Distribution of AMPA receptor subunit glur1 in the bed nucleus of the stria terminalis and effect of stress.

The brain circuitry thought to be involved in stress responses includes several nuclei of the extended amygdala. The bed nucleus of the stria terminalis (BNST) is thought to be involved in the generation of sustained, nonspecific anxiety. Previous behavioral and electrophysiological experiments demonstrate that glutamate systems are involved in anxiety-like behaviors in the BNST. Antagonists for AMPA receptors injected into the BNST decrease anxiety-like behaviors. However, little is known about the role of AMPA receptors and the mechanism by which they act in the establishment of anxiety-like behavior in response to a stressor. We hypothesized that the distribution of AMPA receptors is changed following a paradigm of unpredictable footshock as has been seen in the basolateral amygdala (BLA). We examined the subcellular localization of the GluR1 subunits of the AMPA receptor. We found that the neuropil of the BNST had a lower density of dendritic spines compared to dendritic shafts in the BLA. The majority of elements immunolabeled for GluR1 were dendritic shafts and spines with axonal and glial elements rarely labeled. Compared with controls, no significant effect was observed on days 1, 6, or 14 poststress. However, there was a trend for an increase at 6 and 14 days poststress. These data demonstrate that GluR1 subunits are primarily located on postsynaptic elements in the BNST. Moreover, it was shown that the response of the AMPA GluR1 subunit does not undergo a significant migration into spines from dendrites in response to a stressor as has been demonstrated in the BLA.

CART peptides as modulators of dopamine and psychostimulants and interactions with the mesolimbic dopaminergic system.

Cocaine- and amphetamine-regulated transcript (CART) peptides (CART 55-102 and CART 62-102) are peptidergic neurotransmitters that are widely but specifically distributed throughout the brain, gut and other parts of the body. They are found in many brain regions associated with drug addiction including the nucleus accumbens, ventral tegmental area and ventral pallidum. Injections of CART 55-102 into the nucleus accumbens have no effect on basal locomotor activity. However, an injection of CART just before an i.p. injection of cocaine reduces the locomotor activating effects of cocaine. These and other data suggest that CART in the accumbens blunts the effects of cocaine. A hypothesis is that CART is homeostatic in the accumbens and tends to oppose large increases in dopamine signaling. These actions would therefore be able to regulate the effects of some abused drugs such as the psychostimulants.

Colocalization of CART peptide with prodynorphin and dopamine D1 receptors in the rat nucleus accumbens.

CART peptide is a peptidergic neurotransmitter that is expressed in brain regions involved in critical biological processes such as feeding and stress, and in areas associated with drug reward and abuse including the dopamine-rich nucleus accumbens (NAcc), which can be considered part of the basal ganglia. Because CART has been shown to colocalize with substance P, a marker of the basal ganglia direct pathway, we now test for colocalization with other markers of the direct pathway to determine if CART colocalizes with dynorphin and dopamine D1 receptors. In the NAcc, CART peptide immunoreactivity (IR) was colocalized with prodynorphin-IR in neurons. Approximately 80.1% of CART-IR cells colocalized with prodynorphin-IR, while only 27.6% of prodynorphin-IR neurons contained CART-IR, suggesting that CART cells are a subset of dynorphin cells. In contrast, only about 25% of CART-IR cell bodies demonstrated dopamine D1 receptor-IR. Because dynorphin and D1 receptors are markers for the basal ganglia direct pathway, from the NAcc to the basal ganglia output nuclei, and because CART significantly colocalizes with these markers, some CART neurons are part of the direct pathway or some comparable pathway in the accumbens. The presence of CART in NAcc neurons and the fact that NAcc projection neurons have extensive local collaterals suggest that CART may have effects in both terminal and cell body regions of the accumbens and may therefore affect information processing in the NAcc by modulating accumbal neurons.

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. 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.

Colocalization of CART with substance P but not enkephalin in the rat nucleus accumbens.

CART peptide is a novel neurotransmitter that, due to its distribution in the brain and its modulation of dopamine systems, may be involved in aspects of reward and drug abuse. In the nucleus accumbens (NAcc), CART peptide immunoreactivity (IR) is colocalized with substance P-IR in neurons. Approximately 86% of CART-IR cells colocalize with substance P, while only 19% of substance P-IR neurons contain CART. CART peptide does not colocalize with enkephalin-IR in this region. The substance P-CART colocalization exists in a rostro-caudal gradient with more colocalization in rostral regions. The presence of CART in substance P NAcc neurons suggests that CART neurons may be a subset of the basal ganglia direct pathway or that CART neurons are involved in limbic projections of the NAcc, such as to the ventral pallidum.

CART in feeding and obesity.

CART (cocaine- and amphetamine-regulated transcript) peptides are neurotransmitters that have received much attention as mediators of feeding behavior and body-weight regulation in mammals. CART peptides and their mRNAs are found in many brain regions and in peripheral tissues that are involved in feeding, and many animal studies implicate CART as an inhibitor of feeding. Animal studies also demonstrate that CART expression is regulated by both leptin and glucocorticoids, two hormones known to be associated with the regulation of body weight. A recent study also links a mutation in the CART gene to obesity in humans. These peptides might become targets for drug development in the area of obesity.