RESUMEN
Environmental enrichment (EE) during a period of forced abstinence attenuates incentive motivational effects of cocaine-paired stimuli. Here we examined whether EE during forced abstinence from cocaine self-administration would prevent time-dependent increases in cue-elicited cocaine-seeking behavior (i.e. the incubation effect). Rats were trained to self-administer cocaine, which was paired with light/tone cues, for 15 days while living in isolated conditions (IC). Controls received yoked saline infusions. Subsequently, rats were assigned to live in either continued IC or EE for either 1 or 21 days of forced abstinence prior to a test for cocaine-seeking behavior. During testing, responding resulted only in presentation of the light/tone cues. Contrary to our prediction, cocaine-seeking behavior increased over time regardless of living condition during abstinence; however, EE attenuated cocaine-seeking behavior relative to IC regardless of length of abstinence. Brains were harvested and trunk blood was collected immediately after the 60-minute test and later assayed. Results indicated that short-term EE elevated hippocampal brain-derived neurotrophic factor and reduced plasma corticosterone compared with IC. Furthermore, 21 days of EE during forced abstinence prevented increases in the cue-elicited amygdala phosphorylated extracellular signal-regulated kinase expression that was observed in IC rats. These findings suggest that EE attenuates incentive motivational effects of cocaine cues through a mechanism other than preventing the incubation effect, perhaps involving reduction of stress and neural activity in response to cocaine-paired cues during acute withdrawal.
Asunto(s)
Trastornos Relacionados con Cocaína/psicología , Señales (Psicología) , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Ambiente , Aislamiento Social/psicología , Estrés Psicológico/prevención & control , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cocaína/administración & dosificación , Cocaína/farmacología , Condicionamiento Operante/efectos de los fármacos , Corticosterona/metabolismo , Extinción Psicológica/efectos de los fármacos , Técnicas In Vitro , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , Motivación/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Autoadministración , Síndrome de Abstinencia a Sustancias/psicología , eIF-2 Quinasa/metabolismoRESUMEN
The goal of the present investigation was to determine the persistence of striatal (DA) dopaminergic dysfunction after a mild chemically induced hypoxic event in Fisher 344 rats. To this end, we gave a single injection of the mitochondrial complex II inhibitor 3-nitropropionic acid (3-NP; 16.5 mg/kg, i.p.) to 2-month old male F344 rats and measured various indices of striatal DA functioning and lipid peroxidation over a 3-month span. Separate groups of rats were used to measure rod walking, evoked DA release, DA content, malondialdehyde (MDA) accumulation, DA receptor binding, and tyrosine hydroxylase (TH) activity. The results showed that 3-NP exposure reduced most measures of DA functioning including motoric ability, DA release, and D(2) receptor densities for 1 to 3 months postdrug administration. Interestingly, DA content was reduced 1 week after 3-NP exposure, but rose to 147% of control values 1 month after 3-NP treatment. MDA accumulation, a measure of lipid peroxidation activity, was increased 24 h and 1 month after 3-NP treatment. 3-NP did not affect TH activity, suggesting that alterations in DA functioning were not the result of nigrostriatal terminal loss. These data demonstrate that a brief mild hypoxic episode caused by 3-NP exposure has long-term detrimental effects on the functioning of the nigrostriatal DA system.