Cocaine-induced changes linked to persistent addictive behaviours

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Washington, Aug 14 : In two separate studies, scientists have identified specific cocaine-induced changes in dopamine (DA) neurons that play a vital role in persistent addictive behaviours linked with drugs.

The knowledge behind the mechanism underlying this phenomenon is the key for designing efficient therapy. DA neurons in an area of the brain called the mesolimbic system play a major role in both reward and motivation and are a primary target for abused drugs. But, how drug-induced synaptic changes in DA neurons relate to the development of addictive behaviours is still a mystery.

Scientists have attributed the process of addiction to plastic changes in excitatory glutamate synapses on DA neurons in the ventral tegmental area (VTA).

Previous research has linked cocaine-induced synaptic strengthening in DA neurons in the VTA with activation of a subtype of glutamate receptors, called NMDA receptors (NMDAR) and with changes in the subunit composition of another type of glutamate receptor, AMPA receptors (AMPAR).

Findings from both studies support the hypothesis that cocaine-evoked synaptic plasticity does not mediate concurrent short-term behaviour effects of the drug but may instead underlie long-term changes responsible for persistent drug-seeking behaviour.

In the first study, Dr. Larry S. Zweifel, and colleagues, from the Howard Hughes Medical Institute and the Department of Biochemistry at the University of Washington in Seattle, analysed the link between glutamate signalling in DA neurons and long-term changes associated with drug exposure. They did this by selectively inactivating NMDAR signalling in DA neurons and testing two widely used models of addiction in mice.

It was found that while the stimulatory effects of cocaine on motor activity were unaltered and behavioural sensitization progressed normally, cue-evoked drug seeking and the enhancement of drug craving following withdrawal were significantly impaired in the mice lacking functional NMDAR in DA neurons.

"Our findings support a role for NMDAR-dependent modulation of DA neurons in cue-induced relapse to drug seeking," said Dr. Zweifel.

In the second study, Dr. Engblom and colleagues from German and Swiss research teams examined the relationship between glutamate signaling and drug-induced behavior using mice lacking the GluR1, GluR2, or NR1 glutamate receptor subunits selectively in DA neurons.

The mice with disturbed NMDAR signalling or AMPAR plasticity in DA neurons lacked cocaine-induced synaptic strengthening but exhibited normal basal and cocaine-induced DA release properties.

But, the researches still saw two alterations in the persistence of drug-seeking behaviour. Interference with NMDAR signalling in DA neurons abolished cocaine relapse behaviour, and deletion of the GluR1 subunit in DA neurons resulted in a specific deficit in extinction of cocaine-induced reinforcement.

"Our findings link NMDAR signaling in DA neurons with relapse behavior and provide a new rationale in the treatment of cocaine addiction. Specifically, the selective activation of the GluR1 subunit could potentially improve the outcome of any given exposure therapy," concluded Dr. Engblom.

The two studies are published in the latest issue of the journal Neuron.

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