CART Peptide Is a Potential Endogenous Antioxidant and Preferentially Localized in Mitochondria

The multifunctional neuropeptide Cocaine and Amphetamine Regulated Transcript (CART) is secreted from hypothalamus, pituitary, adrenal gland and pancreas. It also can be found in circulatory system. This feature suggests a general role for CART in different cells. In the present study, we demonstrate that CART protects mitochondrial DNA (mtDNA), cellular proteins and lipids against the oxidative action of hydrogen peroxide, a widely used oxidant. Using cis-parinaric acid as a sensitive reporting probe for peroxidation in membranes, and a lipid-soluble azo initiator of peroxyl radicals, 2,2′-Azobis(2,4-dimethylvaleronitrile) we found that CART is an antioxidant. Furthermore, we found that CART localized to mitochondria in cultured cells and mouse brain neuronal cells. More importantly, pretreatment with CART by systemic injection protects against a mouse oxidative stress model, which mimics the main features of Parkinson's disease. Given the unique molecular structure and biological features of CART, we conclude that CART is an antioxidant peptide (or antioxidant hormone). We further propose that it may have strong therapeutic properties for human diseases in which oxidative stress is strongly involved such as Parkinson's disease

Lateral Hypothalamus GABAergic Neurons Modulate Consummatory Behaviors Regardless of the Caloric Content or Biological Relevance of the Consumed Stimuli

It was recently reported that activation of a subset of lateral hypothalamus (LH) GABAergic neurons induced both appetitive (food-seeking) and consummatory (eating) behaviors in vGat-ires-cre mice, while inhibition or deletion of GABAergic neurons blunted these behaviors. As food and caloric-dense liquid solutions were used, the data reported suggest that these LH GABAergic neurons may modulate behaviors that function to maintain homeostatic caloric balance. Here we report that chemogenetic activation of this GABAergic population in vGat-ires-cre mice increased consummatory behavior directed at any available stimulus, including those entailing calories (food, sucrose, and ethanol), those that do not (saccharin and water), and those lacking biological relevance (wood). Chemogenetic inhibition of these neurons attenuated consummatory behaviors. These data indicate that LH GABAergic neurons modulate consummatory behaviors regardless of the caloric content or biological relevance of the consumed stimuli

Cocaine- and amphetamine-regulated transcript peptides play a role in drug abuse and are potential therapeutic targets

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

Cortico-Basal Ganglia Reward Network: Microcircuitry

Many of the brain's reward systems converge on the nucleus accumbens, a region richly innervated by excitatory, inhibitory, and modulatory afferents representing the circuitry necessary for selecting adaptive motivated behaviors. The ventral subiculum of the hippocampus provides contextual and spatial information, the basolateral amygdala conveys affective influence, and the prefrontal cortex provides an integrative impact on goal-directed behavior. The balance of these afferents is under the modulatory influence of dopamine neurons in the ventral tegmental area. This midbrain region receives its own complex mix of excitatory and inhibitory inputs, some of which have only recently been identified. Such afferent regulation positions the dopamine system to bias goal-directed behavior based on internal drives and environmental contingencies. Conditions that result in reward promote phasic dopamine release, which serves to maintain ongoing behavior by selectively potentiating ventral subicular drive to the accumbens. Behaviors that fail to produce an expected reward decrease dopamine transmission, which favors prefrontal cortical-driven switching to new behavioral strategies. As such, the limbic reward system is designed to optimize action plans for maximizing reward outcomes. This system can be commandeered by drugs of abuse or psychiatric disorders, resulting in inappropriate behaviors that sustain failed reward strategies. A fuller appreciation of the circuitry interconnecting the nucleus accumbens and ventral tegmental area should serve to advance discovery of new treatment options for these conditions