There are three known high-affinity targets for cocaine: the dopamine transporter (DAT), the serotonin transporter (SERT), and the norepinephrine transporter (NET). Decades of studies support the dopamine (DA) hypothesis that the blockade of DAT and the subsequent increase in extracellular DA primarily mediate cocaine reward and reinforcement. Contrary to expectations, DAT knockout (DAT-KO) mice and SERT or NET knockout mice still selfadminister cocaine and͞or display conditioned place preference (CPP) to cocaine, which led to the reevaluation of the DA hypothesis and the proposal of redundant reward pathways. To study the role of DAT in cocaine reward, we have generated a knockin mouse line carrying a functional DAT that is insensitive to cocaine. In these mice, cocaine suppressed locomotor activity, did not elevate extracellular DA in the nucleus accumbens, and did not produce reward as measured by CPP. This result suggests that blockade of DAT is necessary for cocaine reward in mice with a functional DAT. This mouse model is unique in that it is specifically designed to differentiate the role of DAT from the roles of NET and SERT in cocaine-induced biochemical and behavioral effects.addiction ͉ amphetamine ͉ conditioned place preference ͉ knockin C ocaine inhibits the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) with similar potencies and elevates extracellular concentrations of these monoamine neurotransmitters, thereby producing complex neurochemical and behavioral effects (1, 2). However, there is a wealth of evidence indicating that the dopaminergic system, especially DAT, is most important in mediating cocaine's addictive properties (3-6). For instance, the potencies of cocaine analogs for producing self-administration, a measure of drug reward, correlate to their affinities for binding DAT, but not SERT or NET (1, 6). Among the drugs that block all three transporters, those with a high affinity for DAT are selfadministered or produce conditioned place preference (CPP), another measure of drug reward, whereas SERT or NET selective inhibitors do not produce reward in WT animals (7-9).The generation of DAT knockout (DAT-KO) mice (10) allowed a direct test of whether DAT inhibition is required for cocaine reward. Contrary to the expectations, these mice still self-administer cocaine (11) and exhibit cocaine-induced CPP (12, 13). These results suggest that DAT inhibition is not solely required for cocaine reward, at least in DAT-KO mice, leading to the reevaluation of the dopamine (DA) hypothesis and the proposal that redundant systems might mediate cocaine reward (14-16). However, complete deletion of DAT causes tremendous adaptive changes in DA homeostasis, including alterations in DA synthesis, storage, extracellular levels, and receptor expression and functions (10, 17). These adaptive changes may significantly alter normal reward pathways. For instance, fluoxetine and nisoxetine, selective inhibitors for SERT and NET, respectively, produce CPP in DAT-KO ...

Interleukin-1 (IL-1) has been implicated as a critical mediator of neuroimmune communication. In the brain, the functional receptor for IL-1, type 1 IL-1 receptor (IL-1R1), is localized primarily to the endothelial cells. In this study, we created an endothelial-specific IL-1R1 knockdown model to test the role of endothelial IL-1R1 in mediating the effects of IL-1. Neuronal activation in the hypothalamus was measured by c-fos expression in the paraventricular nucleus and the ventromedial preoptic area. In addition, two specific sickness symptoms, febrile response and reduction of locomotor activity, were studied. Intracerebroventricular injection of IL-1 induced leukocyte infiltration into the CNS, activation of hypothalamic neurons, fever, and reduced locomotor activity in normal mice. Endothelialspecific knockdown of IL-1R1 abrogated all these responses. Intraperitoneal injection of IL-1 also induced neuronal activation in the hypothalamus, fever, and reduced locomotor activity, without inducing leukocyte infiltration into the brain. Endothelial-specific knockdown of IL-1R1 suppressed intraperitoneal IL-1-induced fever, but not the induction of c-fos in hypothalamus. When IL-1 was given intravenously, endothelial knockdown of IL-1R1 abolished intravenous IL-1-induced CNS activation and the two monitored sickness symptoms. In addition, endothelial-specific knockdown of IL-1R1 blocked the induction of cyclooxygenase-2 expression induced by all three routes of IL-1 administration. These results show that the effects of intravenous and intracerebroventricular IL-1 are mediated by endothelial IL-1R1, whereas the effects of intraperitoneal IL-1 are partially dependent on endothelial IL-1R1.

