RT Journal Article
SR Electronic
T1 Sensitization of Midbrain Dopamine Neuron Reactivity Promotes the Pursuit of Amphetamine
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 4654
OP 4662
DO 10.1523/JNEUROSCI.22-11-04654.2002
VO 22
IS 11
A1 Paul Vezina
A1 Daniel S. Lorrain
A1 Gretchen M. Arnold
A1 Jennifer D. Austin
A1 Nobuyoshi Suto
YR 2002
UL http://www.jneurosci.org/content/22/11/4654.abstract
AB Stimulant drugs such as amphetamine are readily self-administered by humans and laboratory animals by virtue of their actions on dopamine (DA) neurons of the midbrain. Repeated exposure to this drug systemically or exclusively in the cell body region of these neurons in the ventral tegmental area (VTA) leads to long-lasting changes in dopaminergic function that can be assessed by increased locomotor activity and enhanced DA overflow in the nucleus accumbens (NAcc) after re-exposure to the drug. Three experiments were conducted to evaluate the possibility that this enduring sensitized reactivity underlies compulsive drug self-administration. In all experiments, rats were pre-exposed to amphetamine and, starting 10 d later, their intravenous self-administration of the drug was assessed. In the first experiment, rats previously exposed to amphetamine systemically or exclusively in the VTA subsequently worked harder than untreated animals to obtain the drug when the work required to obtain successive infusions was increased progressively. In the second experiment, this progressively increasing workload was found to decrease the magnitude of amphetamine-induced DA overflow observed with successive infusions until responding ceased. Rats previously exposed to amphetamine were more resistant to this decline and more apt to maintain responding. Finally, in experiment three, a noncontingent priming injection of the drug produced a greater NAcc DA response and a greater parallel increase in lever pressing in drug compared with saline pre-exposed rats. Together, these results demonstrate a direct relation between drug-induced sensitization of midbrain dopamine neuron reactivity and the excessive pursuit and self-administration of an abused substance.