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06-08-09 Why do drugs of abuse cause a euphoric 'high'?

Question of the Week

June 8, 2009

Why do drugs of abuse cause a euphoric high?

Simplistically, euphoria (from either natural rewards or drugs of abuse) occurs as a result of the release of Dopamine (DA) into the neuronal synapse in the limbic area of the brain.

Neurotransmitters (NT) such as Dopamine are chemicals that are produced in the nerve and stored in synaptic vesicles located in the axonal nerve terminal. Vesicular transporters move the NT into the protective vesicles. Depolarization of the nerve causes the vesicle to move to the the plasma membrane, fuse with it, and release the NT into the synapse. The amount of NT released is determined by the synaptic and vesicular concentration of the NT. The NT diffuses through the synaptic cleft and produces effects by binding to a receptor on the postsynaptic nerve cell membrane. Synaptic effects are terminated by active uptake via a plasma membrane NT transporter.

Hedonistic activity (natural or drug-induced) is associated with firing of Dopamine (DA) neurons which causes release of DA into the synapse. When a pleasurable activity is repeated, neuronal firing (and release of DA into the synapse) begins when stimuli (or cues) predict the activity will follow. Drug-induced neuronal firing causes supraphysiologic concentrations of synaptic DA. The greater the concentration of synaptic DA, the greater the high. As drug use continues, the set point (synaptic concentration) at which pleasure is achieved is changed and there is a blunting of mechanisms that mediate positive reinforcement. In contrast, natural reinforcers lose their ability to increase synaptic DA with repeated exposure. Synaptic DA is removed from the synapse by the dopamine plasma membrane transporter (DAT) which carries synaptic DA back into the neuronal cytoplasm.

Question prepared by Donna Seger, M.D. Medical Toxicologist