine in response to the lowest dose of oxycodone (not found in adults), suggest differential sensitivity to the reinforcing and neurobiological effects of oxycodone in the younger mice.


Asunto(s)
Envejecimiento , Conducta Adictiva , Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Oxicodona/administración & dosificación , Autoadministración , Análisis de Varianza , Animales , Cuerpo Estriado/metabolismo , Relación Dosis-Respuesta a Droga , Extinción Psicológica , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Estadísticos
7.
J Neurosci ; 28(39): 9670-81, 2008 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-18815253

RESUMEN

Opiate addiction is characterized by progressive increases in drug intake over time suggesting maladaptive changes in motivational and reward systems. These behaviors are mediated by dopaminergic neurons originating from the ventral tegmental area (VTA), and long-term changes of these dopaminergic neurons are attributed to increased postsynaptic glutamatergic activation. Indeed, chronic morphine administration is known to increase AMPA receptor glutamate receptor 1 (GluR1) subunit in the VTA. However, there is no ultrastructural evidence that morphine affects the expression or surface availability of GluR1 subunits in VTA neurons of defined distribution or transmitter phenotype. Therefore, we examined electron microscopic immunolabeling of GluR1 and tyrosine hydroxylase (TH) in two VTA regions of rats perfused 1 h after a single injection of morphine, or chronic morphine in intermittent-escalating doses for 14 d, and appropriate saline controls. Acute morphine administration produced a significant increase in GluR1 immunogold particles at the plasma membrane and postsynaptic densities in both TH- and non-TH-containing dendrites in the parabrachial VTA, a region that contains mainly prefrontal-cortical-projecting dopaminergic neurons involved in motivation and drug-seeking behavior. Chronic morphine administration maintained the increased synaptic GluR1 labeling in the parabrachial VTA, but also increased the number of GluR1-labeled synapses and TH immunoreactivity in dendrites of the paranigral VTA where substantially more dopaminergic neurons project to limbic structures implicated in locomotor activation and reward. These results demonstrate a region- and dose-dependent redistribution of GluR1-containing AMPA receptors, which is consistent with acute morphine activation of cortical-projecting VTA neurons and chronic morphine activation of limbic-projecting VTA neurons.


Asunto(s)
Analgésicos Opioides/administración & dosificación , Morfina/administración & dosificación , Neuronas , Receptores AMPA/metabolismo , Área Tegmental Ventral/citología , Animales , Dendritas/efectos de los fármacos , Dendritas/metabolismo , Dendritas/ultraestructura , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Masculino , Microscopía Inmunoelectrónica/métodos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/ultraestructura , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Estilbamidinas/metabolismo , Fracciones Subcelulares/efectos de los fármacos , Fracciones Subcelulares/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Sinapsis/ultraestructura , Factores de Tiempo , Tirosina 3-Monooxigenasa/metabolismo , Área Tegmental Ventral/efectos de los fármacos
8.
Neurosci Lett ; 440(3): 284-8, 2008 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-18579303

RESUMEN

Differences in the locomotor stimulating and rewarding properties of drugs of abuse have been described in several inbred strains of mice, and comparisons of inbred strains with differing responses to drugs of abuse may provide crucial insight into the question of individual vulnerability to the effects of drugs of abuse. The present study was designed to examine the rewarding and locomotor-stimulating effects of heroin in C57BL/6J and 129P3/J mice. Heroin produced a robust dose-dependent locomotor stimulation in both strains. Both strains also developed conditioned place preference to heroin, again in a dose-dependent manner. However C57BL/6J mice developed conditioned place preference to only the two lowest doses of heroin tested, while the 129P3/J counterparts showed conditioned place preference to only the three highest doses tested. These studies indicate that 129P3/J mice are less sensitive to the rewarding effects of heroin than are age-matched C57BL/6J mice.


