|Addiction Research Unit|
|Department of Psychology/University at Buffalo|
Before preceding, please read the important note below. For easy perusal of this table, click on the hyperlinks associated with each item; use your browser's back button to return to the table, and click here to return to the ARU home page.
Chronology of Major Empirical and Theoretical Contributions
|1980||development of a novel microinjection procedure|
|1981a||localization of ventral tegmental site of opiate reward|
|1981b||demonstration of dopamine involvement in opiate reward|
|1981c||review suggesting a common neural basis of opiate and psychomotor stimulant reward|
|1983||review suggesting criteria for studying intracranial
review of opiate reward mechanisms which linked opiate and psychomotor stimulant rewards to the mesolimbic dopamine system
|1983/84||neuroanatomical dissociation of opiate reward and physical dependence|
|1985a||controlled study of cocaine toxicity including a comparison with heroin|
|1985b||concept of motivational toxicity introduced|
|1987a||psychomotor stimulant theory of addiction|
|1987b||publication of an interdisciplinary book on assessing drug reinforcement|
|1988||demonstration that another motivated behavior (i.e., feeding) can be elicited by a ventral tegmental action of opioids|
|1989a||publication of an original paper in Russian describing opiate reward mechanisms|
|1989b||demonstration of lowered dopamine levels following
intravenous cocaine self-administration
animal model of cocaine withdrawal
|1990||review presenting a psychobiological model of drug addition which acknowledged nonpharmacological processes|
|1993||finding that nitric oxide is involved in cocaine sensitization|
|1994a||finding that cocaine fatalities are increased by restraint stress|
|1994b||review of opiate reinforcement processes suggesting multiple mechanisms|
|1997||finding that suggests a possible pharmacological treatment for minimizing the complications associated with long-term management of schizophrenia (i.e., relapse, neurological side-effects, and increased risk for cocaine abuse)|
Research highlights are presented here for developments that the ARU director has played a significant role. These items are considered the most significant contributions. The unit director is deeply indebted to his mentors, Professors Larry D. Reid and Roy A. Wise for the intellectual stimulation, training, and opportunities that have made this and subsequent work possible. For a personal profile, see Biographical Sketch.
Scientific discoveries are not made in isolation. Much of the work described here was done in collaboration with other scientists and much was completed before establishing the ARU. More importantly, most "discoveries" developed directly from the earlier work of other scientists and no attempt is made to claim propriety of ideas or discoveries. Occasionally, however, seemingly unrelated findings or ideas are brought together by scientists who see more similarities than differences in ideas or data. Similarly, identifying how to adapt a technique for a novel application or conducting a critical experiment that tests an important hypothesis make especially important contributions to the field. Some of these "insights" produce the leaps made by science that otherwise precedes in a slow, linear pace. Most importantly, new insights sometimes lead to "revolutions" in science that produce paradigmatic shifts in the way a subject is viewed.
1980: A novel microinjection method was developed for delivering nanoliter volumes of drug to freely moving animals. This procedure made possible the studies involving intracranial self-administration by permitting precise, response-contingent drug delivery into the brains of freely moving animals. This method is currently being used by other laboratories studying intracranial self-administration and is being commercially manufactured. [see M.A. Bozarth & R. A. Wise (1980), Electrolytic microinfusion transducer system: An alternative method of intracranial drug application. Journal of Neuroscience Methods 2, 273-275.]
1981a: Morphine was shown to be reinforcing when microinjected into the brain region containing the cell bodies of the mesolimbic dopamine system. This study localized one important brain site where opiates initiate their rewarding effects. [see M. A. Bozarth & R. A. Wise (1981), Intracranial self-administration of morphine into the ventral tegmental area in rats. Life Sciences 28, 551-555.]
1981b: Heroin reward was shown to be attenuated by blocking dopaminergic receptors. The conditioned place preference method was used to test this hypothesis, because other measures requiring lever pressing might be influenced by possible response impairment caused by the combined sedative actions of heroin and a dopamine-receptor blocker. [see M. A. Bozarth & R. A. Wise (1981), Heroin reward is dependent on a dopaminergic substrate. Life Sciences 29, 1881-1886.
1981c: The first in a series of reviews postulating that opiates and psychomotor stimulants activate a common dopaminergic reward systems. Later papers provided stronger arguments and more detailed descriptions of reward mechanisms. [see R. A. Wise & M. A. Bozarth (1981), Brain substrates for reinforcement and drug self-administration. Progress in Neuro-Psychopharmacology 5, 467-474.]
1983: A review that summarized much of the evidence suggesting a common neural basis for opiate and psychomotor stimulant rewards. Criteria were also outlined for conducting intracranial self-administration studies. [see M. A. Bozarth (1983), Opiate reward mechanisms mapped by intracranial self-administration. In J. E. Smith and J. D. Lane (Eds.), Neurobiology of opiate reward processes (pp. 331-359). Amsterdam: Elsevier/North Holland Biomedical Press.]
