Delineation of discrete domains for substrate, cocaine, and tricyclic antidepressant interactions using chimeric dopamine-norepinephrine transporters.

Assessment of Paroxetine Molecular Interactions with Selected Monoamine and γ-Aminobutyric Acid Transporters

“…Additionally, the identity between hNET and hDAT is 86% [31]. The hDAT shows the greatest homology to hNET within the binding site with an amino acid sequence identity of 78% [32,33]. The homology for each human transporter related to the others was sequence identified is approximately hDAT/hNET = 67%, hDAT/hSERT = 50%, hNET/hSERT = 53%.…”

“…hDAT hDAT is the major target of addictive psychostimulants such as cocaine, which bind to the active site and prevent the conformational transition of the transporter, thereby inhibiting the reuptake of dopamine [40]. DAT mediates reuptake of DA (pIC 50SERT << 4, pIC 50NET ≈ 5.28, pIC 50DAT ≈ 5.06 [21] − 5.61 [32]) from the synaptic cleft and thereby controls the termination of dopaminergic signaling.…”

“…The selective NE reuptake potencies inhibitor, reboxetine (pIC 50 ≈ 8.96 [16]), has demonstrated equivalent efficacy to the TCA in some studies and is approved as an antidepressant in Europe but not in the USA [58] (Figure 4). The inhibitory potencies R/S-NE for its transporter lie in the range pIC 50NET (6.17 [32]; 5.06 [21]). Comparison of the data obtained for our docking experiment (Table 1) clearly leads to the conclusion that S-NE shows stronger binding affinity than the other studied neurotransmitters.…”

Psychiatric Disorders - Trends and Developments

“…This result is somewhat surprising given the dense dopaminergic innervation and the high expression of DAT in the frontal cortex (Kuikka et al, 1995). The lack of increase in cortical DA extracellular levels may be explained by its heterologous reuptake from the NET (Moron et al, 2002;Giros et al, 1994). However the observations that catecholamine uptake blockers such as nomifensine, desipramine or GBR12909 increase DA levels (Devoto et al, 2004;Valentini et al, 2004;Gresh et al, 1995) could emphasize the importance of the reciprocal interactions between the DA and NE or 5-HT system at nerve terminal.…”

“…Differences in transporter occupancy cannot explain these findings since this parameter followed the same trend observed with cortical extracellular monoamines levels. It has therefore been proposed that the high cortical levels of DA might have resulted from the blockade of the NET by this drug, which displays a high affinity for the DAT (Moron et al, 2002;Giros et al, 1994).…”