No abstract

Oxidative stress (OS) generates or intensifies cocaine-evoked toxicity in the brain and peripheral organs. The aim of this study was to examine superoxide dismutase (SOD) activity and lipid peroxidation [measured by malondialdehyde (MDA) levels] in rats during maintenance of cocaine self-administration and after withdrawal by a yoked-triad procedure. Our results indicate that repeated cocaine self-administration provoked an elevation of SOD activity in the hippocampus, frontal cortex, dorsal striatum, and liver. MDA levels were reduced in the brain, increased in the liver, kidney, and heart during maintenance of self-administration, and increased in the kidney in cocaine-yoked rats. In addition, following extinction training, we found enhanced MDA levels and SOD activity in the rat hippocampus, while changes in the activity of OS biomarkers in other brain structures and peripheral tissues were reminiscent of the changes seen during cocaine self-administration. These findings highlight the association between OS biomarkers in motivational processes related to voluntary cocaine intake in rats. OS participates in memory and learning impairments that could be involved in drug toxicity and addiction mechanisms. Therefore, further studies are necessary to address protective mechanisms against cocaine-induced brain and peripheral tissue damage.

Recent studies indicate that adenosine may influence dopamine neurotransmission via A2A receptors which antagonistically interact with D2 receptor-mediated signaling in the brain. We examined the effects of selective A2A receptor ligands such as the agonist CGS 21680 and the antagonists KW 6002 or SCH 58261 as well as of the D2-like receptor antagonist raclopride on reinstatement of cocaine seeking induced by cocaine, the cocaine-conditioned cue, or the D2-like receptor agonist quinpirole in rats. For comparison, effects of the A2A receptor ligands on reinstatement of food seeking were also studied. CGS 21680 significantly attenuated the reinstatement of cocaine (ip) seeking, and even more potently it reduced quinpirole (ip) or the cue-induced relapse of cocaine seeking as well as cue-induced food seeking. A potent reduction toward the cocaine-, quinpirole-, or cue-induced reinstatement of cocaine seeking was seen with raclopride. Pretreatment with KW 6002 or SCH 58261 reinstated cocaine seeking, and such increases were blocked by raclopride. In the higher doses, KW 6002 or SCH 58261 evoked food-seeking. In combination with the subthreshold dose of cocaine (2.5 mg/kg) or with the cue, low doses of KW 6002 but not SCH 58261 reinstated cocaine-seeking behavior, while none of the A2A receptor antagonists affected the cue-induced food-seeking behavior. The results indicate that A2A activation and D2-like receptor blockade counteract cocaine and food relapse. It is proposed that A2A receptor- and D2 receptor-mediated adenosine and dopamine signaling antagonistically interact in the striato-pallidal GABA neurons to regulate cocaine and food-seeking behavior.