Presynaptic inhibition of GABA(B)-mediated synaptic potentials in the ventral tegmental area during morphine withdrawal

Yoshihisa Shoji, Jill Delfs, John T. Williams

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

Opioids increase the firing of dopamine cells in the ventral tegmental area by presynaptic inhibition of GABA release. This report describes an acute presynaptic inhibition of GABA(B)mediated IPSPs by μ- and κ-opioid receptors and the effects of withdrawal from chronic morphine treatment on the release of GABA at this synapse. In slices taken from morphine-treated guinea pigs after washing out the morphine (withdrawn slices), a low concentration of a μ receptor agonist increased, rather than decreased, the amplitude of the GABA(B) IPSP. In withdrawn slices, after blocking A1- adenosine receptors with 8-cyclopentyl-1,3-dipropylxantine, μ-opioid receptor activation inhibited the IPSP at all concentrations and increased the maximal inhibition. In addition, during withdrawal, there was a tonic increase in adenosine tone that was further increased by forskolin or D1- dopamine receptor activation, suggesting that metabolism of cAMP was the source of adenosine. The results indicate that during acute morphine withdrawal, there was an upregulation of the basal level of an opioid- sensitive adenylyl cyclase. Inhibition of this basal activity by opioids had two effects. First, a decrease in the formation of cAMP that decreased adenosine tone. This effect predominated at low receptor occupancy and increased the amplitude of the IPSP. Higher agonist concentrations inhibited transmitter release by both kinase-dependent and -independent pathways. This study indicates that the consequences of the morphine-induced upregulation of the cAMP cascade on synaptic transmission are dependent on the makeup of receptors and second messenger pathways present on any given terminal.

Original languageEnglish (US)
Pages (from-to)2347-2355
Number of pages9
JournalJournal of Neuroscience
Volume19
Issue number6
StatePublished - Mar 15 1999

    Fingerprint

Keywords

  • Adenosine
  • CAMP
  • Dependence
  • GABA
  • Tolerance
  • κ-opioid receptor
  • μ-opioid receptor

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this