COT-TT vaccine attenuates cocaine-seeking and cocaine-conditioned place preference in rats

Abstract

Vaccination active, promising alternative immunological strategy to treat of CUD. Various models of cocaine vaccines have been evaluated in animals and humans with relative success. In this sense, it is necessary to improve or optimize the cocaine vaccines already evaluated. Our laboratory previously reported the efficacy of the tetanus toxoid-conjugated morphine vaccine (M₆-TT). The M₆-TT vaccine can generate high titers of antibodies and reduce heroin-induced behavioral effects in rodents. So, it would be plausible to assume that if we modify the M₆-TT vaccine by changing the hapten and maintaining the rest of the structural elements of the vaccine, we will maintain the properties of the M₆-TT vaccine (high antibody titers). The objective of this study was to determine whether the antibodies generated by a tetanus toxoid-conjugated cocaine vaccine (COC-TT) can recognize and capture cocaine and decrease the cocaine-induced reinforcing effects. Male Wistar rats were immunized with the COC-TT. A solid-phase antibody-capture ELISA was used to monitor antibody titer responses after each booster dose in vaccinated animals. The study used cocaine self-administration and place-preference testing to evaluate the cocaine-reinforcing effects. The COC-TT vaccine could generate high levels of anti-cocaine antibodies. The antibodies reduced the cocaine self-administration and cocaine place preference. In addition, they decreased the cocaine-induced Fos protein expression. These findings suggest that the COC-TT vaccine generates a robust immunogenic response capable of reducing the reinforcing effects of cocaine, which supports its possible future use in clinical trials in patients with CUD.

Keywords: Active vaccination; COC-TT vaccine; antibodies; cocaine; cocaine place preference; cocaine self-administration.

Figure 1.

Experiment timeline (a). Antibody titer responses (to the sixth boost) in rats immunized with the TT or COC-TT vaccine (b). Serum samples were collected 14 days after each immunization. Mean titers (± S.E.M.). *p < .01 significant effects of the antibody titers generated by the COC-TT vaccine to the 6th booster compared to the antibody titers generated by the TT vaccine in wistar rats. The COC-TT vaccine reduces cocaine self-administration. Total cocaine seeking during re-acquisition (c). Mean responses on the active and inactive lever during the re-acquisition period (d). *p < .01 significant effects on the active and inactive lever responses in the TT + COC and COC-TT + COC groups compared to saline-treated groups. ^#p < .01 significant effects on the active and inactive lever responses in the TT + COC group compared to the COC-TT + COC group. As determined by two-way ANOVA followed by Tukey’s tests.

Figure 2.

COC-TT vaccine reduces the number of cells immunoreactive to c-fos. Number of cells immunoreactive to c-fos (±S.E.M.) by group (n = 8 animals per group) in the infralimbic cortex (a), AcbC (b), AcbSh (c), and ventral-tegmental area (d). *p < .01 significant effects on the number of cells immunoreactive to c-fos in the TT + COC group compared to the TT + SAL group. ^#p < .01 significant effects between the TT + COC and COC-TT + COC groups, as determined by two-way ANOVA followed by Tukey’s tests.

Figure 3.

Representative photomicrographs of Fos protein expression in the IL, AcbS, AcbC, and VTA of rats from all experimental groups at 20× magnification, where Fos protein expression was visible as dark ovals (highlighted by arrows). Scale bar = 100 μm.

Figure 4.

COC-TT vaccine attenuated the re-acquisition of cocaine-induced CPP. Experiment timeline (a). Antibody titer responses (to the sixth boost) in rats immunized with the TT or COC-TT vaccine (b). Mean titers (± S.E.M.). *p < .01 significant effects of the antibody titers generated by the COC-TT vaccine to the 6th booster compared to the antibody titers generated by the TT vaccine in wistar rats. Mean time spent in the cocaine-paired chamber (± S.E.M.) by group (n = 8 animals per group), during acquisition (c) and re-acquisition (d). *p < .01 significant effects on the time in the cocaine-paired side in the TT + COC and COC-TT + COC groups compared to the TT + SAL and COC + SAL groups. ^#p < .01 significant effects between the TT + COC and COC-TT + COC groups, as determined by two-way ANOVA followed by Tukey’s tests.