Asunto(s)
Condicionamiento Operante/efectos de los fármacos , Heroína/farmacología , Actividad Motora/efectos de los fármacos , Narcóticos/farmacología , Animales , Conducta Animal/efectos de los fármacos , Condicionamiento Operante/fisiología , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos , Recompensa , Especificidad de la Especie
9.
Exp Neurol ; 210(2): 750-61, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18294632

RESUMEN

The nucleus accumbens (Acb) is an extensively studied neuroanatomical substrate of opiate reward and the neural plasticity associated with chronic opioid use. The cellular mechanisms mediating opioid-dependent plasticity are uncertain, however AMPA-type glutamate receptor trafficking in dopamine D1 dopamine receptor (D1R) expressing neurons may be a potential cellular pathway for these adaptations, although there is no evidence for this possibility. Immunogold electron microscopy was used to quantify the surface expression of the AMPA GluR1 subunit in dendritic profiles of neurons in the Acb in response to intermittent 14-day non-contingent injections of escalating doses of morphine, a model that parallels opioid self-administration. To determine if changes in GluR1 trafficking occurred in neurons potentially sensitive to dopamine-induced D1R activation, immunoperoxidase labeling of D1R was combined with immunogold labeling of GluR1. Immunogold quantification was performed in two distinct Acb subregions, the shell, an area involved in processing incentive salience related to rewarding stimuli, and the core, an area involved in reward-seeking behaviors. We provide the first report that chronic morphine administration is associated with a receptor-phenotypic decrease in surface trafficking of GluR1 in Acb subregions. When compared to saline injected animals, morphine produced a decrease in plasma membrane GluR1 labeling in medium- and large-sized D1R expressing dendritic profiles in the Acb shell. In contrast, in the Acb core, surface GluR1 was decreased in small-sized dendrites that did not express the dopamine receptor. These results indicate that chronic intermittent injection of escalating doses of morphine is accompanied by ultrastructural plasticity of GluR1 in neurons that are responsive to glutamate and dopamine-induced D1R activation in the Acb shell, and neurons capable of responding to glutamate but not D1R receptor stimulation in the Acb core. Thus, AMPA receptor trafficking associated with chronic opiate exposure in functionally distinct areas of the Acb may be distinguished by D1R receptor activation, suggesting the potential for differing neural substrates of reward and motor aspects of addictive processes involving glutamate and dopamine signaling.


Asunto(s)
Morfina/administración & dosificación , Narcóticos/administración & dosificación , Neuronas/efectos de los fármacos , Núcleo Accumbens/citología , Receptores AMPA/metabolismo , Receptores de Dopamina D1/metabolismo , Animales , Conducta Animal , Dendritas/efectos de los fármacos , Dendritas/metabolismo , Dendritas/ultraestructura , Esquema de Medicación , Masculino , Microscopía Inmunoelectrónica/métodos , Neuronas/ultraestructura , Núcleo Accumbens/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacos , Radioinmunoensayo , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/genética
10.
Brain Res Bull ; 67(3): 169-75, 2005 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-16144651

RESUMEN

This study examined the effects of chronic (14-day) steady-dose and escalating-dose "binge" pattern cocaine administration on striatal preprodynorphin (ppDyn) mRNA levels and behavioral stereotypies. Animals in the steady-state and escalating groups received cocaine in a "binge" pattern (three equal injections starting 30 min following the start of the daily light cycle, separated by 1 h). The dose of cocaine in the "steady-dose" group was 15 mg/kg/injection and remained constant throughout the study. The escalating group received 15 mg/kg/injection on days 1-3, 20 mg/kg/injection on days 4-6, 25 mg/kg/injection on days 7-9 and 30 mg/kg/injection thereafter, for a maximum daily dose of 90 mg/kg. Levels of ppDyn mRNA were determined by solution hybridization. Cocaine significantly affected body weight. Both steady-dose and escalating-dose "binge" cocaine administration resulted in expression of behavioral stereotypy and induced intense, rapid head movements which were dose- and time-dependent. Cocaine, independent of dose, increased ppDyn mRNA levels in the caudate putamen (CPu), but not in the nucleus accumbens (NAc). These data suggest that the ppDyn response to cocaine in the CPu is not dose-dependent or that it has reached a maximal level at the 45 mg/kg daily dose.


