RESUMEN
Cocaine- and amphetamine-regulated transcript (CART) peptides appear to modulate various effects of psychostimulant drugs. Injections of CART peptide into the nucleus accumbens (NAcc) inhibit locomotion produced by systemic injections of the psychostimulants cocaine and amphetamine. Intra-NAcc injections of CART peptide also inhibit locomotion produced by microinfusions of dopamine into the NAcc, suggesting that the effects of CART peptides may be due to an interaction with the dopaminergic system in the NAcc. We sought to determine if this inhibitory effect of CART peptide generalizes to other measures of dopaminergic function such as reward/reinforcement by testing the effect of bilateral intra-NAcc CART infusions (0, 0.25, 1.0 and 2.5 microg per side) on cocaine and food self-administration. One group of rats self-administered cocaine (0.75 mg/kg per 140 microl IV infusion) on a progressive ratio schedule. A separate group received 45 mg food pellets on the same progressive ratio schedule. Bilateral intra-NAcc injections of CART peptide dose-dependently decreased the number of cocaine infusions, the breakpoint of cocaine self-administration, and the total number of bar presses on the cocaine-associated lever. There were no effects of CART injections on the breakpoint for food reward. Thus, we conclude that injections of CART into the NAcc appear to functionally antagonize a major site of action for cocaine self-administration in rats.
Asunto(s)
Cocaína/administración & dosificación , Condicionamiento Operante/efectos de los fármacos , Inhibidores de Captación de Dopamina/administración & dosificación , Proteínas del Tejido Nervioso/farmacología , Núcleo Accumbens/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Animales , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Masculino , Microinyecciones/métodos , Núcleo Accumbens/fisiología , Ratas , Ratas Sprague-Dawley , Refuerzo en Psicología , AutoadministraciónRESUMEN
CART (cocaine- and amphetamine-regulated transcript) peptides appear to be mediators or modulators of psychostimulant drugs. An interesting result in the nucleus accumbens has been that injection of CART peptide has no effect by itself on locomotor activity, but it reduces the locomotor activity induced by cocaine or amphetamine. However, in the ventral tegmental area (VTA), injections of CART peptide have been shown to increase locomotor activity, although to a lesser degree [Kimmel, H.L., Gong, W., Vechia, S.D., Hunter, R.G., Kuhar, M.J., 2000. Intra-ventral tegmental area injection of rat cocaine and amphetamine-regulated transcript peptide 55-102 induces locomotor activity and promotes conditioned place preference. J. Pharmacol. Exp. Ther. 294, 784-792]. This study was carried out to clarify the interaction of intra-VTA CART 55-102 and systemic cocaine on locomotor activity. The CART-cocaine interaction has been examined using the rigorous isobolographic approach. This type of analysis permits an assessment of additivity, subadditivity, or synergism of two substances. By measuring locomotor activity and using a range of doses of CART peptide and cocaine, both alone and together, with different dosing strategies, clear evidence of subadditivity was found. CART reduced the locomotor activating effects of systemic cocaine, especially at higher doses of CART. These results imply that intra-VTA CART is not simply acting in the same manner as cocaine, and is likely to oppose the action of cocaine. This has implications for the physiological significance of CART-DA (dopamine) interactions and for medications development.
Asunto(s)
Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Actividad Motora/efectos de los fármacos , Proteínas del Tejido Nervioso/farmacología , Fragmentos de Péptidos/farmacología , Área Tegmental Ventral/efectos de los fármacos , Animales , Interacciones Farmacológicas , Masculino , Microinyecciones , Modelos Biológicos , Ratas , Ratas Sprague-DawleyRESUMEN
Cocaine- and amphetamine-regulated transcript (CART) peptides are putative neurotransmitters which appear to play a role in the rewarding and reinforcing effects of both natural (food) and unnatural (psychostimulants) stimuli. There is extensive anatomical, pharmacological, and behavioral evidence supporting the importance of CART peptides in psychostimulant, namely cocaine and amphetamine, abuse. For instance, CART mRNA and peptides are found in brain regions considered important in the reward and reinforcement of psychostimulants including the ventral tegmental area and the nucleus accumbens, which are part of the mesolimbic dopamine system. Consequently, in a pharmacological sense, CART peptides have been closely linked to the actions of mesolimbic dopamine. In addition, under certain conditions, psychostimulants alter CART mRNA and peptide levels. However, the exact conditions and mechanisms are unclear and may involve CART modulation by corticosterone and/or cyclic AMP response element binding protein (CREB). Finally, behavioral studies on CART and psychostimulants suggest a modulatory role for CART in the actions of psychostimulants as central administration of CART attenuates the behavioral effects of cocaine. This review discusses the anatomical, pharmacological, and behavioral evidence implicating a role for CART peptide in the rewarding and reinforcing properties of psychostimulants.
