Reduction of zif268 messenger RNA expression during prolonged withdrawal following "binge" cocaine self-administration in rats.
Cocaine self-administration increases dopamine efflux and neuronal activity in the mesocorticolimbic dopamine system compared with experimenter-administered cocaine. Following a prolonged cocaine self-administration binge, dopamine efflux in the nucleus accumbens is attenuated and behaviors emerge that are indicative of anhedonia and anxiety. The neuronal correlates of these behavioral and neurochemical effects of a cocaine binge were assessed using in situ hybridization histochemistry to detect changes in zif268 messenger RNA expression. Rats were fitted with intravenous catheters; one group was trained to self-administer cocaine (0.5mg/injection), then allowed continuous access to cocaine during a 16h binge, while yoked animals received either saline or cocaine according to the same schedule. Measurement of tactile startle responses and ultrasonic distress calls either immediately after termination of cocaine access or one or 14 days later confirmed peak withdrawal at 24h after the binge. The level of zif268 messenger RNA was lower upon termination of cocaine self-administration than in both yoked treatment groups in the ventral tegmental area and hippocampus. In contrast, zif268 messenger RNA expression increased in the periaqueductal gray matter one day after termination of passive cocaine treatment, coincident with enhanced expression of ultrasonic vocalizations. Zif268 messenger RNA expression decreased over time in the nucleus accumbens core and infralimbic cortex, with reduced expression observed in the nucleus accumbens core, caudatoputamen, hippocampus and amygdala 14 days after termination of cocaine self-administration. The results suggest that withdrawal following a cocaine self-administration binge produces a long-lasting reduction of constitutive zif268 messenger RNA expression in mesocorticolimbic brain regions related to the nucleus accumbens. The relatively greater effect in animals that self-administered cocaine implies a relationship of certain regional responses to behavioral conditioning.
Mutschler
N H
NH
Department of Psychology, Tufts University, Medford, MA, USA.
Miczek
K A
KA
Hammer
R P
RP
D000818:Animals; D001921:Brain / Q000378:metabolism*; D003042:Cocaine / Q000008:administration & dosage* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics*; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D008297:Male; D012333:RNA, Messenger / Q000037:antagonists & inhibitors*; D051381:Rats; D020318:Rats, Long-Evans; D013216:Reflex, Startle; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*; D013997:Time Factors; D014018:Tissue Distribution; D014157:Transcription Factors / Q000235:genetics*; D014828:Vocalization, Animal
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D003042:Cocaine