Antidepressant drug induced alterations in binding to central dopamine transporter sites in the Wistar Kyoto rat strain.

The Wistar Kyoto (WKY) rat has been proposed as an animal model of depressive behavior. Exposing WKY rats to stress stimulation produces symptoms such as anhedonia, psychomotor retardation, ambivalence and negative memory bias. Given the role of the mesolimbic dopamine (DA) system in cognitive, emotional and motivational behaviors, we previously examined the distribution of DA transporter (DAT) sites in the brains of WKY compared to Wistar (WIS) and Sprague-Dawley (S-D) rats. WKY rats exhibited significant differences in DAT binding sites in the cell body as well as mesolimbic areas compared to the other strains. It was reasoned that these differences may lead to altered synaptic levels of DA in specific brain regions thus contributing to the behavioral differences observed in this rat strain. Thus, the present study examined whether repeated treatment with antidepressant drugs that block the uptake of DA (nomifensine and bupropion) would modify [3H]-GBR12935 binding to DAT sites in WKY rats compared to WIS and S-D rats. The results indicate that while nomifensine and bupropion increased the binding of [3H]-GBR12935 to DAT sites in the mesocorticolimbic regions in WKY rats, these drugs increased the binding of [3H]-GBR12935 to DAT sites in the cell body areas in WIS rats but not in S-D and WKY rats. The data from this study suggest that antidepressant induced alterations in DAT sites in the mesocorticolimbic brain regions may play a role in the behavioral improvement seen in WKY rats, as measured by the Open Field Test (OFT) and the Porsolt Forced Swim Test (FST).

Strain differences in the distribution of dopamine transporter sites in rat brain.

The Wistar Kyoto (WKY) rat has long been proposed as an animal model of depressive behavior. Exposure to stress produces symptoms such as anhedonia, psychomotor retardation, ambivalence, and negative memory bias. Autoradiographic studies have revealed significant differences in the density of norepinephrine transporter (NET) and serotonin transporter (5-HTT) sites in several brain regions in WKY rats compared to Sprague-Dawley (S-D) rats. Since the mesolimbic dopamine (DA) system is involved in cognitive, emotional, and motivational behaviors, this study examined the distribution of dopamine transporter (DAT) sites in the brains of WKY compared to Wistar (WIS) and S-D rats. DAT sites were labeled with [3H]-GBR12935 (1 nM), and mazindol (50 microM) was used to define nonspecific binding. Quantitative analysis of the specific binding indicated that WKY rats exhibited significant differences in DAT binding sites in the cell body as well as mesolimbic areas in comparison to WIS and S-D rats. While the binding of [3H]-GBR to DAT sites was significantly decreased in the nucleus accumbens (NAc), the amygdala, the ventral tegmental area (VTA), and the reticular part of the substantia nigra (P<.05), the binding was significantly increased in the hippocampal subregions and the hypothalamus (P<.05) in WKY rats compared to the other two strains. In contrast, no strain differences were found in the caudate-putamen. The observed differences in the density and distribution of DAT sites in WKY rats may lead to altered modulation of synaptic DA levels in the cell body and mesolimbic regions, thereby contributing to the noted depression-like behaviors reported in this rat strain.

Strain-dependent modification of behavior following antidepressant treatment.

The effects of repeated antidepressant drug treatment on behavioral outcome in Wistar Kyoto (WKY) rats, a putative animal model of depressive behavior, were compared to Wistar and Sprague-Dawley (SD) rats. Rats were treated with desipramine (norepinephrine [NE] uptake blocker), nomifensine (NE and dopamine [DA] uptake blocker), paroxetine (serotonin [5-HT] uptake blocker) or saline, for 12 days. On Day 11, rats were tested in the Porsolt forced swim test (FST). On Day 12, rats were tested in the open field test (OFT). Stress reactivity was assessed on Day 13 when all rats were exposed to water-restraint ulcerogenic stress. Significant strain differences in behavioral responses to the drug treatments were observed. Control WKY rats showed the typical freezing behavior in the OFT and excessive floating behavior in the FST as compared to Wistar and SD rats. Desipramine and nomifensine decreased immobility and increased swim time in the FST in WKY rats. Nomifensine reduced response latency in the OFT in WKY rats and increased activity in the OFT in WKY and SD rats. None of the drugs altered the FST in SD rats. Following ulcerogenic stress, desipramine was the only antidepressant that decreased ulcer incidence in all rat strains compared to saline controls. These results suggest that the "depressive behavior" in WKY rats may be modified by antidepressants that alter synaptic levels of NE and/or DA, but not 5-HT.