We have shown that although the neuropeptide galanin potentiates morphine analgesia in the spinal cord, galanin and galanin agonists can antagonize morphine reinforcement and withdrawal in the brain. Our hypothesis is that the galanin system in the brain protects against opiate reinforcement by attenuating opiate-induced dopamine (DA) signaling in the ventral tegmental area and nucleus accumbens (Nac) and protects against opiate withdrawal by down-regulating noradrenergic signaling in the locus coeruleus (LC) and its targets. Thus, galanin agonists may be useful for potentiating opiate analgesia while minimizing its abuse liability. The effects of galanin are mediated through activation of a family of G protein-coupled receptors (GaIR1, GalR2 and GaIR3). GalR1 and GalR2 are expressed in brain areas associated with drug addiction, such as the mesolimbic DA system and the LC, as well as in the spinal cord. The distribution and second messenger coupling of GalR1 and GalR2 are distinct, suggesting that they have different roles in galanin neurotransmission. This study will analyze the interactions between galanin and morphine in the CNS.
Our first aim i s to determine whether the galanin system attenuates morphine place preference by modulating the DA system and to identify the galanin receptor subtypes that affect morphine reward. We will determine whether morphine-induced DA release or morphine place preference is altered in mice lacking galanin or in mice treated with the systemic galanin agonist Galnon. Galanin binding will be used to determine whether any of the pharmacological, behavioral or genetic manipulations used alter GalR levels.
The second aim i s to determine whether galanin attenuates opiate withdrawal by modulating the noradrenergic system and to identify the GalR subtypes regulated during opiate withdrawal. Transgenic mice over-expressing galanin in the noradrenergic system will be used to identify the role of galanin in these neurons in modulating opiate withdrawal. Using in situ hybridization we will determine whether GalR1, 2 and 3 mRNA levels are regulated by chronic morphine treatment or naltrexone-precipitated withdrawal in brain and spinal cord. We have already shown that GalR1 is upregulated following opiate withdrawal in the LC but it is not known whether GalR2 or 3 are also regulated. Since there are not selective antagonists for GalR subtypes, we will also generate mice lacking GalR1 to use in behavioral studies to elucidate the role of GalR1 in opiate analgesia and dependence. These experiments are designed to characterize an endogenous system that opposes opiate reward and withdrawal. The proposed studies will identify the pathways in the brain involved in galanin's actions on these processes.
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