Ondansetron given in the acute withdrawal from a repeated cocaine sensitization dosing regimen reverses the expression of sensitization and inhibits self-administration.

Male Sprague-Dawley rats were given two separate sensitizing regimens of cocaine (7 days on, 7 days off, 7 days on; 40 mg/kg/day s.c.) along with saline controls. Furthermore, animals also received the 5-HT(3) antagonist ondansetron (0.2 mg/kg s.c.) either during the second dosing regimen (3.5 h after each cocaine/saline injection) or during the first five days of the second withdrawal period. Animals were then challenged, on day 10 of withdrawal, with cocaine (7.5 mg/kg i.p.) and assessed by a behavioral rating scale and locomotor activity monitoring. The cocaine regimen induced behavioral and locomotor sensitization on day 10 of withdrawal, further, ondansetron inhibited sensitization regardless of whether given after each second cocaine regimen dose or during the second withdrawal period, although treatment 3.5 h after each cocaine injection appeared more effective. Ondansetron did not inhibit behavior in control animals. In a second experiment animals were trained to self-administer cocaine via an indwelling jugular catheter. After stable fixed-ratio responding (FR1 then FR2) they were given a progressive ratio (PR) schedule until PR each day was stable. During the first five days of withdrawal they were given either ondansetron (0.2 mg/kg s.c.) or saline injections. On day 10 of withdrawal the cocaine PR schedule was reinstated. The ondansetron treated rats showed only a non-significant decrease in break point. After day 2 of the PR session rats were again injected with either ondansetron (0.2 mg/kg s.c.) or saline, 3.5 h after each PR session for five days. Ondansetron inhibited cocaine self-administration on each of the following days. Ondansetron may be a useful treatment for cocaine addicts who have undergone previous sensitization periods.