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Cross Sensitization Between Drugs:
A Behavioral and Neural Basis for "Gateway"

Sensitization refers to the progressively enhanced behavioral and neural activation seen after repeated exposure to a single dose of a drug. The issue our participants will focus on is whether prior experience with one drug enhances the neural, behavioral, reinforcing or subjective characteristics of a second, different, drug (cross-sensitization). This question is important in that cross-sensitization may be linked to an individual's increased vulnerability to drugs over time. This symposium will examine the clinical features of cross-sensitization between classes of abused drugs (i.e., stimulants and opiates), and describe clinical and preclinical data on mechanisms at the cellular and molecular levels underlying this phenomenon.

1:00 - Harriet De Wit, Ph.D., "What is the evidence for sensitization in humans?"

Sensitization and cross-sensitization to neural, locomotor and other behavioral effects of stimulant drugs have been well documented in laboratory animals. However, evidence for sensitization to the effects of stimulants in humans is limited. Few controlled studies have examined the phenomenon in humans, in part because of practical and ethical concerns about administering drugs repeatedly to human volunteers. In addition, few studies have directly compared the effects of stimulants in experienced and inexperienced users. The limited evidence that is available suggests that some drug effects increase with repeated administration, while others decrease or remain unchanged. An important question is which, if any, of these effects is related to the etiology of drug abuse or dependence.

1:35 - Marilyn Carroll, Ph.D., "Factors that prime the initiation of drug self-administration"

This presentation will discuss cross-sensitization from exposure to other drugs, dietary conditions, stress and alternative nondrug activities (e.g., running wheel) to the reinforcing effects of self-administered drugs. Results to be examined are based on animal models such as orally self-administered drugs in rats and intravenously self-administered drugs in primates. Phases of drug addiction that are of interest are acquisition in drug-naive animals, maintenance, and reinstatement or relapse.

2:10 - Susan Schenk, Ph.D., "Sensitization as a mechanism underlying the progression of drug use via 'Gateway' drugs"

It has long been recognized that there is a progression of drug use from "soft" drugs, like nicotine and alcohol, to "hard" drugs like cocaine. This talk will review some of the human literature that supports this progression of drug use and has led to the concept of "gateway" drugs. Other data from the animal literature will be presented that support the idea that gateway drugs are those that produce sensitization in reward relevant neural pathways thereby increasing the response to subsequent drug exposures.

2:45 - Break

3:00 - Paul Vezina, Ph.D., "Locomotion, nucleus accumbens dopamine and pursuit of drug in previously drug-exposed animals"

A number of experiments have now been conducted showing that rats previously exposed to amphetamine subsequently show enhanced locomotor and nucleus accumbens dopamine responding to this drug as well as to others like cocaine. These amphetamine pre-exposed animals will also work more to self-administer each of these drugs. Interestingly, rats previously exposed to THC also subsequently show sensitized locomotor responding to amphetamine. However, these animals do not show an enhanced nucleus accumbens dopamine response nor do they show an enhanced predisposition to pursue and self-administer this drug. These findings are consistent with the view that sensitization of midbrain dopamine neuron reactivity promotes the excessive pursuit of stimulant drugs.

3:35 - Peter Kalivas, Ph.D., "Neurobiological correlates of cross-sensitization"

Cross-sensitization has been described between many drugs of abuse using behavioral measures of locomotor activity and drug self-administration. The neurobiological underpinnings of behavioral cross-sensitization are not well characterized. This presentation will describe potential neural substrates permitting cross-sensitization to occur, and focus on common actions by cross-sensitizing treatments at synaptic activity regulated gene expression within cortico-striatal circuitry.

4:10 - Marina Wolf, Ph.D., "Sensitization and Addiction: Maladaptive Forms of Neuroplasticity?"

Behavioral sensitization provides an animal model for the induction of persistent changes in the neural circuitry of motivation and reward as a result of chronic exposure to drugs of abuse. Different classes of addictive drugs exert different effects on this circuitry via different mechanisms. However, commonality may lie in the cellular "building blocks" used to accomplish these diverse adaptations. I will discuss evidence that drug-induced plasticity involves glutamate-dependent changes in synaptic strength similar to those involved in long-term potentiation and long-term depression.

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