Changes in accumbal and pallidal pCREB and deltaFosB in morphine-sensitized rats: correlations with receptor-evoked electrophysiological measures in the ventral pallidum.
Activation of mu-opioid receptors in the ventral pallidum (VP) is important for the induction of behavioral sensitization to morphine in rats. The present study was designed to ascertain if neurons within the VP demonstrate sensitization at a time when morphine-induced behavioral sensitization occurred (ie 3 or 14 days after five once-daily injections of 10 mg/kg i.p. morphine) in rats. Western blotting was used to evaluate transcription factors altered by opiates, CREB and deltaFosB. CREB levels did not change in the VP, but there was a significant decrease in levels of its active, phosphorylated form (pCREB) at both 3- and 14-days withdrawal. DeltaFosB levels were elevated following a 3-day withdrawal, but returned to normal by 14 days. This profile also was obtained from nucleus accumbens tissue. In a separate group of similarly treated rats, in vivo electrophysiological recordings of VP neuronal responses to microiontophoretically applied ligands were carried out after 14-days withdrawal. The firing rate effects of local applications of morphine were diminished in rats withdrawn from i.p. morphine. Repeated i.p. morphine did not alter GABA-mediated suppression of firing, or the rate enhancing effects of the D1 dopamine receptor agonist SKF82958 or glutamate. However, VP neurons from rats withdrawn from repeated i.p. morphine showed a higher propensity to enter a state of depolarization inactivation to locally applied glutamate. Overall, these findings reveal that decreased pCREB in brain regions such as the VP accompanies persistent behavioral sensitization to morphine and that this biochemical alteration may influence the excitability of neurons in this brain region.
McDaid
John
J
Department of Pharmacology and Experimental Therapeutics, Loyola University Chicago School of Medicine, Maywood, IL 60153, USA.
Dallimore
Jeanine E
JE
Mackie
Alexander R
AR
Napier
T Celeste
TC
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001552:Benzazepines / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005917:Globus Pallidus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018698:Glutamic Acid / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000009:adverse effects*; D009294:Narcotics / Q000009:adverse effects*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009293:Opioid-Related Disorders / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D001552:Benzazepines; D017362:Cyclic AMP Response Element-Binding Protein; D018491:Dopamine Agonists; C483820:Fosb protein, rat; D009294:Narcotics; D016760:Proto-Oncogene Proteins c-fos; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D009020:Morphine; C071262:SK&F 82958