An Update on CRF Mechanisms Underlying Alcohol Use Disorders and Dependence.

Alcohol is the most commonly used and abused substance worldwide. The emergence of alcohol use disorders, and alcohol dependence in particular, is accompanied by functional changes in brain reward and stress systems, which contribute to escalated alcohol drinking and seeking. Corticotropin-releasing factor (CRF) systems have been critically implied in the transition toward problematic alcohol drinking and alcohol dependence. This review will discuss how dysregulation of CRF function contributes to the vulnerability for escalated alcohol drinking and other consequences of alcohol consumption, based on preclinical evidence. CRF signaling, mostly via CRF1 receptors, seems to be particularly important in conditions of excessive alcohol taking and seeking, including during early and protracted withdrawal, relapse, as well as during withdrawal-induced anxiety and escalated aggression promoted by alcohol. Modulation of CRF1 function seems to exert a less prominent role over low to moderate alcohol intake, or to species-typical behaviors. While CRF mechanisms in the hypothalamic-pituitary-adrenal axis have some contribution to the neurobiology of alcohol abuse and dependence, a pivotal role for extra-hypothalamic CRF pathways, particularly in the extended amygdala, is well characterized. More recent studies further suggest a direct modulation of brain reward function by CRF signaling in the ventral tegmental area, nucleus accumbens, and the prefrontal cortex, among other structures. This review will further discuss a putative role for other components of the CRF system that contribute for the overall balance of CRF function in reward and stress pathways, including CRF2 receptors, CRF-binding protein, and urocortins, a family of CRF-related peptides.

Effect of Early Overfeeding on Palatable Food Preference and Brain Dopaminergic Reward System at Adulthood: Role of Calcium Supplementation.

Rats raised in small litters (SL) are obese and hyperphagic. In the present study, we evaluated whether obesity is associated with changes in the mesocorticolimbic dopaminergic reward system in these animals at adulthood. We also assessed the anti-obesity effects of dietary calcium supplementation. To induce early overfeeding, litters were adjusted to three pups on postnatal day (PN)3 (SL group). Control litters were kept with 10 pups each until weaning (NL group). On PN120, SL animals were subdivided into two groups: SL (standard diet) and SL-Ca [SL with calcium supplementation (10 g calcium carbonate/kg rat chow) for 60 days]. On PN175, animals were subjected to a food challenge: animals could choose between a high-fat (HFD) or a high-sugar diet (HSD). Food intake was recorded after 30 min and 12 h. Euthanasia occurred on PN180. SL rats had higher food intake, body mass and central adiposity. Sixty days of dietary calcium supplementation (SL-Ca) prevented these changes. Only SL animals preferred the HFD at 12 h. Both SL groups had lower tyrosine hydroxylase content in the ventral tegmental area, lower dopaminergic transporter content in the nucleus accumbens, and higher type 2 dopamine receptor (D2R) content in the hypothalamic arcuate nucleus (ARC). They also had higher neuropeptide Y (NPY) and lower pro-opiomelanocortin contents in the ARC. Calcium treatment normalised only D2R and NPY contents. Precocious obesity induces long-term effects in the brain dopaminergic system, which can be associated with an increased preference for fat at adulthood. Calcium treatment prevents this last alteration, partially through its actions on ARC D2R and NPY proteins.

Participación de los sistemas endógenos de péptidos opioides en los mecanismos de reforzamiento y dependencia al alcohol / Role of endogenous opioid systems in alcohol reinforcement and dependence mechanisms

Biochemical and behavioral evidence indicates that the dopaminergic mesolimbic system plays a key role in the mechanisms of reinforcement and reward elicited by alcohol (ethanol) and other drugs of abuse. In addition, the dopaminergic activity of the nigrostriatal pathway has been proposed to determine brain sensitivity to ethanol, a process which could be associated to drug addiction. Besides dopamine, several neurotransmitters and neuromodulators are involved in ethanol reinforcement, including gamma aminobutyric acid (GABA), glutamate, serotonin, acetylcholine and opioid peptides (enkephalins, endorphins and dynorphins). Ethanol and opioids share several pharmacological properties and exhibit similar behavioral effects in animals and humans. These and other studies suggest that the alcohol reinforcing properties are due, at least in part, to the ethanol-induced activation of endogenous opioidergic systems. This activation could in turn increase the hedonic value and the reinforcing effects of the drug. Thus, ethanol-induced changes in opioidergic transmission could contribute to alcohol intoxication and to the neuroadaptive responses produced by the long-lasting exposure to the drug. Opioidergic transmission may be altered by ethanol at different levels, including biosynthesis, release and inactivation of opioid peptides, as well as binding of endogenous opioids to their receptors. Several studies suggest that mu and delta opioid receptors play a key role in ethanol reinforcement and dependence. Therefore, enkephalins and (β-endorphin could mediate ethanol actions in the brain and play a major role in high alcohol drinking behavior. During the last years, our research group has focused on the role of the endogenous opioid systems in these processes. Evidence obtained in our laboratory suggests that enkephalins and (β-endorphin differentially and selectively participate in ethanol reinforcement and dependence.

Evidencias bioquímicas y conductuales indican que el sistema dopaminérgico mesolímbico cumple un papel fundamental en los mecanismos de reforzamiento y recompensa del alcohol (etanol) y otras drogas de abuso. Se ha propuesto también que la actividad de la vía dopaminérgica nigroestriatal determina la sensibilidad cerebral a etanol, lo que parece estar directamente relacionado con los procesos de adicción a la droga. Además de la dopamina, varios neurotransmisores y neuromoduladores están implicados en los mecanismos de reforzamiento del etanol, entre ellos, el ácido gama-aminobutírico (GABA), el glutamato, la serotonina, la acetilcolina y los péptidos opioides (encefalinas, endorfinas y dinorfinas). El alcohol y los opioides comparten características farmacológicas y exhiben efectos similares sobre el comportamiento en animales y en el hombre. Éstos y otros estudios sugieren que las propiedades reforzadoras del etanol se deben, al menos parcialmente, a la activación de los sistemas endógenos de péptidos opioides, proceso que es inducido por el propio alcohol. Esta activación podría, a su vez, aumentar el valor hedónico y los efectos reforzadores de la droga. Los cambios inducidos por etanol sobre la transmisión de opioides podrían contribuir de manera importante a los procesos de intoxicación y a las respuestas neuronales adaptativas que produce el consumo prolongado de la droga. La transmisión opioidérgica puede ser afectada por etanol a distintos niveles, incluyendo la biosíntesis, liberación e inactivación de los opioides endógenos, así como la unión de éstos a sus receptores. Numerosas evidencias sugieren que los receptores opioides mu y delta desempeñan un papel fundamental en el reforzamiento y la dependencia al etanol. Así, las encefalinas y la (β-endorfina actuarían como mediadores fisiológicos de las acciones del etanol en el cerebro, desempeñando un papel crucial en las conductas de alto consumo de la droga. En los últimos años, nuestro grupo se ha centrado en investigar el papel de los sistemas endógenos de péptidos opioides en estos procesos. Las evidencias obtenidas en nuestro laboratorio sugieren que las encefalinas y la (β-endorfina participan en forma diferencial y selectiva en el reforzamiento y la dependencia al etanol.