Alterations in brain monoamines and GABA A receptors in transgenic mice overexpressing TGFα

Abstract

This study investigated the possibility that overexpression of transforming growth factor α (TGFα) changes those neurotransmitter systems that have been associated with behaviors found to be altered in the transgenic TGFα CD-1 mice. The female TGFα mice showed elevated levels of norepinephrine (NE) in the hypothalamus and serotonin (5-HT) in the cortex and brain stem when compared with nontransgenic CD-1 females. The concentrations of monoamines were not altered in the male transgenic brain. The 5-hydroxyindoleacitic acid (5-HIAA) 5-HT ratio was significantly reduced in the brain stem of the male TGFα mice and frontal cortex in the female transgenics. The binding of the [ 3H]GBR 12935-labeled DA transporter was lower in the frontal cortex in the transgenic male TGFα mice than in the female TGFα mice. No gender difference in dopamine (DA) transporter binding was noted between the nontransgenic male and female mice. Serotonin and GABA A receptors were measured only in males. No differences in the number of 5-HT 1A and 5-HT 2 receptors were found in the cortex or hippocampus. Maximal GABA stimulation of [ 3H]flunitrazepam binding in the forebrain hemispheres and cerebellar binding of an imidazobenzodiazepine, [ 3H]Ro 15-4513, were not different between transgenic and nontransgenic male mice. However, forebrain [ 35S]TBPS binding in male TGFa mice was less affected by the blockade of the GABA agonist sites by the specific GABA A antagonists SR 95531 and bicuculline than the binding of the controls, suggesting either altered endogenous GABA concentrations or a change in receptor populations. Taken together, the previously reported behavioral alterations in male TGFa 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 be due to a reduced 5-HIAA 5-HT ratio, [ 3H]GBR 12935-labeled DA transporter binding, or altered regulation of [ 35S]TBPS binding by endogenous GABA in the brain. Reduced aggressive behavior and shortened immobility in the swim test in the female TGFa mice, on the other hand, might reflect elevated levels of NE and 5-HT in the brain. It is possible that TGFα-induced increase in plasma estrogen levels in the transgenic mice is the common mechanism of action that causes gender-specific changes in certain neurotransmitter systems.