Cocaine-induced expression changes of axon guidance molecules in the adult rat brain

Abstract

Administration of drugs of abuse induces strong molecular adaptations and plasticity within the mesolimbic dopamine (DA) system, a pathway essential for reward-seeking behavior. Little is known about the specific targets involved in this neuroadaptation process, but there are indications that cocaine and other drugs of abuse share the ability to alter the morphology of neuronal dendrites and spines, the primary site of excitatory synapses in the brain. Axon guidance molecules, the very molecular cues that regulate the formation of axon-target connections during development, may mediate these alterations. To test this hypothesis, we investigated mRNA expression changes of 39 axon guidance molecules, including 17 Semaphorins, 12 Ephs, 8 Ephrins and 2 neuropilins in the mesolimbic dopamine system of cocaine-treated animals under different paradigms by mean of DNA-Microarray and quantitative real-time PCR. In all cases, strong changes in gene expression are observed, yielding to up or down-regulation of these axon guidance molecules. Our data suggest that cocaine treatment induces activation of a complex program of synaptic rearrangements, which may partly recapitulate the plastic changes occurring during development, and may underlie the important neuroplastic adaptations that occur in the reward-and memory-related brain centers following drug action. We conclude that in some brain regions, exposure to psychomotor-stimulant drugs produce expression changes in axon guidance molecules, which may contribute to cognitive deficits associated with drug abuse.2

Regulation of netrin-1 receptors by amphetamine in the adult brain

“…These findings are in agreement with the recent observation that repeated pretreatment with stimulant drugs during adulthood regulates gene expression of a wide variety of guidance molecules (Bahi and Dreyer, 2005;Yue et al, 1999). We have also shown here that the effects of repeated AMPH on netrin-1 receptor expression are mediated by NMDA receptor activation, suggesting that netrin-1 signaling may play a role in the development of AMPH-induced sensitization.…”

Cytosolic proteomic alterations in the nucleus accumbens of cocaine overdose victims

“…7,8,19 In addition to the cocaine-induced NAc plasticity, studies in rodent models indicate persistent or even permanent biochemical alterations in regions associated with the mesolimbic dopamine pathway including upregulation of the cyclic AMP (cAMP) pathway, [20][21][22][23][24][25][26] activator protein 1 family members [27][28][29][30][31][32] as well as glutamate, dopamine, gaminobutyric acid (GABA) and opiate receptors, growth factors, cytoskeletal elements and cell metabolism. [33][34][35][36][37][38][39][40][41] Genomic analyses in human post-mortem tissue of cocaine overdose (COD) victims have confirmed the findings of studies employing rodent models and have revealed novel mechanisms of drug-induced neuronal and non-neuronal dysregulation in human post-mortem brain tissue. [42][43][44][45] For example, Bannon and co-workers 42 examined gene expression in the NAc of post-mortem brain tissue of human cocaine abusers and controls and found significant alterations in several novel functional classes and transcripts including signal transduction, transcriptional and translational processing, neurotransmission and synaptic function, glia, structural and cell adhesion, receptors/transporters/ion channels, cell cycle and growth and lipid and protein processing.…”

Associative Learning and CA3–CA1 Synaptic Plasticity Are Impaired in D1R Null,Drd1a−/−Mice and in Hippocampal siRNA SilencedDrd1aMice

“…The ⌬Ct for each candidate was calculated as ⌬Ct ϭ [Ct (candidate) Ϫ Ct (Gapdh or B-actin)]. The relative abundance of each target in each protocol was calculated as the ratio between treated and untreated samples (Bahi and Dreyer, 2004;Bahi et al, 2004b;Mühlbauer et al, 2004).…”