After coming to UNC, Dr. Breese introduced an important early advance by developing models in which brain dopamine and norepinephrine-containing neurons were preferentially destroyed with the neurotoxin 6-hydroxydopamine. This model development led to finding that the actions of central stimulants and self-stimulation were dependent upon the integrity of central dopamine-containing neurons. Based upon destruction of serotonergic neurons with a neurotoxin, the hypothesis was proposed that activation of serotonin-containing neurons by central stimulants contributed to the therapeutic action of these drugs to treat attention-deficit disorder. In addition to this research, Dr. Breese also spent considerable effort studying the mechanism of the acute and chronic actions of antidepressant and antipsychotic drug actions.
Early in his career, another area of seminal research at UNC was the discovery that thyrotropin releasing hormone (TRH) reversed barbiturate and alcohol anesthesia. Finding that the TRH analeptic action was apparent after thyroidectomy and hypophysectomy indicated that this action was not related to its endocrine function. Subsequently, it was discovered that the analeptic effect of TRH against alcohol was dependent upon TRH receptors in the medial septum—evidence for an extra-hypothalamic function of this peptide.
In 1984, Dr. Breese discovered that differing types of behavioral responses were observed depending upon the age at which dopaminergic neurons were destroyed. Specifically, rats with reduced brain dopamine during development exhibited self-injury when challenged with dopamine agonists at adulthood, whereas rats lesioned as adults did not. The reduced dopamine during development was proposed to model the dopamine reduction in Lesch-Nyhan disease, a genetic disorder displaying self-injury. With this model, several drugs have been identified that block this induced behavior. These preclinical findings ultimately led to successful clinical drug trials to treat this debilitating symptom in the mentally retarded. Additional work in the rats lesioned as neonates led to the discovery of behavioral sensitization with repeated exposure to a D1-dopamine receptor agonist, as well as the demonstration of a functional interaction between D1/D2-dopamine receptors. More recent work has implicated p-ERK in the D1-agonist “priming” sensitization.
In the arena of alcohol studies, Dr. Breese and colleagues made several key seminal findings that repeated chronic ethanol exposures and accompanying withdrawals result in a "kindling" of seizure activity and an enhancement of anxiety not seen with continuous ethanol exposure. Most recently, other work complemented this discovery of adaptation facilitated by repeated ethanol exposures by demonstrating the persistence of this adaptation to sensitize withdrawal-induced anxiety upon re-exposure to chronic ethanol. Further, the discovery has been made that stress prior to chronic ethanol can facilitate withdrawal-induced anxiety and that stress can exhibit anxiety after multiple withdrawals from chronic ethanol not seen if animals are not exposed to ethanol. These latter findings led his laboratory to propose the “kindling”/stress hypothesis of alcoholism to account for relapse.
From the various published studies related to this research, Dr. Breese was recognized as being among the 1000 most cited contemporary scientists between 1965 and 1978. Since that period of his career, he has been cited more than 10,000 times from the nearly 400 publications with which he is associated.
|
Bowles Center for Alcohol Studies at the University of North Carolina at Chapel Hill