About CTNA

A gap remains in the translation of basic research advances into clinical neuroscience insights related to alcoholism, despite a growing array of outstanding basic and clinical studies. A new generation of psychopharmacology, neuroimaging, and molecular genetic studies rooted in molecular neuroscience with broad clinical implications may contribute to bridging the gap between basic and clinical research. Basic and clinical neuroscience research has implicated cortico-limbic glutamatergic circuitry in ethanol reward, the vulnerability to alcoholism, and adaptations to chronic ethanol administration. The CTNA is designed to bridge the gap between the basic and clinical neuroscience of alcoholism. It will attempt;
  1. to conduct programmatic research that will identify factors modulating cortico-limbic glutamatergic circuitry that contribute to ethanol reward, vulnerability to self-administration, and dependence;
  2. to build from basic neuroscience insights to hypotheses regarding the etiology, pathophysiology, and treatment of alcoholism;
  3. to facilitate transdisciplinary research within projects and between projects;
  4. to establish a mechanism to rapidly review and fund pilot promising pilot projects;
  5. to provide career development activities for graduate and medical students, postdoctoral trainees, and junior faculty that will promote their development and retention within the field of alcoholism research; and
  6. to promote ethical and humane clinical neuroscience studies of alcoholism.

1. The History of the Center

At Yale, E.M. Jellinek advanced the hypothesis that alcoholism was a medical illness. Framed from a neuroscience perspective, this model could be viewed as having several components: 1) ethanol has specific effects on brain function that promote its abuse and account for tolerance and dependence, 2) discrete factors influencing the development of the brain interact in defined ways with the specific actions of ethanol to promote its abuse, and 3) understanding mechanisms contributing to the abuse of ethanol may help to design medical treatments for this disorder. The specificity of the pathogenesis of some forms of alcoholism is illustrated by evidence that a component of the heritable risk for alcoholism is distinct from the risk of developing other substance abuse disorders. Also, DNA regions identified by the multicenter genetics study of alcoholism the collaborative genetics study (COGA) may help to identify genes relevant to prevention and pharmacotherapy. At the basic level, candidate genes have been identified that influence ethanol self-administration. The advances in identifying ethanol targets in the brain and the specificity of the genetic vulnerability to alcoholism suggest that a translational neuroscience initiative aimed at linking genetic and pathophysiologic perspectives may provide fundamental insights into alcoholism and its treatment.

The CTNA builds on pioneering Yale pharmacotherapy research. In the 1980’s Drs. Stephanie O’Malley and Bruce Rounsaville, in collaboration with the NIAAA Center at the University of Connecticut, led to one of two pivotal trials that provided the basis for the FDA approval of naltrexone treatment of alcoholism. Currently, Drs. Krystal and Rosenheck co-direct the 15-site VA study of long-term naltrexone treatment. This study complements other pharmacotherapy trials at Yale including industry-, VA- and NIAAA-supported studies of acamprosate, naltrexone, naltrexone combinations with other medications, and the NIAAA-supported multicenter treatment study (Project COMBINE). Thus, existing structures within the Yale community rapidly develop new agents once their therapeutic potential has been identified. It is the hypothesis of this application that the critical gap at Yale and in the national medications development mission is the shortage of basic mechanistic hypotheses supported by clinical neuroscience that might guide the development of new medications or medication combinations for alcoholism. Thus, the CTNA mission is to generate new hypotheses regarding the neurobiology of alcoholism and its treatment and to test these mechanisms using cutting edge clinical neuroscience.

The CTNA translational neuroscience focus grows directly from the VA-Yale Alcohol Research Center (VYARC) headed by Dr. Krystal, supported by the VA, and based at the VA Connecticut Healthcare System (VACHS). This small Center was established in 1991 and it recently underwent its second competitive renewal. The Center has brought basic and clinical researchers within the Yale community into the field of alcoholism research by providing support for pilot studies. Through this mechanism, the VYARC supported the interplay of basic and clinical neuroscience research related to mechanisms of ethanol reward, dependence, and self-administration.

John H. Krystal, M.D., Professor Psychiatry, CTNA Director

The Scientific Objectives of the CTNA Dictate its Design

The scientific theme of this Center is “cortico-limbic glutamatergic circuitry, ethanol reward, alcoholism vulnerability and treatment.” The PFC and NAc are two critical nodes in networks that underlie the experience of reward, the anticipation of reward, and “reward seeking behavior” in the context of substance abuse, instinctive behavior, and learned behavior. These regions also are implicated in human drug cue-induced craving in functional neuroimaging studies. While the rewarding properties of ethanol and the brain’s adaptations to its chronic administration are mediated by many neurochemical systems in multiple sites in the brain, the PFC and NAc figure prominently in these processes as well. The CTNA focuses on glutamatergic components of cortico-limbic interactions that may contribute to the vulnerability to alcoholism and adaptations to chronic ethanol administration for many reasons. The N-methyl-D-aspartate (NMDA) glutamate receptor is one of the principal targets for ethanol in the brain. The capacity of ethanol to block this site contributes significantly to its behavioral effects in animals and humans. In the NAc, the capacity to attenuate the release of glutamate from cortical projections or to block the postsynaptic glutamatergic stimulation of the output neurons is a common action exhibited by drugs with the component actions associated with ethanol: NMDA antagonism, GABA-A facilitation, opiate agonists, and 5-HT agonists. Genetic differences that give rise to altered postsynaptic sensitivity to glutamate in the NAc, therefore, may substantially alter the rewarding properties of ethanol (the focus of Project 1). Within the NAc, the convergence of glutamate and opiate systems may also underlie a component of the therapeutic efficacy of naltrexone (the focus of Project 6). Similarly, factors that influce PFC glutamatergic function, as reflected in the cortical processing of novelty (P300, response or altered 5-HT function, would be predicted to change the PFC-NAc interplay implicated in ethanol reward or ethanol sensitivity more generally (the focus of Projects 3 and 4). This hypothesis may be consist with the association between P300 abnormalities or frontal EEG measures and increased familial risk for alcoholism (the focus of Projects 2 and 5) or CTNA pilot data suggesting the existance of blunted NMDA antagonist responses in individuals with increased familial risk of alcoholism (the focus of Project 5). Glutamate systems show many adaptations to chronic ethanol administration, including enhanced expression and/or protein levels for NMDA receptor subunits and increased NMDA receptor binding. Glutamate release is increased during acute withdrawal, but it may be reduced during a protracted phase of increased vulnerability to alcohol use.

In summary, the CTNA is organized around four hypotheses pertaining to cortico-limbic circuitry that link the proposed projects: 1) the rewarding properties of ethanol and related drugs are associated with their capacity to attenuate PFC and NAc output; 2) factors within the PFC or NAc that alter the regulation of NAc output neurons would be predicted to alter sensitivity to the rewarding effects of ethanol and to influence the vulnerability to ethanol self-administration; 3) following acute withdrawal, reduction in PFC glutamatergic activity occurs in recovering alcohol dependent patients in association with reductions in PFC neuronal viability, glucose metabolism, P300 amplitude, and cognitive deficits; 4) altered glutamate receptor function may be associated with cortical dysfunction described in individuals at high familial risk of alcoholism. These hypotheses are logical extensions of the simplified circuitry presented schematically in figure 1. In this circuitry, PFC glutamate neurons are modulated by GABA, opiate, and 5-HT receptors. PFC projections to the NAc are modulated by interplay of glutamate receptors with GABA, opiate and 5-HT receptors.

 

 
 
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