SUMMARY

Corticostriatal systems and learning: changes induced by drug sensitization

Behavior of humans and other animals is determined by processes that take place in the brain, with various specialized areas acting in concert to produce coherent actions. The corticostriatal system, consisting of the prefrontal cortex and the striatum, is a group of interconnected areas within the brain. Subareas within the prefrontal cortex and striatum are connected in a highly specific, topographical manner. The delicate balance of interactions within the corticostriatal system is disturbed in various psychiatric disorders, including schizophrenia and obsessive-compulsive disorder, as well as in drug addicts. The studies covered in this thesis work were designed to investigate 1) the roles of specific sub-areas within the corticostriatal system in learning, 2) alterations within this system following drug sensitization, and 3) alterations following drug sensitization in behavioral processes that are regulated by the corticostriatal system.

To investigate the first question, we examined the role of the corticostriatal system in classical conditioning in rats using the immediate-early gene c-fos as a marker of cellular activation. The role of sub-areas within the prefrontal cortex during the development of classical conditioning was determined. Various areas within the prefrontal cortex (specifically the orbital and lateral areas) showed high activation during beginning phases of the task, but not later, indicating a high specialization of function within the prefrontal cortex.

The second question raised regarded changes in the corticostriatal system during expression of drug sensitization in rats. The corticostriatal system is highly implicated in drug abuse. One process proposed to be involved in drug addiction is drug sensitization, or progressively greater behavioral responding to a drug after repeated administration. Alterations in neurotransmission and morphological changes have been repeatedly documented within the corticostriatal system during and following drug sensitization. In this thesis, further investigation of regional specificity with the corticostriatal system using c-fos determined that the nucleus accumbens core, but not shell, showed sensitized reactivity to amphetamine. Furthermore, although an activity was induced by acute amphetamine in the prefrontal cortex, this activity did not sensitize.

The third set of studies addressed alterations in processes that are normally regulated by the corticostriatal system when this system has been altered by drug sensitization. To investigate effects of the alterations within the corticostriatal system that drug sensitization produces, we examined operant conditioning in sensitized and non-sensitized animals. In rats that had been previously exposed to amphetamine (but were not given the drug on the task day itself), long-lasting increases were seen in responding for sucrose on a random ratio schedule. These alterations in responding were time-dependent, with a transient decrease in responding observed during induction of sensitization, followed by a long-lasting increase in responding. This increase was not observed on a random interval schedule, a schedule in which the response-reinforcement association is less direct. Together, these results indicate that the reward value is increased in sensitized animals. Testing of sensitized animals in a devaluation paradigm also indicated that habit formation (S-R learning) occurs faster in these animals than in non-sensitized animals. Both the increase in reinforcer value and the acceleration of habit formation seen in sensitized animals may be involved in the development of drug addiction.