Sensitization of midbrain dopamine neuron reactivity and the self-administration of psychomotor stimulant drugs

Abstract

Psychostimulant drugs like amphetamine are readily self-administered by humans and laboratory animals by virtue of their actions on dopamine (DA) neurons in the midbrain. Exposing animals to this drug either systemically or in the cell body region of these neurons in the ventral tegmental area leads to long-lasting alterations in dopaminergic function. These have most often been assessed as increased locomotor activity and enhanced DA overflow in the nucleus accumbens (NAcc) after re-exposure to the drug weeks to months later. Evidence is presented showing that manipulations that produce this sensitization of midbrain DA neuron reactivity enhance the pursuit and self-administration of psychostimulant drugs. Procedures known to prevent the induction of sensitization by amphetamine also prevent the facilitation of drug taking. Enhanced drug self-administration and primed reinstatement of drug seeking are also accompanied by enhanced NAcc DA reactivity. Finally, drugs that increase NAcc DA overflow acutely but fail to produce sensitization of this effect are not associated with the subsequent enhancement of self-administration. These results indicate a direct relationship between the sensitization of midbrain dopamine neuron reactivity and the excessive pursuit and self-administration of psychostimulant drugs. Understanding the neuronal events and adaptations that underlie the induction and expression of sensitization may thus help elucidate how drug abuse develops, how it is reinstated and ultimately how both may be prevented.

Introduction

Psychomotor stimulant drugs such as amphetamine produce multiple effects. Notable among them is their ability to activate brain dopamine (DA) neurotransmission, increase locomotor activity and support self-administration in humans and laboratory animals. When repeatedly administered, their ability to produce these as well as other effects becomes enhanced so that re-exposure to the drug, weeks to months later, produces greater dopaminergic and behavioral activation than seen initially. This long-term enhancement in the ability of such drugs to activate DA neurotransmission and elicit appetitive behaviors is termed sensitization and may have particular bearing for understanding the escalation of drug use that is characteristic of the transition from casual experimentation with drugs to drug craving and abuse. Sensitization may also figure importantly in the reinstatement of drug taking in individuals that have been drug-free for some time. Understanding the neuronal events and neuroadaptations that underlie the induction and expression of sensitization may thus help elucidate how drug abuse develops, how it is reinstated and how both may be prevented.

The mesocorticolimbic DA pathways, particularly those projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc), are known to be critical for the production of locomotor and drug self-administration behaviors by psychomotor stimulants like amphetamine. This fact together with the knowledge that repeated exposure to these drugs sensitizes their ability to increase extracellular levels of DA in the NAcc suggests a potentially important relation between the sensitization of mesoaccumbens DA neuron reactivity and the excessive pursuit and self-administration of drugs observed in sensitized animals. The evidence supporting this relation is examined below for amphetamine.