Neuropharmacology
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Drug addiction can be defined by a compulsion to seek and take drug, loss of control in limiting intake, and the emergence of a negative emotional state when access to the drug is prevented. Drug addiction impacts multiple motivational mechanisms and can be conceptualized as a disorder that progresses from impulsivity (positive reinforcement) to compulsivity (negative reinforcement). The construct of negative reinforcement is defined as drug taking that alleviates a negative emotional state. ⋯ A brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the compulsivity of addiction. Other components of brain stress systems in the extended amygdala that interact with CRF and may contribute to the negative motivational state of withdrawal include norepinephrine, dynorphin, and neuropeptide Y. The combination of loss of reward function and recruitment of brain stress systems provides a powerful neurochemical basis for a negative emotional state that is responsible for the negative reinforcement driving, at least in part, the compulsivity of addiction.
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It is well recognized that drugs of abuse lead to plastic changes in synapses and that these long-term modifications have the potential to underlie adaptive changes of the brain that lead to substance abuse. However the variety of molecular mechanisms involved in these responses are not completely defined. We are just beginning to understand some of the roles of glial cells that are associated with synapses. ⋯ Studies using Drosophila show important roles of fly glia in mediating responses to cocaine pointing to the potential for the involvement of mammalian glia in the brain's responses to this as well as other drugs. In agreement with this possibility three receptor systems known to be important in substance abuse, mGluR5, GABA(B) and CB-1 receptors, are all expressed by astrocytes and the activation of these glial receptors is now known to impact neuronal excitability and synaptic transmission. Given our new knowledge about the presence of reciprocal signaling between astrocytes and synapses we are now at a time when it becomes appropriate to determine how glial cells respond to drugs of abuse and whether they contribute to the changes in brain function underlying substance abuse.