Barrows and gilts of 2 genetic lines with differing lean gain potentials (high-lean = 375 g of fat-free lean/d; low-lean = 280 g of fat-free lean/d) were used to determine tissue and organ weights and compositions from 20 to 125 kg of BW. The experiment was a 2 (genetic line) x 2 (sex) x 5 (BW) factorial arrangement of treatments in a completely randomized design conducted with 2 groups of pigs in 6 replicates (n = 120 pigs). Six pigs from each sex and genetic line were slaughtered at 20 kg of BW and at 25 kg of BW intervals to 125 kg of BW. At slaughter, the internal tissues and organs were weighed. Loin and ham muscles were dissected from the carcass and trimmed of skin and external fat, and the ham was deboned. Residuals from the loin and ham were combined with the remaining carcass. Body components were ground, and their compositions were determined. The results demonstrated that tissue weights increased (P < 0.01) as BW increased. Loin and ham muscle weights increased but at a greater rate in the high-lean line and in gilts resulting in genetic line x BW and sex x BW interactions (P < 0.01). Liver and heart expressed on a BW or a percentage of empty BW basis increased at a greater rate in the high-lean line resulting in a genetic line x BW interaction (P < 0.01). Liver and intestinal tract weights were heavier in barrows than in gilts, significant only at 45 (P < 0.05), 75 (P < 0.01), and 100 (P < 0.05) kg of BW. Loin and ham muscles from the high-lean genetic line and gilts had greater (P < 0.01) water, protein, and ash contents compared with the low-lean genetic line and barrows resulting in genetic line x BW and sex x BW interactions (P < 0.01). The remaining carcass (minus loin and ham muscles) had greater (P < 0.01) amounts of water and protein, and less (P < 0.01) fat in the high-lean genetic line and gilts. The high-lean genetic line and gilts had more total body water, protein, and ash, but less body fat, with these differences diverging as BW increased, resulting in a genetic line x BW interaction (P < 0.01). The results indicated that liver and heart weights were greater in high-lean pigs, reflecting the greater amino acid metabolism, whereas the liver and intestinal tract weights were greater in barrow than gilts, reflecting their greater feed intakes and metabolism of total nutrients consumed.

No abstract

Interleukin-1 (IL-1) has been implicated in the disease progression of multiple sclerosis (MS). In the animal model of MS, experimental autoimmune encephalomyelitis (EAE), the induction of disease is significantly attenuated in mice lacking the type I IL-1 receptor (IL-1R1). In this study, we created a transgenic mouse (eIL-1R1 kd) in which IL-1R1 expression is knocked down specifically in endothelial cells. Induction of EAE in eIL-1R1 kd mice results in a decrease in incidence, severity and delayed onset of EAE. In addition, eIL-1R1 kd mice show significant decrease in VCAM-1 expression and diminished CD45 + and CD3 + infiltrating leukocytes in the spinal cord in animals challenged with EAE. Further, IL-1 and IL-23 stimulate IL-17 production by splenocytes from both wild type and the eIL-1R1 kd animals. Similarly, IL-1 and IL-23 synergistically stimulate splenocytes proliferation in these two strains of animals. After immunization with MOG 79-96 , although eIL-1R1 kd mice displayed greatly reduced clinical scores, their splenocytes produced IL-17 and proliferated in response to a second MOG challenge, similar to wild type animals. These findings indicate a critical role for endothelial IL-1R1 in mediating the pathogenesis of EAE, and describe a new model that can be used to study endothelial IL-1R1.