Neuronal nitric oxide synthase inhibition decreases cocaine self-administration behavior in rats.
BACKGROUND
Inhibitors of nitric oxide synthase (NOS) have been shown to alter behaviors related to cocaine addiction, including its self-administration. However, previous studies have largely used mixed-action NOS inhibitors and have not examined the effects of a neuronal NOS inhibitor on cocaine self-administration.


OBJECTIVE
Pretreatment with the neuronal NOS inhibitor 7-nitroindazole (7-NI) was used and its effects on cocaine self-administration were compared with those produced by pretreatment with an indirect dopamine receptor agonist (cocaine) and a D(1)-like dopamine receptor antagonist (SCH 23390).


METHODS
Rats were trained to self-administer 1 mg/kg cocaine under a second-order schedule of drug delivery, which measures drug-seeking behavior independently from drug intake. Pretreatment with various doses of 7-NI, cocaine, and SCH 23390 were tested in combination with the training dose of cocaine followed by studies examining the effects of a selected dose of each pretreatment drug in combination with a range of cocaine doses. Other rats were trained under a second-order schedule of food pellet delivery and pretreated with 7-NI, cocaine, or SCH 23390 to determine the behavioral specificity of the effects of these drugs for cocaine-maintained responding.


RESULTS
The results demonstrated that 7-NI reduced responses maintained by the cocaine training dose and produced a downward shift in the cocaine dose-response curve. Changes in drug intake were minor by comparison. Cocaine pretreatment produced effects similar to 7-NI, while the changes observed after SCH 23390 pretreatment were different from 7-NI and cocaine. The reductions in cocaine-maintained responding after 7-NI pretreatment were behaviorally specific because there was no effect of 7-NI on food-maintained responding within the dose range examined.


CONCLUSIONS
By selectively reducing drug-seeking behavior, these data suggest that 7-NI may enhance the reinforcing effects of cocaine.
Collins
Stephanie L
SL
Laboratory of Behavioral Neuroscience, Department of Psychology, 64 Cummington Street, Boston University, Boston, MA 02215, USA.
Kantak
Kathleen M
KM
D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy* / Q000201:enzymology* / Q000523:psychology; D003042:Cocaine / Q000008:administration & dosage*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D007191:Indazoles / Q000627:therapeutic use; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration / Q000523:psychology
D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D007191:Indazoles; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D003042:Cocaine; C080122:7-nitroindazole