Differential effects of chronic amphetamine and baclofen administration on cAMP levels and phosphorylation of CREB in distinct brain regions of wild type and monoamine oxidase B-deficient mice.
Roles of GABA(B) transmission were explored in the action of amphetamine (Amph) on the brain. Adult male wild type (WT) and monoamine oxidase B-knocked out (MAOBKO) mice received i.p. injections of saline, d-Amph (5 mg/kg), plus baclofen (GABA(B) receptor agonist, 10 mg/kg), or baclofen and Amph, twice daily for 3 days and single treatments on day 4, followed by immuno-cyclic-AMP (cAMP) and immunoblotting assays on the brain tissue. The WT mice responded with higher levels of behavioral responses than the KO to the daily Amph injection; however, baclofen blocked the Amph-induced behavioral hyperactivity of both WT and KO mice. After the last treatment, levels of cAMP and phosphorylated (p) cyclic-AMP response element binding protein (CREB) were up-regulated in the striatum and somatosensory cortex of Amph-treated WT mice, while similar to the saline-controls in the baclofen+Amph-treated group, indicating the blockade by baclofen to Amph. Baclofen similarly suppressed the Amph-induced increases in pCREB levels of WT hippocampus and amygdala, and decreases of olfactory bulb and thalamus. For MAOBKO mice, baclofen hindered the Amph-generated increases in motor cortical cAMP and pCREB, and amygdaloid pCREB, and the decrease in olfactory bulb pCREB, whereas did not affect the Amph-raised hippocampal pCREB. Furthermore, the levels of CREB were variably modified in distinct regions by the drug exposures. The data reveal that the GABA(B)-mediated intracellular signaling differentially participates in mechanisms underlying Amph perturbation to various regions, and may thereby contribute explanations to the behavioral consequences. Moreover, MAOB is region-dependently involved in responses of the brain to Amph and baclofen, supporting interactions between GABA and monoamines.
Yin
Hsiang-Shu
HS
Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan. hsyin@ha.mc.ntu.edu.tw
Chen
Kevin
K
Kalpana
Sriram
S
Shih
Jean C
JC
D000661:Amphetamine / Q000009:adverse effects*; D019969:Amphetamine-Related Disorders / Q000201:enzymology* / Q000503:physiopathology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects* / Q000201:enzymology; D000697:Central Nervous System Stimulants / Q000009:adverse effects; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D018755:GABA Agonists / Q000494:pharmacology; D006948:Hyperkinesis / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008995:Monoamine Oxidase / Q000235:genetics*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D018080:Receptors, GABA-B / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D015306:Biogenic Monoamines; D000697:Central Nervous System Stimulants; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D018755:GABA Agonists; D018080:Receptors, GABA-B; D005680:gamma-Aminobutyric Acid; D000661:Amphetamine; D000242:Cyclic AMP; D008995:Monoamine Oxidase; D001418:Baclofen