Enhancement of locomotor activity and conditioned reward to cocaine by brain-derived neurotrophic factor.
The mesolimbic dopamine (DA) system has been implicated in drug reward, locomotor sensitization, and responding for reward-related stimuli [termed conditioned reinforcers (CR)]. Here, we investigated the effect of brain-derived neurotrophic factor (BDNF), which enhances the survival and function of dopaminergic neurons, on stimulant-induced locomotor sensitization and responding for CR. In experiment 1, BDNF was infused into the nucleus accumbens (NAc) or ventral tegmental area over 2 weeks via chronically implanted minipumps (1-2.5 microgram/d), and the psychomotor stimulant effects of cocaine (5-15 mg/kg, i.p.) were studied. We found that BDNF enhanced the initial stimulant effects of cocaine and seemed to facilitate the development of sensitization to repeated cocaine doses. In experiment 2, we studied the effects of intra-NAc BDNF infusions on responding for CR. BDNF-treated rats showed twice as many CR responses compared with controls when saline was first administered. BDNF enhanced responding on the CR lever more than four times that seen in control animals after a cocaine injection (10 mg/kg, i.p.). The enhanced response to cocaine in BDNF-treated animals persisted for more than a month after the BDNF infusions had stopped, indicating long-lasting changes in the mesolimbic DA system caused by BDNF administration. In experiment 3, we examined locomotor sensitization to cocaine in heterozygous BDNF knock-out mice and found that the development of sensitization was delayed compared with wild-type littermates. These results demonstrate the profound effects of BDNF on the enhancement of both cocaine-induced locomotion and facilitation of CR and suggest a possible role for BDNF in long-term adaptations of the brain to cocaine.
Horger
B A
BA
Laboratory of Molecular Psychiatry, Departments of Psychiatry, Pharmacology, and Neurobiology, Yale University School of Medicine, Connecticut Mental Health Center, New Haven, Connecticut 06520, USA.
Iyasere
C A
CA
Berhow
M T
MT
Messer
C J
CJ
Nestler
E J
EJ
Taylor
J R
JR
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D007260:Infusion Pumps; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects*; D009414:Nerve Growth Factors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward
D019208:Brain-Derived Neurotrophic Factor; D018765:Dopamine Uptake Inhibitors; D009414:Nerve Growth Factors; D003042:Cocaine