Asunto(s)
Cocaína/administración & dosificación , Cuerpo Estriado/efectos de los fármacos , Inhibidores de Captación de Dopamina/administración & dosificación , Dinorfinas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Precursores de Proteínas/metabolismo , Conducta Estereotipada/efectos de los fármacos , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Cuerpo Estriado/metabolismo , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Dinorfinas/genética , Masculino , Precursores de Proteínas/genética , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas F344 , Factores de Tiempo
11.
Brain Res Mol Brain Res ; 137(1-2): 258-62, 2005 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-15950784
12.
Psychopharmacology (Berl) ; 179(3): 551-8, 2005 May.
Artículo en Inglés | MEDLINE | ID: mdl-15682306

RESUMEN

RATIONALE: Salvinorin A is a naturally occurring hallucinogen derived from the plant Salvia divinorum. Salvinorin A is also a potent and selective kappa opioid receptor agonist in vitro. It has been shown that kappa agonists decrease dopamine levels in the caudate putamen and nucleus accumbens and cause conditioned place aversion in rodents. OBJECTIVES: To study the effects of salvinorin A on basal dopamine levels in the caudate putamen and nucleus accumbens, and to determine whether salvinorin A induces conditioned place preference or aversion and changes in locomotor activity in the mouse. METHODS: In the first experiment, changes in dopamine levels in these brain regions after administration of salvinorin A were measured with in vivo microdialysis. In the second experiment, we examined whether salvinorin A led to conditioned place preference or aversion, and changes in locomotor activity during conditioning sessions. RESULTS: The higher doses of salvinorin A studied (1.0 mg/kg and 3.2 mg/kg, i.p.) significantly decreased dopamine levels in the caudate putamen, but not in the nucleus accumbens, and this effect was completely blocked by pre-injection with 10 mg/kg of the kappa opioid receptor antagonist nor-binaltorphimine. The same doses of salvinorin A caused conditioned place aversion and decreased locomotor activity. CONCLUSIONS: The inhibitory effect of salvinorin A on striatal dopamine levels may contribute to its induction of conditioned place aversion and decreases in locomotion in mice. These findings are consistent with the in vitro characterization of salvinorin A as a kappa opioid receptor agonist. It is of interest that a compound such as salvinorin A, that lowers striatal dopamine levels and leads to conditioned place aversion in rodents, is self-administered by humans under certain conditions.


Asunto(s)
Condicionamiento Psicológico/efectos de los fármacos , Diterpenos/farmacología , Dopamina/metabolismo , Alucinógenos/farmacología , Neostriado/efectos de los fármacos , Receptores Opioides kappa/metabolismo , Animales , Núcleo Caudado/efectos de los fármacos , Núcleo Caudado/metabolismo , Condicionamiento Psicológico/fisiología , Diterpenos de Tipo Clerodano , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos C57BL , Neostriado/metabolismo , Extractos Vegetales/farmacología , Putamen/efectos de los fármacos , Putamen/metabolismo , Salvia
13.
Neuropharmacology ; 47 Suppl 1: 324-44, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-15464148

RESUMEN

The roots of the Laboratory of the Biology of the Addictive Diseases are in the development of methadone maintenance for the treatment of opiate addiction. Methadone maintenance therapy continues to be one of the major effective forms of addiction pharmacotherapy and underscores the importance of biological factors in the physiology and treatment of the addictive diseases. Recent work in the Laboratory has focused on the neurobiological, neurochemical, neuroendocrine and behavioral aspects of addictive diseases (principally cocaine and the opiate addictions), using an interdisciplinary approach. The models we have focused on range from in vitro molecular biology and neuroscience, to in vivo animal models, to experiments in normal human populations and patients with specific addictive diseases, and most recently to the human molecular genetics of different addictive diseases. Two long-term corollary hypotheses have guided the Laboratory's work: (1) That the endogenous opioid peptide/receptor systems play a central role in the addictive states and therefore in their treatment. (2) That atypical responsivity to stressors (e.g., in the hypothalamic-pituitary-adrenal axis) plays a role in vulnerability and relapse to specific addictive diseases. This atypical responsivity may be drug-induced, environmentally acquired, and/or due to genetic variation.