1983/84: Two reports demonstrating a neuroanatomical dissociation of opiate reward and physical dependence. Chronic morphine microinjections into the brain region supporting intracranial self-administration failed to produce physical dependence, and morphine microinjections into a brain region that produced physical dependence failed to support intracranial self-administration. This showed that physical dependence was not a necessary condition for opiate reward and provided a strong argument for excluding physical dependence from definitions of opiate addition. It was also shown that a single heroin injection could produce a conditioned place preference, thus temporally dissociating reward and physical dependence (i.e., the first injection of heroin could be shown to be rewarding and therefore relief from withdrawal discomfort could not contribute to the measured rewarding effect). Other methods of demonstrating reward from systemic drug injections require repeated drug administration and thus cannot eliminate negative reinforcement mechanisms in their demonstration of drug reward. These studies provided empirical evidence for the neuroanatomical separation of opiate reward and physical dependence suggested in the earlier review listed above. [see M. A. Bozarth & R. A. Wise (1983), Dissociation of the rewarding and physical dependence-producing properties of morphine. In L. S. Harris (Ed.), Problems of drug dependence, 1982 (National Institute on Drug Abuse Research Monograph 43, pp. 171-177). Washington, DC: U. S. Government Printing Office. And see M. A. Bozarth & R. A. Wise (1984), Anatomically distinct opiate receptor fields mediate reward and physical dependence. Science 244, 516-517.]
1985a: This study reported an extremely high fatality rate in laboratory rats permitted continuous access to intravenous cocaine. The toxicity of cocaine was much higher than that seen with rats intravenously self-administering heroin. This was the first systematic study of cocaine toxicity during voluntary drug administration, although earlier studies have reported fatalities with animals self-administering cocaine and other psychomotor stimulants.
The paper was published during the peak of the cocaine epidemic. Cocaine was viewed by many as a relatively safe drug, and this paper provided dramatic, scientific evidence to the contrary. Publication in the Journal of the American Medical Association was accompanied by a press release produced by the American Medical Association. This was met with considerable media interest and coverage (see Media Coverage). Although we did not consider the high cocaine fatality rate a "discovery," this report had considerable social and political impact. [see M. A. Bozarth & R. A. Wise (1985), Toxicity associated with long-term intravenous heroin and cocaine self-administration in the rat. Journal of the American Medical Association 254, 81-83.]
1985b: The concept of motivational toxicity was introduced as an important consideration for evaluating the neurotoxic profile of addictive substances. [see R. A. Wise & M. A. Bozarth (1985), Interaction of drugs of abuse with brain mechanisms of reward. In K. Blum and L. Manzo (Eds.), Neurotoxicology (pp. 111-133). New York: Marcel Dekker.]
1987a: This paper provided the most comprehensive statement of the reward model suggesting that a common brain reward system mediates the rewarding effects of multiple classes of addictive drugs and the rewarding effects of natural reinforcers. [see R. A. Wise & M. A. Bozarth (1987), A psychomotor stimulant theory of addiction. Psychological Review 94, 469-492.]
1987b: This book provided a synopsis of the methods used to study drug reinforcement. It was designed to facilitate communication among investigators using much different methods of studying drug reinforcement and to stimulate better interactions between scientists conducting preclinical and clinical research. Developed from a satellite symposium held in conjunction with the 1983 Society for Neuroscience meeting, difficulties with the initial publisher delayed publication until Springer-Verlag enthusiastically completed this project. [see M. A. Bozarth (1987) (Ed.), Methods of assessing the reinforcing properties of abused drugs. New York: Springer-Verlag.]
1988: This paper reported that ventral tegmental opioid microinjections elicited feeding in food satiated animals. This was particularly significant because it was the first demonstration that a naturally occurring behavior could be elicited by opiate activation of the ventral tegmental system. Also, the opioid peptide dynorphin1-13was found to be 50,000-times more potent than morphine in eliciting a feeding response. This report was a key element in encouraging other investigators to examine the effects of ventral tegmental opioids (including dynorphin1-13) on other behaviors. Since this initial report, other scientists have shown that sexual and maternal behaviors can be elicited by opioid activation of this system. [see M E. Hamilton & M. A. Bozarth (1988), Feeding elicited by dynorphin1-13 microinjections into the ventral tegmental area in rats. Life Sciences 43, 941-946.]
1989a: An original review of opiate reinforcement mechanisms was published in a Russian journal. [Bibliographic information for this article is omitted because most browsers do not support the Cyrillic character set.]
1989b: This paper combined a comprehensive review with theory and new empirical findings. The most notable new findings were a tentative model of cocaine withdrawal following termination of experimenter-delivered cocaine injections and lowered monoamine levels (i.e., dopamine and serotonin) following intravenous cocaine self-administration. New considerations for cocaine addiction and preclinical measures of addiction liability were also discussed.
