In vivo comparison of the reinforcing and dopamine transporter effects of local anesthetics in rhesus monkeys.

Article Details

Citation

Wilcox KM, Kimmel HL, Lindsey KP, Votaw JR, Goodman MM, Howell LL

In vivo comparison of the reinforcing and dopamine transporter effects of local anesthetics in rhesus monkeys.

Synapse. 2005 Dec 15;58(4):220-8.

PubMed ID
16206183 [ View in PubMed
]
Abstract

Dopaminergic mechanisms are thought to play a central role in the reinforcing effects of cocaine. Similar to cocaine, other local anesthetics bind to the dopamine transporter (DAT) and inhibit DA uptake in rodent and monkey brain. Additionally, local anesthetics are self-administered in rhesus monkeys, indicative of abuse liability. The present study examined the reinforcing and DAT effects of the local anesthetics dimethocaine, procaine and cocaine using in vivo techniques. Monkeys were trained to respond under a second-order schedule for i.v. cocaine administration (0.10 or 0.30 mg/kg/infusion). When responding was stable, dimethocaine (0.030-1.7 mg/kg/ infusion) or procaine (0.10-10 mg/kg/ infusion) was substituted for the cocaine training dose. Dimethocaine administration produced higher response rates compared with that of procaine, and was a more potent reinforcer. Drug effects on behavior were related to DAT occupancy in monkey striatum during neuroimaging with positron emission tomography (PET). DAT occupancy was determined by displacement of 8-(2-[(18)F]fluroethyl)2beta-carbomethoxy-3beta-(4-chlorophenyl)nortropane (FECNT). DAT occupancy was between 66 and 82% and <10-41% for doses of dimethocaine and procaine that maintained maximum response rates, respectively. Finally, in vivo microdialysis in awake subjects determined drug-induced changes in extracellular DA in the caudate nucleus. There was close correspondence between peak increases in DA and DAT occupancy. Overall, reinforcing effects were consistent with DAT effects determined with in vivo techniques. The results further support a role for the DAT in the abuse liability of local anesthetics.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
ProcaineSodium-dependent dopamine transporterProteinHumans
Yes
Inhibitor
Details