Asunto(s)
Neurobiología/historia , Neurobiología/tendencias , Trastornos Relacionados con Sustancias/historia , Animales , Modelos Animales de Enfermedad , Endorfinas/fisiología , Historia del Siglo XX , Humanos , Narcóticos/farmacocinética , National Institutes of Health (U.S.) , Receptores Opioides/efectos de los fármacos , Receptores Opioides/genética , Receptores Opioides/fisiología , Trastornos Relacionados con Sustancias/genética , Trastornos Relacionados con Sustancias/psicología , Estados Unidos
14.
Psychopharmacology (Berl) ; 172(4): 422-9, 2004 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-14712335

RESUMEN

RATIONALE: Effects of synthetic kappa opioid receptor agonists on cocaine-induced reward have been studied extensively in rats but relatively few studies have used the endogenous kappa agonist dynorphin A(1-17). OBJECTIVES: Three studies were conducted to examine the effect of the natural sequence dynorphin on cocaine-induced increases in dopamine, on the formation of conditioned place preference and on increases in locomotor activity in C57BL/6 J mice. METHODS: After implantation of guide cannulae into the caudate putamen, mice were allowed 4-5 days to recover from surgery. In the first study, dynorphin A (0, 1, 2, 4.4 nmol) was infused into the caudate putamen and dopamine levels were measured by in vivo microdialysis in that brain region. Then, the effect of dynorphin A (4.4 nmol) on increases in dopamine levels induced by 15 mg/kg cocaine i.p. was also measured with in vivo microdialysis. The third experiment examined the effect of dynorphin A (4.4 nmol) on conditioned place preference and locomotion induced by 15 mg/kg cocaine. RESULTS: Dynorphin A significantly decreased basal dopamine levels in a dose-dependent manner by more than 60% at the highest dose, and this effect was completely blocked by pre-injection of the kappa-opioid receptor antagonist nor-BNI (10 mg/kg). The highest dose of dynorphin (4.4 nmol) blocked increases in dopamine levels, the formation of conditioned place preference and attenuated locomotion induced by 15 mg/kg cocaine. CONCLUSION: The blockade of the cocaine-induced rise in striatal dopamine may contribute to both dynorphin's ability to prevent the development of cocaine-induced conditioned place preference and to attenuate the increase in locomotor activity.


Asunto(s)
Cocaína/farmacología , Condicionamiento Operante/efectos de los fármacos , Dopamina/metabolismo , Dinorfinas/farmacología , Actividad Motora/efectos de los fármacos , Neostriado/metabolismo , Receptores Opioides kappa/agonistas , Animales , Conducta Animal/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Microdiálisis , Recompensa
15.
Psychopharmacology (Berl) ; 173(1-2): 146-52, 2004 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-14712342