Asunto(s)
Estimulantes del Sistema Nervioso Central/farmacología , Proteínas del Tejido Nervioso/farmacología , Refuerzo en Psicología , Recompensa , Anfetaminas/farmacología , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Encéfalo/metabolismo , Cocaína/farmacología , Expresión Génica , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/fisiologíaRESUMEN
Cocaine- and amphetamine-regulated transcript (CART) peptides (55 to 102 and 62 to 102) are neurotransmitters with important roles in a number of physiologic processes. They have a role in drug abuse by virtue of the fact that they are modulators of mesolimbic function. Key findings supporting a role in drug abuse are as follows. First, high densities of CART-containing nerve terminals are localized in mesolimbic areas. Second, CART 55 to 102 blunts some of the behavioral effects of cocaine and dopamine (DA). This functional antagonism suggests that CART peptides be considered as targets for medications development. Third, CREB in the nucleus accumbens has been shown to have an opposing effect on cocaine self-administration. CREB may activate CART expression in that region, and, if so, CART may mediate at least some of the effects of CREB. Fourth, in addition to the effects of CART on DA, DA can influence CART in the accumbens. Thus a complex interacting circuitry likely exists. Fifth, in humans, CART is altered in the ventral tegmental area of cocaine overdose victims, and a mutation in the CART gene associates with alcoholism. Overall, it is clear that there are functional interactions among CART, DA, and cocaine and that plausible cellular mechanisms exist to explain some of these actions. Future studies will clarify and extend these findings.
Asunto(s)
Cocaína/efectos adversos , Proteínas del Tejido Nervioso/fisiología , Fragmentos de Péptidos/fisiología , Trastornos Relacionados con Sustancias/metabolismo , Alcoholismo/genética , Alcoholismo/metabolismo , Anfetaminas/farmacología , Peso Corporal/genética , Línea Celular , Cocaína/antagonistas & inhibidores , Cocaína/farmacología , AMP Cíclico/fisiología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/fisiología , Dopamina/farmacología , Dopamina/fisiología , Antagonistas de Dopamina/farmacología , Sobredosis de Droga , Hormonas/metabolismo , Área Hipotalámica Lateral/metabolismo , Terminaciones Nerviosas/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/farmacología , Vías Nerviosas/fisiología , Núcleo Accumbens/metabolismo , Especificidad de Órganos , Dolor/fisiopatología , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/farmacología , ARN Mensajero/biosíntesis , Sistemas de Mensajero Secundario/fisiología , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Tegmento Mesencefálico/efectos de los fármacos , Tegmento Mesencefálico/metabolismo , Transcripción GenéticaRESUMEN
Evidence suggests that CART (cocaine-amphetamine regulated transcript) peptides are mediators or modulators of the actions of psychostimulant drugs. In this study, the effects of intra-accumbal injections of rat long form (rl) CART 55-102 were examined. Injection of the peptide alone had no effect, but pretreatment with the peptide blunted or reduced the locomotor-inducing effects of cocaine after an i.p. injection. This effect was dose related and time limited, as expected. rlCART 1-27, a CART peptide fragment not active in other studies, was without effect on cocaine-induced locomotor activity. Because the actions of cocaine involve dopamine, the effect of rlCART 55-102 on dopamine-induced locomotor activity was examined. Intraaccumbal injection of dopamine produced a dose-related and time-limited increase in locomotor activity, as expected. Coinjection of rlCART 55-102 with dopamine blunted the effect. In summary, these data suggest that CART peptides in the nucleus accumbens would tend to oppose the actions of cocaine.