Cocaine vaccines: antibody protection against relapse in a rat model

Abstract

The efficacy of active immunization with the cocaine immunogen GNC-keyhole limpet hemocyanin (KLH) in preventing cocaine self-administration reinstatement was assessed in rats. An animal model of relapse was used where rats were trained to self-administer cocaine, subjected to a period of extinction by substituting the drug for saline, vaccinated, and re-exposed to cocaine. Compared with controls, animals immunized with GNC-KLH did not reinstate cocaine self-administration behavior when given a noncontingent cocaine infusion on two consecutive days. Upon double and triple infusions, 38-62% of vaccinated animals failed to reinstate as compared with full reinstatement in all control animals. Exposure to ad libitum cocaine reinstated baseline values in control animals and resulted in double to triple the baseline values of self-infusions in vaccinated animals, suggesting a partial antibody-mediated blockade of cocaine access to the central nervous system. This compensating effect was blocked by passive immunization pretreatment with the monoclonal IgG GNC92H2 in both vaccinated and control groups. To further assess the surmountability potential of GNC-KLH-induced antibody titers by cocaine self-administration, and the capacity of these titers to block the reinforcing effects of the drug, rats were tested at various doses of cocaine (0.015-0.5 mg/infusion). Active immunization with GNC-KLH produced approximately an 8-fold rightward shift of the dose-effect function for cocaine. The results reported suggest that immunopharmacotherapy may offer a promising means to treat cocaine abuse by aiding in the prevention of relapse.

Figure 1

Active immunization with GNC-KLH prevents cocaine (0.25 mg/infusion) self-administration relapse in rats. Mean response rates per 1-h session are shown during baseline training, extinction (saline substitution), relapse (noncontingent cocaine delivery), and free access to cocaine, under a fixed ratio 1:20 schedule of reinforcement. Animals were treated with either the cocaine conjugate GNC-KLH (A) or the carrier protein KLH (B). * indicate a significant difference between groups during the relapse phase, P < 0.029, ANOVA. † indicate that response rate values for each group were significantly different from their respective baseline values, P < 0.01, ANOVA.

Figure 2

Reinforcer delivery record for GNC-KLH (A) and KLH (B) groups on four different phases of the relapse study (rats 13 and 18, respectively). Each horizontal line is a time line representing a 60-min cocaine self-administration session. The horizontal axis denotes time, and each vertical mark represents a single cocaine infusion (0.25 mg/infusion). The experimental phase is shown to the left of each line. The number shown to the right of each time line is the total number of infusions delivered during the session.

Figure 3

Comparison of the effects of pretreatment with GNC92H2 (30 mg/kg) or control IgG (30 mg/kg) on cocaine self-administration between GNC-KLH- and KLH-treated animals in a 1-h session. Horizontal line depicts average baseline value. Values represent means ± SEM of 16 animals (n = 8). *, P < 0.018, ANOVA, significant difference from baseline.

Figure 4

Effects of pretreatment with GNC92H2 or a control IgG on cocaine self-administration in a 1-h session. Horizontal line depicts average baseline value. Values represent means ± SEM in nine animals. *, P < 0.05, Newman–Keuls test, significant difference from control IgG.

Figure 5

Self-administration dose-effect function for cocaine in animals immunized with GNC-KLH or KLH alone. The unit dose of cocaine was varied between test sessions. Values represent means ± SEM in 16 animals (n = 8). *, P < 0.018, ANOVA.