RESUMEN

RATIONALE: While the effects of several kappa opioid receptor agonists on cocaine-induced reward have been studied, such effects of R-84760, a novel non-peptidic, potent and selective kappa opioid agonist that has been studied in humans, are not yet known. OBJECTIVE: To study the effects of R-84760 on basal levels of dopamine, cocaine-induced increases in dopamine levels, cocaine-induced conditioned place preference and locomotor activity in mice. METHODS: In the first experiment, R-84760 was administered i.p. (0, 0.01, 0.05 or 0.1 mg/kg) to C57BL/6J mice. Its effect on basal dopamine levels in the caudate putamen was measured with in vivo microdialysis. In the second experiment, the effect of pretreatment with 0.1 mg/kg R-84760 on cocaine-induced increases in dopamine levels was studied. The third experiment examined the effect of R-84760 (0.1 mg/kg) on the development of cocaine-induced conditioned place preference and locomotor activity in the conditioning chamber. RESULTS: R-84760 decreased dopamine levels in a dose-dependent manner. The highest dose of R-84760 (0.1 mg/kg, i.p.) significantly decreased dopamine levels relative to vehicle, an effect completely blocked by pre-injection with 10 mg/kg of the kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI). The same dose of R-84760 blocked cocaine-induced increases in dopamine levels, cocaine-induced conditioned place preference and attenuated cocaine-induced locomotor response. CONCLUSION: These findings suggest that R-84760 decreases dopamine levels in the caudate putamen through kappa-opioid receptors. The inhibitory effect of R-84760 on striatal dopamine may contribute to its blockade of cocaine-induced increases in dopamine levels, cocaine-induced conditioned place preference and the associated increases in locomotor activity.


Asunto(s)
Cocaína/farmacología , Condicionamiento Operante/efectos de los fármacos , Inhibidores de Captación de Dopamina/farmacología , Dopamina/metabolismo , Naltrexona/análogos & derivados , Neostriado/efectos de los fármacos , Pirrolidinas/farmacología , Receptores Opioides kappa/agonistas , Tiazinas/farmacología , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Alimentos , Masculino , Ratones , Ratones Endogámicos C57BL , Microdiálisis , Actividad Motora/efectos de los fármacos , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Neostriado/metabolismo
16.
Synapse ; 50(3): 191-9, 2003 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-14515336

RESUMEN

In vivo microdialysis was used to measure the effect of chronic "binge" pattern cocaine administration on basal and cocaine-induced dopamine levels in the caudate putamen and nucleus accumbens of C57BL/6J and 129/J mice. Mice were implanted with a guide cannula in the caudate putamen or nucleus accumbens and after 4 days recovery, one group received "binge" pattern cocaine administration for 13 days (15 mg/kg x 3, i.p. at hourly intervals) while another group received saline in the same pattern. On the day before microdialysis, dialysis probes were lowered into the caudate putamen and nucleus accumbens. The next morning, after baseline dopamine collection, all animals received "binge" cocaine administration. Dialysates were collected every 20 min and dopamine content was determined by HPLC with electrochemical detection. In the basal condition, the mean level of dopamine in the dialysate from both brain regions of mice pretreated with "binge" pattern cocaine administration was significantly lower than that of the mice pretreated with saline administration. The absolute levels of dopamine achieved following "binge" pattern cocaine challenge were lower in the mice that had received chronic cocaine administration. However, when expressed as percent increase over baseline, the dopamine response to cocaine in the nucleus accumbens was significantly higher in mice that received chronic than in mice that received acute cocaine administration. Chronic cocaine administration led to a lowering of both basal dopamine and the absolute levels of cocaine-induced increases of dopamine in the two brain regions, but enhanced the percent increases over the baseline in response to cocaine in the nucleus accumbens of both mouse strains.


Asunto(s)
Núcleo Caudado/efectos de los fármacos , Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Dopamina/metabolismo , Núcleo Accumbens/efectos de los fármacos , Putamen/efectos de los fármacos , Animales , Núcleo Caudado/metabolismo , Cromatografía Líquida de Alta Presión , Esquema de Medicación , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Microdiálisis , Núcleo Accumbens/metabolismo , Putamen/metabolismo , Factores de Tiempo
17.
Brain Res ; 974(1-2): 249-53, 2003 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-12742644

RESUMEN

Preprodynorphin mRNA was measured in the nucleus accumbens (NAc) and caudate putamen (CPu) after 3-day 'binge' pattern cocaine administration in C57BL/6J and 129/J mice, strains which differ in behavior and in dopamine increases in the CPu after 'binge' cocaine. In the CPu, there was increased preprodynorphin mRNA in C57BL/6J (P<0.05), but not in 129/J mice, with no differences in the NAc. Thus, 129/J mice are hyporesponsive to the preprodynorphin activating effects of acute 'binge' cocaine in the CPu.


