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
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.