Fluctuations in nucleus accumbens dopamine concentration during intravenous cocaine self-administration in rats

Abstract

Fluctuations in extracellular dopamine and DOPAC levels in nucleus accumbens septi (NAS) were monitored in 1-min microdialysis samples taken from rats engaged in intravenous cocaine self-administration. For four rats the dose per injection was fixed at 2.0 mg/kg; for four others the dose per injection was varied irregularly, from one response to the next, between three levels (0.5, 1.0 and 2.0 mg/kg). Regardless of the dosing regimen, extracellular dopamine levels were tonically elevated by 200-800% within the cocaine self-administration periods, fluctuating phasically within this range between responses. In the fixed dose condition, the phasic increases following each injection (and the phasic decreases preceding them) averaged approximately 50% of the mean tonic elevation. Phasic fluctuations in dopamine levels remained time-locked to lever-presses even when response rate was irregular, because of the variable dose condition. In the variable dose condition greater increases in dopamine and longer inter-response times followed injections of the higher doses; dopamine fluctuations were consistent with the multiple-infusion pharmacokinetics of cocaine. DOPAC levels showed a slow tonic depression during cocaine self-administration, but individual injections were not associated with discernible phasic fluctuations of DOPAC. These data are consistent with the hypothesis that falling dopamine levels trigger successive responses in the intravenous cocaine self-administration paradigm, but inconsistent with the notion that extracellular dopamine levels are depleted at the times within sessions when the animal initiates drug-seeking responses.

Anxiogenic-Like Effects Limit Rewarding Effects of Cocaine in BALB/cByJ Mice

“…Co-infusion of equimolar concentrations of sulpiride and cocaine attenuates cocaine self-administration into the prefrontal cortex of the rat, which seems to activate NAc dopaminergic elements Smith 1983, 1993). This effect also is consistent with a role of NAc dopamine and dopamine D2 receptors in cocaine IVSA (Roberts and Vickers 1984;Woolverton 1986;Robledo et al 1992;Wise et al 1995) and local electrophysiological effects of cocaine (White et al 1993;Uzwiak et al 1997). Although it is known that cocaine decreases dopamine (Komiskey et al 1977;, noradrenaline (Dubocovich et al 1979;Hadfield and Nugent 1980), and serotonin uptake (Taylor and Ho 1978), and increases acetylcholine release (Day et al 1997), our results point to a role for a dopa-minergic D2 mechanism in the rewarding effects of cocaine administered into the NAc.…”

The Novel Dopamine D3 Receptor Antagonist NGB 2904 Inhibits Cocaine's Rewarding Effects and Cocaine-Induced Reinstatement of Drug-Seeking Behavior in Rats

“…This suggestion is consistent with our findings that NGB 2904 or SB-277011A had no effect on cocaine self-administration under continuous FR reinforcement conditions in which a high cumulative dose is easily built up, but significantly inhibited cocaine self-administration under PR reinforcement conditions in which a high cumulative dose of drug is difficult to achieve (Di Ciano et al, 2003;Gilbert et al, 2003). Similarly, BP-897 (a D 3 partial agonist whose antagonist properties may predominate; see Wood et al, 2000;Wicke and Garcia-Ladona, 2001) also fails to inhibit cocaine self-administration under FR reinforcement conditions, but significantly inhibits cocaine-seeking behavior under second-order reinforcement conditions (Pilla et al, 1999), under which the brain's DA response to the cocaineassociated cues that drive second-order reinforced drugseeking behavior is substantially lower than to cocaine itself (ie approximately a 25% increase in accumbens DA produced by cocaine-associated cues (Gerasimov et al, 2001) vs approximately a 200-800% increase in accumbens DA produced by either exogenously or self-administered cocaine (Wise et al, 1995;Dewey et al, 1997)). …”

Impairment of acquisition of intravenous cocaine self-administration by RNA-interference of dopamine D1-receptors in the nucleus accumbens shell

“…Microdialysis studies, in addition, have shown that cocaine increases extracellular DA in the NAc even after i.v. self-administration (Di Ciano et al, 1995;Justice, 1989, 1991;Wise et al, 1995;Lecca et al, 2007a). Moreover, preferential stimulation of DA transmission in the ventral striatum by amphetamine has been demonstrated in humans by Positron Emission Tomography of [ 11 C] raclopride binding (Drevets et al,1999(Drevets et al, , 2001Leyton et al, 2002;Martinez et al, 2003).…”