The experimental work was actually completed earlier in 1985, but publication was delayed because of a lack of funding to pursue important follow-up studies. Because of the media attention (e.g., NIDA's infamous "this is your brain on drugs" public service announcement), publication without replication and without extension of this finding was considered imprudent. A grant application was submitted to NIDA to pursue this finding in 1986, but the proposal was not funded. NIDA funding for other projects ceased a year after moving to Buffalo (1988). After two other failed applications to NIDA, it became apparent that this line of research would not be pursued here. With the hope of stimulating interest in this research, a preliminary report was published in 1989. Subsequently, several laboratories have shown a reduction in brain dopamine levels following cocaine administration. [see M. A. Bozarth (1989), New perspectives on cocaine addiction: Recent findings from animal research. Canadian Journal of Physiology & Pharmacology 67, 1158-1167.]
1990: This book chapter presented a model of addiction (with special reference to opioids and psychomotor stimulants) acknowledging the potential influence of psychological and sociological variables. It was argued that addiction does not represent a unique motivational condition but rather involves normal motivational processes. It was also argued that simple activation of the neural substrate underlying reward processes is not sufficient to produce addictive behavior and that conclusions drawn regarding the addiction potential of various substances need to examine more closely the behavioral characteristics of the drug-taking behavior. The possibility that nicotine was not addictive was raised, thus challenging the assertions of both the Surgeon General of the United States and the National Institute on Drug Abuse. This line of argument would later be followed by intense empirical study during 1995 through 1997, with the first publications emerging in 1998. [see M. A. Bozarth (1990), Drug addiction as a psychobiological process. In D. M. Warburton (Ed.), Addiction controversies (pp. 112-134 + refs). London: Harwood Academic Publishers.]
1993: The involvement of nitric oxide in cocaine sensitization was established and the role of NMDA-receptors was confirmed. Nitric oxide was Science magazine's molecule of the year, and several authors had suggested that nitric oxide was involved in cellular learning and neuroadaptation. A series of exploratory studies was begun to investigate the role of nitric oxide in dopamine-mediated behaviors. Most of this work was disappointing, but one important finding that did emerge was nitric oxide's involvement in cocaine sensitization. [see C. M. Pudiak & M. A. Bozarth (1993), Pudiak, C.M., L-NAME and MK-801 attenuate sensitization to the locomotor-stimulating effect of cocaine. Life Sciences, 53, 1517-1524.]
1994a: Restraint stress was shown to increase fatalities from high-dose cocaine. This finding has important implications for the emergency management of cocaine overdose. Individuals under the influence of moderate to high cocaine doses are extremely active and frequently agitated. Law enforcement officers and medical workers may restrain these individuals to manage their agitated behavioral state. The results from this study strongly caution against restraint by revealing that some fatalities that appear due to cocaine overdose may actually involve an interaction of high-dose cocaine and restraint stress. While it may not be possible to avoid partial restraint during the management of cocaine overdose, restraint should be minimized to avoid exacerbating cocaine's potentially lethal effects. The practice of binding the individual to a hospital bed or handcuffing them in a jail cell is strongly contraindicated and may be a contributing factor to the fatalities reported in these cases. [see C. M. Pudiak & M. A. Bozarth (1994), Cocaine fatalities increased by restraint stress. Life Sciences, 55, PL379-PL382.]
1994b: This theoretical review suggests that multiple mechanisms are involved in opiate reinforcement. This contrasts with earlier work emphasizing a simple positive reinforcement process. The importance of positive reinforcement processes is still underscored, but additional processes involving negative reinforcement are also suggested to be important for opiate addiction. [see M. A. Bozarth (1994), Opiate reinforcement processes: Reassembling multiple mechanisms. Addiction,89, 1425-1435.]
1997: Inhibition of nitric oxide synthase
was shown to attenuate the development of supersensitivity to chronic haloperidol
treatment. This finding suggests a simple, adjunct pharmacological treatment
that may diminish several problems associated with chronic neuroleptic
treatments used to manage schizophrenia. Antipsychotic medications produce
an enhanced responsiveness to dopamine (i.e., supersensitivity to dopamine
and related compounds), and this neuroadaptive process can produce neurological
side-effects, such as tardive dyskinesia, and may contribute to the psychotic
relapse that sometimes follows years of stable pharmacological management.
Concurrent treatment with a nitric oxide synthase inhibitor appears to
diminish the development of this neuroadaptive change and may prolong the
effectiveness of antipsychotic medication without increasing the occurrence
of neurological side-effects. Furthermore, the increased abuse of psychomotor
stimulants among schizophrenics may also be related to supersensitivity,
and the same pharmacological treatment may blunt the increased impact of
cocaine and other drugs. [see C. M. Pudiak & M. A. Bozarth (1997),
Nitric oxide synthesis inhibition attenuates haloperidol-induced supersensitivity.
of Psychiatry & Neuroscience, 22, 61-64. [PDF
file from the Canadian
Psychiatric Association web site requiring Adobe Acrobat Reader.]
page was last revised 29 November 1999.
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