What Is Behavioral Sensitization and Its Role in Addiction?

Behavioral sensitization is a phenomenon where repeated, intermittent exposure to a stimulus results in a progressively amplified response. This is sometimes called “reverse tolerance” because it is the opposite of tolerance, where the response to a stimulus decreases with repeated exposure. Sensitization is a form of learning and memory; past experiences with a stimulus cause an increased reaction to that same stimulus or a related one. This process represents a facilitation within a neural system, making a specific effect easier to elicit in the future. This enhanced response can be long-lasting and helps explain how substances of abuse become addicting, as the rewarding effects may be amplified with each use.

The Development Process of Sensitization

The development of behavioral sensitization depends on the pattern of exposure to a stimulus. Intermittent exposure, rather than continuous, leads to the most robust sensitization. The specific timing, dosage, and interval between exposures to a drug play a large part in the strength of the sensitization that develops. For example, intermittent schedules of administration are particularly important for inducing sensitization to psychostimulant drugs like cocaine and methamphetamine.

A feature of sensitization is its context-dependency, meaning the environment where the stimulus is encountered can influence its development and expression. For example, animals repeatedly exposed to drugs in a specific environment show a more robust sensitized response when re-exposed to the drug in that same environment. This suggests that learned associations between the environment and the stimulus contribute to the sensitized response.

The enhanced behavioral response from sensitization can persist for at least a year in some cases. This persistence indicates that the underlying neural changes represent a long-term adaptation of the brain. The process can be divided into two phases: initiation, which involves the immediate neural events that induce sensitization, and expression, which refers to the long-term consequences of these initial events.

Neurobiological Foundations of Sensitization

The neurobiological foundations of behavioral sensitization are rooted in long-lasting adaptations within the brain’s mesolimbic dopamine system. This system, including the ventral tegmental area (VTA) and nucleus accumbens (NAc), is involved in reward and motivation. Drugs of abuse activate this system, increasing dopamine concentrations in the NAc, an effect that can be potentiated with repeated drug administration. The VTA is associated with the initiation of sensitization, while the NAc is linked to its expression.

One neuroadaptation that occurs during sensitization is an alteration in dopamine receptor sensitivity, particularly the D1 receptors in the NAc. Studies have shown an electrophysiological supersensitivity of these receptors in the expression of behavioral sensitization to drugs like amphetamine, cocaine, and morphine. This increased sensitivity means the brain becomes more responsive to dopamine, contributing to the amplified behavioral effects of the stimulus.

In addition to changes in receptor sensitivity, sensitization also involves structural plasticity, such as changes in the physical structure of neurons. This includes alterations in dendritic spines, the small protrusions on dendrites that receive signals from other neurons. These structural changes can lead to long-term alterations in synaptic strength and connectivity within the mesolimbic system, further solidifying the sensitized response.

Common Triggers and Resulting Behavioral Changes

A variety of stimuli can trigger behavioral sensitization, with psychostimulant drugs like amphetamine and cocaine being among the most well-studied. Other substances, including opioids, ethanol, and nicotine, can also induce sensitization. Beyond drugs, chronic or intermittent stress is another trigger. Repeated exposure to stressors such as footshock or social defeat can lead to a sensitized response to later drug administration.

A significant aspect of sensitization is the phenomenon of cross-sensitization, where exposure to one sensitizing stimulus can increase the response to another. For example, animals repeatedly exposed to stress may show a sensitized behavioral response to a subsequent dose of a psychostimulant drug. Cross-sensitization has also been observed between different drugs, such as between ethanol and cocaine, or between THC and morphine. This suggests that different stimuli can produce similar long-term changes in the brain’s reward and stress pathways.

The behavioral changes resulting from sensitization are often observed as increased locomotor activity and stereotyped behaviors, which are repetitive, purposeless movements, in animal models. In humans, sensitization can manifest as heightened drug craving, paranoia, or psychosis-like symptoms in response to the sensitizing drug or associated cues. These behavioral changes reflect the underlying neuroadaptations in the mesolimbic dopamine system.

Significance of Sensitization in Health and Disease

Behavioral sensitization has significant implications for understanding substance use disorders. It is thought to play a part in the transition from casual to compulsive drug use, as the sensitized response to drugs and drug-related cues can intensify craving and increase the likelihood of relapse. The long-lasting nature of sensitization helps to explain why individuals with a history of substance use remain vulnerable to relapse even after long periods of abstinence.

The concept of sensitization extends beyond addiction and is relevant to other psychiatric conditions. In schizophrenia, for instance, the dopamine dysregulation hypothesis suggests that a hyper-responsive dopamine system contributes to psychotic symptoms. Sensitization provides a model for how this hyper-responsive state might develop, as individuals with schizophrenia often show an increased sensitivity to the effects of psychostimulants.

In post-traumatic stress disorder (PTSD), sensitization may explain the heightened sensitivity to subsequent stressors and the recurrence of symptoms. Individuals with PTSD exhibit a form of behavioral sensitization where trauma-associated stress leads to increased reactivity to future stressors. This suggests that shared mechanisms of sensitization may underlie the high rates of comorbidity between PTSD and substance use disorders.