Asunto(s)
Núcleo Caudado/metabolismo , Trastornos Relacionados con Cocaína/metabolismo , Dinorfinas/biosíntesis , Putamen/metabolismo , ARN Mensajero/biosíntesis , Animales , Conducta Animal/efectos de los fármacos , Núcleo Caudado/efectos de los fármacos , Cocaína/administración & dosificación , Cocaína/farmacología , Relación Dosis-Respuesta a Droga , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Precursores de Proteínas/biosíntesis , Putamen/efectos de los fármacos , Especificidad de la Especie
18.
Pharmacol Biochem Behav ; 75(1): 123-31, 2003 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-12759120

RESUMEN

We have shown that C57BL/6J and 129/J mice differ in their behavioral response to "binge" pattern cocaine (three daily injections of 15 mg/kg separated by 1 h). To determine if these differences persist during chronic binge cocaine administration, we examined the effects of 14-day binge pattern cocaine on home cage behavior. Since the dopamine D(1) receptor may be an important mediator of cocaine-induced locomotor activity, we examined binding to the dopamine D(1) receptor. Locomotor activity was increased by chronic binge cocaine in C57BL/6J (P<.0001) but not in 129/J mice. C57BL/6J mice developed tolerance to the locomotor-activating effects of cocaine. Stereotypic responses were greater in C57BL/6J than in 129/J mice (P=.03), with neither tolerance nor sensitization in either strain. Dopamine D(1) receptor binding in the nucleus accumbens and olfactory tubercle did not differ between strains and was not affected by chronic binge cocaine. In the caudate putamen, subregion specific strain differences in dopamine D(1) receptor binding were observed; chronic binge cocaine increased dopamine D(1) receptor binding in the caudal (P<.05), but not rostral caudate putamen. There was no correlation between locomotor activity or stereotypy and dopamine D(1) receptor density. Thus, with chronic binge cocaine administration, behavioral differences persist between the C57BL/6J and 129/J mice, and cocaine-induced locomotor activity is not correlated with changes in dopamine D(1) receptor binding.


Asunto(s)
Trastornos Relacionados con Cocaína/psicología , Cocaína/toxicidad , Inhibidores de Captación de Dopamina/toxicidad , Actividad Motora/efectos de los fármacos , Receptores de Dopamina D1/efectos de los fármacos , Conducta Estereotipada/efectos de los fármacos , Animales , Autorradiografía , Cocaína/administración & dosificación , Inhibidores de Captación de Dopamina/administración & dosificación , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos C57BL , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Bulbo Olfatorio/efectos de los fármacos , Bulbo Olfatorio/metabolismo , Putamen/efectos de los fármacos , Putamen/metabolismo , Especificidad de la Especie
19.
Brain Res ; 964(2): 187-99, 2003 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-12576179

