Behavior of knock-in mice with a cocaine-insensitive dopamine transporter after virogenetic restoration of cocaine sensitivity in the striatum

Abstract

Cocaine's main pharmacological actions are the inhibition of the dopamine, serotonin, and norepinephrine transporters. Its main behavioral effects are reward and locomotor stimulation, potentially leading to addiction. Using knock-in mice with a cocaine-insensitive dopamine transporter (DAT-CI mice) we have shown previously that inhibition of the dopamine transporter (DAT) is necessary for both of these behaviors. In this study, we sought to determine brain regions in which DAT inhibition by cocaine stimulates locomotor activity and/or produces reward. We used adeno-associated viral vectors to reintroduce the cocaine-sensitive wild-type DAT in specific brain regions of DAT-CI mice, which otherwise only express a cocaine-insensitive DAT globally. Viral-mediated expression of wild-type DAT in the rostrolateral striatum restored cocaine-induced locomotor stimulation and sensitization in DAT-CI mice. In contrast, the expression of wild-type DAT in the dorsal striatum, or in the medial nucleus accumbens, did not restore cocaine-induced locomotor stimulation. These data help to determine cocaine's molecular actions and anatomical loci that cause hyperlocomotion. Interestingly, cocaine did not produce significant reward – as measured by conditioned place-preference – in any of the three cohorts of DAT-CI mice with the virus injections. Therefore, the locus or loci underlying cocaine-induced reward remain underdetermined. It is possible that multiple dopamine-related brain regions are involved in producing the robust rewarding effect of cocaine.

A Single Amphetamine Infusion Reverses Deficits in Dopamine Nerve-Terminal Function Caused by a History of Cocaine Self-Administration

“…These newly inserted DATs might be equally sensitive to cocaine as DATs from naive animals, thus reversing the reduced cocaine effects at the DAT. This hypothesis is consistent with recent reports showing that inducible expression of wild-type DATs can reestablish cocaine potency in mice that initially only express cocaineinsensitive DATs (O'Neill et al, 2014). Further investigation is needed to test this hypothesis particularly since there was no significant fluctuation in cytosolic DAT expression across our groups.…”

A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference

“…It is possible that although cocaine binding to DAT may be necessary to initiate cocaine reward subsequent alterations in DA signals may lead to modulation of other neuronal substrates including NET regulation, which in collaboration may evoke cocaine-associated behaviors. In addition, it is now clear that multiple DA brain regions are implicated in producing different aspects of cocaine reward, which may be attributed by the differences in DAT expression levels in different brain regions (78,79). NET expression is localized to noradrenergic terminals where it facilitates transport of NE and DA (80,81).…”

Interactions of Cathinone NPS with Human Transporters and Receptors in Transfected Cells

“…For example, SERT knockout mice exhibit greater rewarding effects of cocaine in the conditioned place preference paradigm compared with wildtype mice (Sora et al, 2001). More sophisticated genetic models with a triple amino acid mutation in the DAT gene showed that DAT inhibition is necessary for cocaine-induced conditioned place preference (O'Neill et al, 2014) and cocaine-evoked synaptic plasticity (Brown et al, 2010). Clinical studies that assess pharmacological interactions between a psychostimulant and receptor-selective antagonists or well-characterized transporter ligands shed light on specific molecular target mediating subjective effects and acute toxicity in humans.…”