The locus coeruleus (LC) system appears to be importantly involved in opiate dependence. The specific alpha2 adrenoceptor agonist, clonidine, potently attenuates LC hyperactivity and elevated NE release during opiate withdrawal (OW) at doses clinically effective in treating OW. During the previous term of this award we shoed that OW-induced LC hyperactivity is due in part to enhanced excitatory amino acid (EAA) input from the nucleus paragigantocellularis (PGi), and that serotonin (5-HT) enhancing agents such as fenfluramine on fluoxetine attenuate OW-induced activation of LC neurons. These findings indicate the circuits afferent to the LC hold the key to a novel pharmacologic intervention in OW. In this renewal, we will extend these findings with a set of specific cellular and circuit studies. Using retrograde transport and immunohistochemical localization of immediate early gene (IEG) proteins including c-fos, we will identify afferents to the LC or PGi that are stimulated by OW. We will test whether elicitation or blockade of local OW in these afferents will mimic or attenuate systemic OW-induced LC activation, respectively. These studies will identify the circuit(s) involved in initiating LC and PGi responses to OW. Recent results have revealed important biochemical changes in the LC after chronic morphine, suggesting changes in the responsiveness of LC neurons to their afferents. Using the LC slice preparation in parallel with neurochemical measurements, we will determine whether chronic administration alters the release of EAAs in the LC or the responsiveness of LC neurons to agents whose effects are modulated by cAMP. We will be the first to use microdialysis to directly measure NE release in LC target areas during OW, and to provide magnitude and time course data. In addition, we will identify neurons in LC targets that are stimulated by OW using localization of IEGs. this withdrawal-induced stimulation will then be tested for its sensitivity to noradrenergic blockers, to ascertain whether the LC is a causative agent. We have recently found that a major part of OW-induced hyperactivity in LC neurons is EAA-mediated, and that augmentation of 5-HT neurotransmission attenuates such hyperactivity. Here we propose to thoroughly characterize and document this important interaction by specifying the EAA and 5-HT receptors involved, developing pharmacologic treatment regimens that maximally attenuate withdrawal hyperactivity, and testing other possible pharmacologic agents that may modulate hyperactivity of LC neurons during OW. These experiments will establish the cellular basis of the LC's involvement in OW, from the input circuits and transmitters, to the changes in intrinsic LC characteristics, to effects of withdrawal-activated LC discharge on neurons in LC target areas. Furthermore, the experiments will determine specific transmitter and receptor mechanisms for manipulating withdrawal-induced LC activity. Together, these studies will provide important cellular insights for the understanding and treatment of OW.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Drug Abuse Biomedical Research Review Committee (DABR)
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Volman, Susan
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Allegheny University of Health Sciences
Schools of Medicine
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