Cocaine-induced Increases In Extracellular Dopamine Research Articles

The 5-HT 3 antagonist zacopride attenuates cocaine-induced increases in extracellular dopamine in rat nucleus accumbens

Pretreatment with the serotonin-3 (5-HT 3) antagonist racemic (±)-Zacopride hydrochloride (ZAC, 0.1 mg/kg, IP) has been previously found to completely abolish the locomotor activity induced by cocaine (10 mg/kg, IP). To determine if this effect was mediated by fluctuations in the extracellular levels of forebrain dopamine (DA), we examined the ability of ZAC to attenuate cocaine-induced increases in extracellular DA levels. Microdialysis samples were collected from the nucleus accumbens region (NAS) of awake, male, Sprague-Dawley rats. ZAC treatment alone (0.1 mg/kg, IP) did not alter DA levels relative to baseline. However, this dose of ZAC given 1 h prior to cocaine challenge (10 mg/kg, IP) caused a 27% reduction in the peak level of extracellular DA produced by cocaine, relative to saline-pretreated control animals. These results suggest that the ability of ZAC to attenuate cocaine-induced increases in extracellular DA levels may contribute to ZAC's ability to suppress cocaine-induced locomotor activity in the rat. However, additional neurochemical mechanisms are likely to be important in mediating the robust behavioral effects previously reported.

The role of the nucleus accumbens in sensitization to drugs of abuse

1. 1. Male rats received cannula implants above the nucleus accumbens for monitoring extracellular concentrations of dopamine via in vivo microdialysis. 2. 2. Daily injections with cocaine led to an augmentation in both the behavioral response and the neurochemical response (i.e. cocaine-induced increase in extracellular dopamine within the nucleus accumbens) to this drug. 3. 3. Pertussis toxin injections into the A10 region led to sensitized behavioral and neurochemical responses to an acute injection of cocaine. 4. 4. Prior exposure to footshock stress augmented the cocaine-induced increase of motor activity and of extracellular dopamine within the nucleus accumbens. 5. 5. These data suggest that treatments which lead to behavioral sensitization also lead to sensitization within the mesolimbic dopamine system as measured by an augmented dopamine release in the nucleus accumbens.

GBR12909 antagonizes the ability of cocaine to elevate extracellular levels of dopamine

Rats were administered various IP doses of the high-affinity dopamine (DA) reuptake inhibitor 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine (GBR12909). The caudate nuclei were removed 60 min after drug administration and stored at −70°C. Striatal membranes were prepared later. The results demonstrated that GBR12909 produced a dose-dependent decrease in the binding of [ 3H]cocaine or [ 3H]GBR12935 to the DA transporter (ED 50 about 10 mg/kg). Saturation binding studies with [ 3H]GBR12935 showed that this was due to both an increase in the K d, due to residual drug, and to a decrease in the B max. At a dose of 25 mg/kg IP, GBR12909 produced a 50% decrease in the B max, and a 3.4-fold increase in the K d. In the in vivo microdialysis studies, GBR12909 (25 mg/kg IP) produced a modest, long-lasting and stable elevation of extracellular DA. Administration of cocaine through the microdialysis probe to rats pretreated with either saline or GBR12909 (25 mg/kg IP) produced a dose-dependent increase in extracellular DA in both groups. GBR12909 inhibited cocaine-induced increases in extracellular DA by about 50% at all doses. These data collectively indicate that a dose sufficient to decrease by 50% the B max of [ 3H]GBR12935 binding sites, GBR12909 antagonizes the ability of cocaine to elevate extracellular DA by 50%. Further studies will be needed to evaluate a possible role for GBR12909 in the medical treatment of cocaine addiction.