PubMed · 5057961
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R N Richards. 1972-02-05. Experience with MDA.. https://pubmed.ncbi.nlm.nih.gov/5057961/
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The nucleus accumbens has been subdivided into a shell and a core compartment on the basis of histochemical and connectional differences. Recently, we reported that behavioral sensitization to morphine is associated with an increased dopamine transmission in the caudate-putamen and in the nucleus accumbens core as well as a decreased response in the nucleus accumbens shell following acute morphine challenge. We have now performed a similar study in rats sensitized to amphetamine and to cocaine. Behavioral sensitization was induced by daily administration of a single dose of 1 mg/kg s.c. of amphetamine for 10 days or of 10 mg/kg i.p. of cocaine twice a day for 14 days. Microdialysis was performed 10-14 days after the last injection of amphetamine and 7-10 days after the last injection of cocaine. Both schedules resulted in robust behavioral sensitization in response to challenge with 0.25 and 0.5 mg/kg of amphetamine and to 5 and 10 mg/kg of cocaine, respectively. Subjects pre-exposed to amphetamine showed a sensitization of dopamine transmission in the nucleus accumbens core but not in the nucleus accumbens shell. Subjects pre-exposed to cocaine showed sensitization of dopamine transmission in the core only to the lower dose of cocaine. In the shell no change was observed after the lower dose of cocaine while a significant reduction of the dopamine response was observed after the higher dose. These results suggest that behavioral sensitization might result from reciprocal changes in the response of nucleus accumbens dopamine in the shell and in the core to drug challenge.
Repeated exposure to amphetamine produces long-lasting increases in sensitivity to its effects. We reported previously that repeated amphetamine treatment results in increased astrocytic expression of basic fibroblast growth factor (bFGF) in the ventral tegmental area (VTA) and substantia nigra compacta (SNc) and that this effect is prevented by coadministration of a nonspecific glutamate receptor antagonist. Here we show that the development of sensitization to amphetamine is prevented when amphetamine injections are preceded by infusions of a neutralizing antibody to bFGF into the VTA. In addition, we show that astrocytic bFGF expression is increased in the VTA and SNc of animals that exhibit behavioral sensitization and that the number of bFGF-immunoreactive astrocytes in these regions is strongly and positively correlated with the magnitude of sensitization. Cotreatment with an NMDA glutamate receptor antagonist blocks both the development of behavioral sensitization and bFGF induction. These results show that endogenous bFGF is necessary for the development of sensitization to amphetamine and suggest that bFGF mediates the glutamatergic-dopaminergic interaction that initiates the long-term consequences of repeated drug use.
Stereotyped behavior is elicited by activation of dopaminergic systems with drugs such as apomorphine and amphetamine. In previous studies, we have reported that the sulfated cholecystokinin octapeptide (CCK-8) decreased apomorphine-induced stereotypy in animals with normal and supersensitive dopamine receptors. The aim of the present study was to evaluate the effects of CCK(1) and CCK(2) receptor antagonists on stereotyped behavior induced by apomorphine or amphetamine. Rats were pretreated with the CCK(1) (SR 27897B; 1-[[2-(4-(2-chlorophenyl) thiazol-2-yl) aminocarbonyl]indolyl]acetic acid; 500 microg/kg; i.p.) or CCK(2) (L-365,260; 3R-(+)-N-(2,3-dihydro-1-methyl-2-oxo-5 phenyl-1H-1, 4-benzodiazepine-3-yl)-N'-(3-methyl phenyl)-urea; 500 microg/kg; i.p. ) receptor antagonists or saline 15 min before apomorphine (0.6 mg/kg; s.c.) or amphetamine (9.0 mg/kg; i.p.) injection. Both CCK(1) and CCK(2) receptor antagonists significantly increased apomorphine-induced stereotypy. In contrast, only the blockade of CCK(2) receptors significantly decreased amphetamine-induced stereotypy. The results suggest a dual opposite mechanism for CCK-dopamine interactions. These data also suggest that both apomorphine- and amphetamine-induced stereotypy should be used whenever effects of drugs acting on dopaminergic systems are being assessed.