Regional Differences in Extracellular Dopamine and Serotonin Assessed by In Vivo Microdialysis in Mice Lacking Dopamine and/or Serotonin Transporters

Abstract

Cocaine conditioned place preference (CPP) is intact in dopamine transporter (DAT) knockout (KO) mice and enhanced in serotonin transporter (SERT) KO mice. However, cocaine CPP is eliminated in double-KO mice with no DAT and either no or one SERT gene copy. To help determine mechanisms underlying these effects, we now report examination of baselines and drug-induced changes of extracellular dopamine (DA ex ) and serotonin (5-HT ex ) levels in microdialysates from nucleus accumbens (NAc), caudate putamen (CPu), and prefrontal cortex (PFc) of wild-type, homozygous DAT-or SERT-KO and heterozygous or homozygous DAT/SERT double-KO mice, which are differentially rewarded by cocaine. Cocaine fails to increase DA ex in NAc of DAT-KO mice. By contrast, systemic cocaine enhances DA ex in both CPu and PFc of DAT-KO mice though local cocaine fails to affect DA ex in CPu. Adding SERT to DAT deletion attenuates the cocaine-induced DA ex increases found in CPu, but not those found in PFc. The selective SERT blocker fluoxetine increases DA ex in CPu of DAT-KO mice, while cocaine and the selective DAT blocker GBR12909 increase 5-HT ex in CPu of SERT-KO mice. These data provide evidence that (a) cocaine increases DA ex in PFc independently of DAT and that (b), in the absence of SERT, CPu levels of 5-HT ex can be increased by blocking DAT. Cocaine-induced alterations in CPu DA levels in DAT-, SERT-, and DAT/SERT double-KO mice appear to provide better correlations with cocaine CPP than cocaine-induced DA level alterations in NAc or PFc.

Parallel Loss of Hippocampal LTD and Cognitive Flexibility in a Genetic Model of Hyperdopaminergia

“…First, whereas the DAT is a major determinant of the intensity and duration of DA neurotransmission in the striatum, microdialysis experiments demonstrate a less prominent role of the DAT in DA clearance in the prefrontal cortex (Cass and Gerhardt, 1995), which correlates with the relative sparse distribution of the DAT in the prefrontal cortex (Sesack et al, 1998), as well as with several studies showing heterologous DA uptake by the norepinephrine transporter in this region (Carboni et al, 1990;Tanda et al, 1997). Second, in DAT-KO mice, dialysate DA is approximately 10-fold higher in both the striatum and nucleus accumbens, whereas the basal level of extracellular DA is not affected in the prefrontal cortex (Shen et al, 2004). Furthermore, the rate of DA uptake in the prefrontal cortex has also been shown to be normal in DAT-KO mice (Mundorf et al, 2001).…”

“…Not surprisingly, the dramatic molecular alterations of both pre-and postsynaptic homeostasis following inactivation of the DAT have been extensively described in the striatum (Giros et al, 1996;Rocha et al, 1998;Jones et al, 1999;Shen et al, 2004), whereas no data are available in these mutant mice concerning the mesencephalo-hippocampal DA projection. We show here that synaptic plasticity is clearly impaired at the Schaffer collateral CA1 synapses.…”

“…Mutant mice (DAT-KO) exhibit extremely high levels of DA synthesis and turnover , with a greatly prolonged (300-fold) extracellular lifetime of DA (Giros et al, 1996), resulting in a five-to ten-fold increase in basal extracellular DA levels in the striatum and nucleus accumbens Spielewoy et al, 2000a;Shen et al, 2004). Besides their obvious hyperactivity, DAT-KO mice exhibit heightened rates of stereotypies and perseverative patterns of nongoal-directed behavior, distorting their motor, exploratory, and social behaviors Spielewoy et al, 2000b;Ralph et al, 2001;Rodriguiz et al, 2004).…”

Increased brain-derived neurotrophic factor (BDNF) protein concentrations in mice lacking brain serotonin

“…Here, we measured BDNF protein levels in Tph2 -/-mice that lack brain serotonin (and show certain features of depression-like behaviors such as impaired maternal care and increased immobility in the Porsolt forced swim test; reviewed in [14]), and SERT -/-mice, which exhibit increased extracellular serotonin levels [15,16] despite an overall reduction (60 to 80%) in serotonin tissue concentrations [17].…”

Norepinephrine Transporter Blockade can Normalize the Prepulse Inhibition Deficits Found in Dopamine Transporter Knockout Mice

“…Microdialysis studies suggest that dopamine transporter knockout (DAT KO) mice exhibit striatal levels of extracellular dopamine (DA), under basal conditions, that are about 10 times higher than wild-type levels while prefrontal cortical levels are similar to those found in wild-type animals (Shen et al, 2004). DAT KO mice exhibit numerous behavioral alterations that can be linked to abnormal dopaminergic function that include hyperlocomotion and perseverative behaviors (Sora et al, 1998;Ralph et al, 2001).…”