Effects of Drugs and Natural Reinforcers

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Many people commonly take stimulant drugs like nicotine, amphetamine, cocaine, or depressant drugs like morphine or alcohol, all of which affect behavior and are thus said to be psychoactive. The long-term consequences of abusing psychoactive drugs are now well-documented, and it has been hypothesized that some of the behavioral symptoms observed in drug addicts or alcoholics are related to abnormalities in the functioning of the prefrontal regions (Robbins and Everitt, 2002). One experimental demonstration of drug-induced changes in the brain is known as drug-induced behavioral sensitization, often referred to just as behavioral sensitization. Behavioral sensitization is the progressive increase in the behavioral actions of a drug that occurs after repeated administration of a constant dose of the drug. Behavioral sensitization occurs with most psychomotor stimulant drugs (e.g. amphetamine, nicotine) and sometimes to morphine. For example, when a rat is given a small dose of amphetamine, it may show a small increase in motor activity. When the rat is given the same dose on subsequent occasions, the increase in activity is progressively larger, thus showing behavioral sensitization. This drug-induced behavioral change persists for weeks or months so that if the drug is given in the same dose as before, the behavioral sensitization is still present. In a sense, the brain has some memory of the effects of the drug.

The parallel between the drug actions and memory led to the question of whether there might be permanent changes in the neurons of the brain that could account for the persistence of the behavior (e.g. Robinson and Kolb, 1999). Indeed, there are. Figure 4 compares the effects of amphetamine and saline treatments on the structure of neurons in Cg3 of the PFC. It can be seen that neurons in the amphetamine-treated brains have greater dendritic material as well as more densely organized spines; the latter being the location of a large percentage of the synapses on these cells. These plastic changes were not found throughout the brain, however, but rather they were localized to regions such as the PFC and nucleus accumbens, both of which are implicated in the rewarding properties of these drugs.

In contrast to the increased synaptic density in the Cg3 neurons exposed to stimulants, there was a decrease in dendritic length and spine density in the insular cortex. This result was completely unexpected and shows that different subregions of the rat PFC may respond dramatically differently to the same stimulation. Further studies showed a similar asymmetry in the medial/orbital regions in response to morphine. In this case, there was a decrease in dendritic length and spine density in the anterior cingulate neurons but an increase in the insular neurons (Robinson et al., 2002). Thus, not only were the effects of stimulants and depressants on the prefrontal neurons qualitatively different, but in both cases there were qualitatively different effects of the drugs on different prefrontal subfields. The contrasting effects of the psychoactive drugs on the two subfields of the rat PFC are intriguing and are reminiscent of the differences seen in metabolic levels of the dorsolateral and orbital regions of human depressed patients (Drevets et al., 1999). These patients show an increase in activity in the orbital regions and a decrease in the dorsolateral region. The parallel between drug effects and depression is intriguing and suggests that plastic changes in the two subfields may act in a reciprocal manner.

Saline Amphetamine

Figure 4: The contrasting effects of saline and amphetamine injections on the structure of cells in the mPFC of rats. Amphetamine increases dendritic length and spine density. Adopted from Robinson and Kolb (1999) with permission.

The effects of psychoactive drugs on cells in the PFC are presumed to be due, at least in part, to actions of the drugs on dopaminergic cells in the brainstem that project to the prefrontal regions. But, not only do drugs affect dopaminergic afferents to the prefrontal neurons but so do naturally-occurring rewards such as sex (Fiorino and Kolb, 2003) and social interaction (Hamilton and Kolb, 2003). For example, analysis of prefrontal neurons of male rats paired daily for two weeks with receptive females confirmed that sex produces changes in prefrontal neurons that are strikingly similar to those observed in rats treated with psychomotor stimulants. In contrast to the drugs, however, similar changes were not seen in nucleus accumbens, a result that may explain why people are addicted to drugs but not normally to natural rewards like sex.

Many questions remain. Why, for example, do rewarding events change synaptic organization? Drugs produce changes in a variety of trophic factors and immediate early genes, but there is as yet no direct evidence of how such changes may alter synaptic organization. Similarly, are there age-related changes in the effects of rewarding events? Given that the reward value of many events, including drugs, appears to wane with age, it would not be surprising to find age-related differences in reward-induced synaptic reorganization. Finally, how do reward-induced synaptic changes interact with other experience-dependent changes? For instance, if neurons in the

PFC are changed by drugs, how do they now respond to experience (e.g. Kolb et al., 2003c)?

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