LOCUS COERULEUS, ROSTRAL MEDULLA, AND MORPHINE ABUSE

  • Aston Jones, Gary (PI)
  • ASTON-JONES, GARY (PI)
  • ASTON-JONES, GARY (PI)
  • ASTON-JONES, GARY (PI)
  • Aston-Jones, Gary S. (PI)
  • ASTON-JONES, GARY (PI)
  • Aston-Jones, Gary S. (PI)
  • Aston-Jones, Gary S. (PI)
  • Aston-Jones, Gary S. (PI)

Project Details

Description

Despite a great deal of evidence that the noradrenergic locus coeruleus
(LC) system is a key brain area involved in opiate abuse and withdrawal,
and extensive knowledge concerning the actions of opiates on LC membrane
properties, the effects and related mechanisms for opiates and opiate
withdrawal on this nucleus in the intact, unanesthetized brain are poorly
understood. Recent insights into afferent regulation of LC open the way for
new investigations of opiate actions on this preeminent noradrenergic
system. Experiments are proposed to study the effects of opiates on discharge of LC
neurons and their major afferents, paragigantocellularis (PGI) and
prepositus hypoglossi (PrH), in unanesthetized behaving rats. Effects of
acute and chronic administration of morphine, and morphine withdrawal, will
determined for spontaneous and sensory-evoked activity of unambiguous
noradrenergic LC neurons in behaving rats. Recordings of impulse activity
from PGI or PrH neurons antidromically identified as projecting to LC will
document the effects of iontophoretically applied selective opiate
agonists, naloxone and dextrorphan in naive and in chronically morphine
treated, anesthetized subjects. In unanesthetized animals, the normative
discharge characteristics of similarly identified LC-projecting PGI and PrH
neurons will be determined, as well as their response to systemic acute and
chronic morphine and morphine withdrawal. Possible morphine-induced changes
in the excitability of afferent terminals in LC will also be examined in
these animals. Responses of LC neurons to electrical stimulation of their major afferents,
and the ability of amino acid antagonists to block afferent influences,
will be established in waking animals. In addition, effects of locally
microinfused, selective opiate agonists and antagonists on regulation of LC
from these major afferents in naive and chronically morphine pretreated,
unanesthetized behaving animals will be determined. These experiments will test the hypotheses that (i) opiates may have
substantial impact on LC activity through altered afferent regulation of
these cells, and (ii) hyperactivity of LC neurons during opiate withdrawal
is caused by increased excitation from PGI, the major afferent to LC. These
studies will set the stage for future experiments in which amino acid
antagonists will be tested for their ability to block hyperactivity of LC
during morphine withdrawal. The ability of excitatory amino acid
antagonists to prevent or reverse withdrawal-induced hyperactivity in LC
would be of particular clinical interest, calling for the design of such
drugs for use in human opiate withdrawal programs. The long term goals of this research are to determine the effects of
morphine on functionally important discharge properties of unambiguous
noradrenergic LC neurons in physiologically intact animals, and to
determine the sites and mechanisms by which opiates affect these cells.
Such data will resolve conflicts and fill gaps in the present literature
concerning the effects of this intravenously abused drug on functions of
the ubiquitous noradrenergic brain system, and clarify the role of this
system in opiate abuse and addiction.
StatusActive
Effective start/end date12/31/8911/30/21

Funding

  • National Institute on Drug Abuse: $262,949.00
  • National Institute on Drug Abuse: $424,447.00
  • National Institute on Drug Abuse: $342,755.00
  • National Institute on Drug Abuse: $424,933.00
  • National Institute on Drug Abuse: $442,500.00
  • National Institute on Drug Abuse: $425,194.00
  • National Institute on Drug Abuse: $269,778.00
  • National Institute on Drug Abuse: $371,345.00
  • National Institute on Drug Abuse
  • National Institute on Drug Abuse: $368,908.00
  • National Institute on Drug Abuse: $350,881.00
  • National Institute on Drug Abuse: $468,570.00
  • National Institute on Drug Abuse: $372,248.00
  • National Institute on Drug Abuse
  • National Institute on Drug Abuse: $81,509.00
  • National Institute on Drug Abuse: $65,048.00
  • National Institute on Drug Abuse: $438,075.00
  • National Institute on Drug Abuse: $54,958.00
  • National Institute on Drug Abuse: $46,448.00
  • National Institute on Drug Abuse: $441,750.00

ASJC

  • Psychiatry and Mental health
  • Medicine(all)
  • Biochemistry
  • Physiology
  • Neuroscience(all)
  • Anatomy
  • Pharmacology

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