ALTERATIONS IN BRAIN MONOAMINES AND GABA(A) RECEPTORS IN TRANSGENIC MICE OVEREXPRESSING TGF-ALPHA

Citation
La. Hilakiviclarke et al., ALTERATIONS IN BRAIN MONOAMINES AND GABA(A) RECEPTORS IN TRANSGENIC MICE OVEREXPRESSING TGF-ALPHA, Pharmacology, biochemistry and behavior, 50(4), 1995, pp. 593-600
Citations number
65
Categorie Soggetti
Pharmacology & Pharmacy","Pharmacology & Pharmacy
ISSN journal
00913057
Volume
50
Issue
4
Year of publication
1995
Pages
593 - 600
Database
ISI
SICI code
0091-3057(1995)50:4<593:AIBMAG>2.0.ZU;2-D
Abstract
This study investigated the possibility that overexpression of transfo rming growth factor alpha (TGF alpha) changes those neurotransmitter s ystems that have been associated with behaviors found to be altered in the transgenic TGF alpha CD-1 mice. The female TGF alpha mice showed elevated levels of norepinephrine (NE) in the hypothalamus and seroton in (5-HT) in the cortex and brain stem when compared with nontransgeni c CD-1 females. The concentrations of monoamines were not altered in t he male transgenic brain. The 5-hydroxyindoleacitic acid (5-HIAA)/5-HT ratio was significantly reduced in the brain stem of the male TGF alp ha mice and frontal cortex in the female transgenics. The binding of t he [H-3]GBR 12935-labeled DA transporter was lower in the frontal cort ex in the transgenic male TGF alpha mice than in the female TGF alpha mice. No gender difference in dopamine (DA) transporter binding was no ted between the nontransgenic male and female mice. Serotonin and GABA (A) receptors were measured only in males. No differences in the numbe r of 5-HT1A and 5-HT2 receptors were found in the cortex or hippocampu s. Maximal GABA stimulation of [H-3]flunitrazepam binding in the foreb rain hemispheres and cerebellar binding of an imidazobenzodiazepine, [ H-3]Ro 15-4513, were not different between transgenic and nontransgeni c male mice. However, forebrain [S-35]TBPS binding in male TGF alpha m ice was less affected by the blockade of the GABA agonist sites by the specific GABA(A) antagonists SR 95531 and bicuculline than the bindin g of the controls, suggesting either altered endogenous GABA concentra tions or a change in receptor populations. Taken together, the previou sly reported behavioral alterations in male TGF alpha mice, including increased levels of aggressive behavior, locomotor activity, voluntary alcohol consumption, and immobility in the swim test, or the altered behavioral responses to alcohol and monoamine uptake inhibitors, may b e due to a reduced 5-HIAA/5-HT ratio, [H-3]GBR 12935-labeled DA transp orter binding, or altered regulation of [S-35]TBPS binding by endogeno us GABA in the brain. Reduced aggressive behavior and shortened immobi lity in the swim test in the female TGF alpha mice, on the other hand, might reflect elevated levels of NE and 5-HT in the brain. It is poss ible that TGF alpha-induced increase in plasma estrogen levels in the transgenic mice is the common mechanism of action that causes gender-s pecific changes in certain neurotransmitter systems.