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e Center Biovest International. We thank the Nikon Imaging Center at Harvard Medical School for help with light microscopy. Convergent evidence suggests that environmental factors BMS 650032 site impact individual susceptibility to drugs of abuse. One animal model that addresses environmental factors uses rats raised in one of the three different conditions: an enriched condition, a standard condition, and an impoverished condition. This animal model provides an ideal approach in elucidating the underlying neurobiological mechanisms of environmental influences on vulnerability to nicotine addiction. Nicotine activates nicotinic acetylcholine receptors throughout the brain, thereby stimulating dopamine release within the mesocorticolimbic system. Repeated exposure to nicotine induces behavioral sensitization. Although behavioral sensitization is not a measure of drug reward, this procedure is sensitive to behavioral changes produced by the psychostimulant effects of abused drugs. This procedure was used in the current study to determine whether enriched environmentinduced alterations in locomotor sensitization to nicotine was associated with changes in dopaminergic signaling proteins. EC rats exhibit a reduction in nicotine-mediated locomotor activity compared to IC and SC rats, which could be mediated by enriched environment-induced alterations of dopaminergic path ways. Indeed, drug-naive EC rats exhibit diminished DA transporter function, less synaptic DA levels in medial prefrontal cortex, and show decreased D1 receptor function and expression in the prefrontal cortex compared with IC and SC groups. In contrast, repeated nicotine administration profoundly increases DA clearance and 3,4Dihydroxyphenylacetic acid levels in the PFC of EC rats but not in IC rats. Therefore, EC rats may have lower dopaminergic tone compared to IC rats under basal conditions, which may contribute to differential behavioral responses to psychostimulants. Activation of the DA/D1 receptor/cAMP/protein kinase A pathway increases phosphorylation of DA and cAMPregulated phosphoprotein-32 at the site Threonine 34, but decreases phosphorylation of DARPP-32 at Threonine 75 . In contrast, phosphorylation of DARPP-32 at Thr75 by cyclindependent kinase 5 has a major inhibitory effect on the pDARPP32 Thr34 by PKA, thereby reducing D1 DA signaling through the DARPP-32/ protein phosphatase 1 cascade. In Enriched Environment Regulates Signaling Proteins addition, activation of the PKA pathway enhances phosphorylation of cAMP response element binding protein at serine 133, which is essential for neuronal plasticity in response to repeated exposure to drugs. PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/2221058 Since phospho-Ser133 is dephosphorylated by PP-1, DARPP-32 also acts as a multifunctional protein that can modulate CREB phosphorylation. On the other hand, activation of Ca2+-dependent calcineurin by D2 receptors results in dephosphorylation of pDARPP-32 Thr34. Since nicotine-induced increased pDARPP-32 Thr34 and nicotine-mediated behavioral sensitization were attenuated by inhibition of calcineurin, we propose that environmental enrichment alters activation of DARPP-32 and CREB, and that these neuroadaptations may be associated with differential regulation of nicotine-mediated locomotor activity. horizontal activity measured all beam breaks in the horizontal plane with total rearing activity measuring all beam breaks in the vertical plane. All activity monitors were located in an isolated room away from the colony. Nicotine Administr