RESUMEN

Tolerance to the stimulatory effects of cocaine on the hypothalamic-pituitary-adrenal (HPA) axis develops after chronic 'binge' cocaine exposure in the rat. This blunting of HPA axis activity in response to cocaine is associated with a cocaine-induced reduction of corticotropin-releasing hormone (CRH) mRNA level in the hypothalamus. There is limited information about the effects of withdrawal from chronic cocaine on HPA activity. The present studies were undertaken to determine levels of the HPA hormones adrenocorticotropic hormone (ACTH) and corticosterone across 10 days of withdrawal following chronic 'binge' pattern cocaine administration (3 x 15 mg/kg/day at hourly intervals) for 14 days. Male Fischer rats showed a significantly attenuated HPA axis response to chronic 'binge' pattern cocaine administration 30 min after the last injection on the 14th day, as measured by both plasma ACTH and corticosterone levels at the nadir time point. Twenty-four hours following the final administration of 'binge' cocaine (the 1st day of withdrawal), a significant elevation of plasma ACTH levels and a modest, but significant, elevation of plasma corticosterone levels were found at the nadir time point. This acute withdrawal-related activation of the hormones of the HPA axis was no longer found on the 10th day of withdrawal. In the anterior pituitary, levels of both proopiomelanocortin (POMC) and CRH-receptor 1 (R1) mRNAs were significantly higher than saline controls on the 14th day of chronic 'binge' cocaine and were at control levels on the 4th day of withdrawal. In the neurointermediate lobe of the pituitary, a sustained reduction in POMC mRNA levels was observed on the 3rd, 7th and 14th day of chronic 'binge' cocaine, but POMC mRNA was at control levels by the 4th day of withdrawal. In the hypothalamus, POMC mRNA levels showed a transient decrease on the 1st day of 'binge' cocaine with no change during chronic 'binge' cocaine or its withdrawal. CRH mRNA levels in the hypothalamus were not different from saline controls on the 1st and 4th days of withdrawal. Taken together, the present results show that after development of adaptation or tolerance to chronic 'binge' cocaine there is an increase in HPA activity during acute cocaine withdrawal. In addition to being associated with CRH input from the hypothalamus, the activation of the HPA axis by cocaine withdrawal may be, at least in part, due to the increased POMC and/or CRH-R1 gene expression observed in the anterior pituitary after chronic 'binge' cocaine.


Asunto(s)
Glándulas Suprarrenales/efectos de los fármacos , Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Hipófisis/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Proopiomelanocortina/metabolismo , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Síndrome de Abstinencia a Sustancias/metabolismo , Glándulas Suprarrenales/metabolismo , Hormona Adrenocorticotrópica/metabolismo , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Animales , Northern Blotting , Cocaína/administración & dosificación , Corticosterona/metabolismo , Hormona Liberadora de Corticotropina/efectos de los fármacos , Hormona Liberadora de Corticotropina/metabolismo , Inhibidores de Captación de Dopamina/administración & dosificación , Encefalinas/metabolismo , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Masculino , Hipófisis/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Proopiomelanocortina/efectos de los fármacos , Precursores de Proteínas/metabolismo , ARN Mensajero/metabolismo , Radioinmunoensayo , Ratas , Ratas Endogámicas F344 , Receptores de Hormona Liberadora de Corticotropina/efectos de los fármacos , Receptores de Hormona Liberadora de Corticotropina/genética , Factores de Tiempo
20.
Pharmacol Biochem Behav ; 73(3): 655-62, 2002 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-12151041

RESUMEN

The rewarding effect of cocaine as reflected by the development of conditioned place preference was examined in C57BL/6J and 129/J mice. Cocaine was administered in a single daily dose (2.5, 5, 10 and 20 mg/kg ip) or in a "binge" pattern (15 mg/kg ip x3, hourly). Mice remained in the conditioning compartment for 30 min immediately after each injection. Single injections of cocaine from 5 to 20 mg/kg induced conditioned place preference in each strain of mice. Only C57BL/6J mice developed conditioned place preference after "binge" cocaine administration. Both strains showed significantly greater locomotion in the conditioning compartment across the range of single doses of cocaine and after "binge" cocaine administration, but only 129/J mice showed sensitization. When mice that had received the single 10 mg/kg dose were retested 4 weeks later, the amount of time spent in the preferred side was significantly reduced compared to the initial test in the 129/J, but not in C57BL/6J mice. Thus, the persistence of conditioned place preference is strain dependent. The fact that 129/J mice did not develop conditioned place preference after "binge" cocaine administration, but did after single doses, suggests that the rewarding effects of cocaine are influenced by pattern of administration, a factor that may be relevant to the development of human cocaine addiction.


Asunto(s)
Trastornos Relacionados con Cocaína/psicología , Cocaína/administración & dosificación , Cocaína/farmacología , Condicionamiento Operante/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Masculino , Memoria/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Actividad Motora/efectos de los fármacos , Especificidad de la Especie
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