Intra-ventral tegmental area injection of rat cocaine and amphetamine-regulated transcript peptide 55-102 induces locomotor activity and promotes conditioned place preference.
ABSTRACT Cocaine- and amphetamine-regulated transcript (CART) is a novel mRNA that has been reported to be increased by acute psychostimulant administration, and that may be involved in the effects of psychostimulants. In this study, we examined the effect of centrally administered CART peptides on locomotor activity and conditioned place preference in the rat. CART peptide fragments were bilaterally injected into the ventral tegmental area. CART 55-102 (0.2-5.0 microg/side), an endogenously occurring peptide, dose dependently increased locomotor activity, whereas CART 1-26 (0.1-2.5 microg/side; not found endogenously) did not. The locomotor effects of CART 55-102 were dose dependently blocked by the dopamine D(2) receptor antagonist haloperidol (0.03-1.0 mg/kg i.p.). Four injections of 1.0 microg/side CART 55-102 induced a significant place preference, suggesting that CART 55-102 is reinforcing. Increases in locomotor activity after each of these CART 55-102 injections were similar and did not show tolerance or sensitization. This treatment regimen of CART 55-102 also did not produce sensitization to locomotor activity after a subsequent challenge with cocaine or amphetamine. When CART 55-102 (0.2-1.0 microg/side) was injected into the substantia nigra, no significant change in motor activity was observed. However, a higher dose of CART 55-102 (5.0 microg/side) induced a delayed increase in motor activity, suggesting a possible diffusion from the substantia nigra into the ventral tegmental area. Our findings suggest that CART 55-102 is behaviorally active and may be involved in the actions of psychostimulants. This is the first demonstration of the psychostimulant-like effects of CART peptides.
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ABSTRACT: Production of mRNA from the cocaine- and amphetamine-regulated transcript (CART) gene is regulated by cocaine and other drugs of abuse in the nucleus accumbens (NAc), a brain reward region. Current hypotheses postulate that CART peptides there oppose the rewarding actions of cocaine by opposing the effects of dopaminergic transmission. Since over expression of CREB was shown to decrease cocaine-mediated reward, we hypothesized that CART could be a target gene for CREB in the NAc and that over expression of CREB would increase CART peptide levels. Transcription factor (TF) binding to DNA is influenced by sequences adjacent to consensus TF binding sites and other factors. We thus examined CREB binding to a 27mer oligonucleotide containing the CRE sequence from the CART gene proximal promoter. Using electrophoretic mobility shift assays and TF-antibody super shift assays, CREB was found to bind to the CRE sequence from the CART promoter. To test if over expression of CREB in the NAc affected CART peptide levels, Herpes simplex virus-1 vectors over expressing CREB (HSV-CREB), or a vector that expressed LacZ (HSV-LacZ) as a control, were injected into the NAc of rats. Western blotting and in situ hybridization showed that HSV-CREB injections increased CART mRNA and peptide levels. Injections of a dominant negative CREB mutant (HSV-mCREB) did not alter either CART mRNA or peptide levels. The finding that CREB can regulate the levels of CART mRNA and peptides in vivo in the NAc supports a role for CART peptides in psychostimulant-induced reward and reinforcement.Brain research 12/2008; 1251:42-52. · 2.46 Impact Factor
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ABSTRACT: Intercellular signaling peptides (SPs) coordinate the activity of cells and influence organism behavior. SPs, a chemically and structurally diverse group of compounds responsible for transferring information between neurons, are broadly involved in neural plasticity, learning and memory, as well as in drug addiction phenomena. Historically, SP discovery and characterization has tracked advances in measurement capabilities. Today, a suite of analytical technologies is available to investigate individual SPs, as well as entire intercellular signaling complements, in samples ranging from individual cells to entire organisms. Immunochemistry and in situ hybridization are commonly used for following preselected SPs. Discovery-type investigations targeting the transcriptome and proteome are accomplished using high-throughput characterization technologies such as microarrays and mass spectrometry. By integrating directed approaches with discovery approaches, multiplatform studies fill critical gaps in our knowledge of drug-induced alterations in intercellular signaling. Throughout the past 35 years, the National Institute on Drug Abuse has made significant resources available to scientists that study the mechanisms of drug addiction. The roles of SPs in the addiction process are highlighted, as are the analytical approaches used to detect and characterize them.Neuropharmacology 09/2008; 56 Suppl 1:196-204. · 4.81 Impact Factor
Article: Injection of CART (cocaine- and amphetamine-regulated transcript) peptide into the nucleus accumbens reduces cocaine self-administration in rats.[show abstract] [hide abstract]
ABSTRACT: Cocaine- and amphetamine-regulated transcript (CART) peptides appear to modulate various effects of psychostimulant drugs. Injections of CART peptide into the nucleus accumbens (NAcc) inhibit locomotion produced by systemic injections of the psychostimulants cocaine and amphetamine. Intra-NAcc injections of CART peptide also inhibit locomotion produced by microinfusions of dopamine into the NAcc, suggesting that the effects of CART peptides may be due to an interaction with the dopaminergic system in the NAcc. We sought to determine if this inhibitory effect of CART peptide generalizes to other measures of dopaminergic function such as reward/reinforcement by testing the effect of bilateral intra-NAcc CART infusions (0, 0.25, 1.0 and 2.5 microg per side) on cocaine and food self-administration. One group of rats self-administered cocaine (0.75 mg/kg per 140 microl IV infusion) on a progressive ratio schedule. A separate group received 45 mg food pellets on the same progressive ratio schedule. Bilateral intra-NAcc injections of CART peptide dose-dependently decreased the number of cocaine infusions, the breakpoint of cocaine self-administration, and the total number of bar presses on the cocaine-associated lever. There were no effects of CART injections on the breakpoint for food reward. Thus, we conclude that injections of CART into the NAcc appear to functionally antagonize a major site of action for cocaine self-administration in rats.Behavioural Brain Research 09/2008; 191(2):266-71. · 3.42 Impact Factor