Cocaine vaccines: Antibody protection against relapse in a rat model

Carrera, Marta; Ashley, Jon; Zhou, Bin; Wirsching, Peter; Koob, George F.; Janda, Kim D.

doi:10.1073/pnas.97.11.6202

Cited by 149 publications

(162 citation statements)

References 26 publications

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“…This observation is very similar to observations of 'extinction burst' responding in rats with high cocaine intake and no 'extinction bursts' in rats with low cocaine intake (Edwards et al, 2007). In addition, when primed with cocaine, control rats reinstated responding on the previously cocaineassociated lever, whereas vaccinated rats did not, consistent with a previous finding (Carrera et al, 2000). Consequently, the data suggest that the antibodies prevented primed cocaine from reaching the brain to initiate cocaine-seeking mechanisms in rats.…”

Section: Discussionsupporting

confidence: 80%

“…Monoclonal antibodies against cocaine decreased cocaine self-administration and its toxic effects in rats (Carrera et al, 2000;Kantak et al, 2000;Mets et al, 1998). However, passively administered antibodies have a rather short half-life compared with active immunization that generates immunological memory (Fox et al, 1996;Kantak et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…For example, active immunization with a cocaine analog linked to keyhole limpet hemocyanin (KLH) significantly attenuated cocaine-induced psychomotor stimulation and sequestered cocaine in the periphery in rodents (Carrera et al, 1995(Carrera et al, , 2001. In addition, a KLHconjugated vaccine against cocaine prevented the reinstatement of responding for cocaine in rats, a rodent model of relapse to cocaine use (Carrera et al, 2000). Immunization with a cocaine-bovine serum albumin (BSA) conjugate also produced specific antibodies against cocaine and increased the distribution of cocaine in plasma relative to the brain in mice (Fox et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Novel Cocaine Vaccine Linked to a Disrupted Adenovirus Gene Transfer Vector Blocks Cocaine Psychostimulant and Reinforcing Effects

Wee

Hicks

et al. 2011

Neuropsychopharmacol

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Immunotherapy is a promising treatment for drug addiction. However, insufficient immune responses to vaccines in most subjects pose a challenge. In this study, we tested the efficacy of a new cocaine vaccine (dAd5GNE) in antagonizing cocaine addiction-related behaviors in rats. This vaccine used a disrupted serotype 5 adenovirus (Ad) gene transfer vector coupled to a third-generation cocaine hapten, termed GNE (6-(2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo [3.2.1] octane-2-carboxamido-hexanoic acid). Three groups of rats were immunized with dAd5GNE. One group was injected with 3 H-cocaine, and radioactivity in the blood and brain was determined. A second group was tested for cocaine-induced locomotor sensitization. A third group was examined for cocaine self-administration, extinction, and reinstatement of responding for cocaine. Antibody titers were determined at various time-points. In each experiment, we added a control group that was immunized with dAd5 without a hapten. The vaccination with dAd5GNE produced long-lasting high titers (410 5 ) of anti-cocaine antibodies in all of the rats. The vaccination inhibited cocaine-induced hyperlocomotor activity and sensitization. Vaccinated rats acquired cocaine self-administration, but they showed less motivation to self-administer cocaine under a progressive-ratio schedule than control rats. When cocaine was not available in a session, control rats exhibited 'extinction burst' responding, whereas vaccinated rats did not. Moreover, when primed with cocaine, vaccinated rats did not reinstate responding, suggesting a blockade of cocaine-seeking behavior. These data strongly suggest that our dAd5GNE vector-based vaccine may be effective in treating cocaine abuse and addiction.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel Cocaine Vaccine Linked to a Disrupted Adenovirus Gene Transfer Vector Blocks Cocaine Psychostimulant and Reinforcing Effects

Wee

Hicks

et al. 2011

Neuropsychopharmacol

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“…Research has focused on immunization by cocaine binding antibodies (27)(28)(29)(30)(31)(32). Active or passive immunization with cocaine binding antibodies effectively reduces the effects of cocaine (28,29).…”

Section: Pharmacokinetic-based Therapies For Cocaine Abusementioning

confidence: 99%

The Rhodococcus sp. Cocaine Esterase: A Bacterial Candidate for Novel Pharmacokinetic‐based Therapies for Cocaine Abuse

2003

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SummaryCocaine is a powerful central nervous stimulant and among the most abused of drugs. Despite decades of efforts, however, no effective pharmacological treatments are available against cocaine addiction or toxic effects. Classical receptor-antagonist therapeutic approaches have not yielded significant effects, although cocaine targets are well known, thus fostering development of alternative therapeutic strategies. Recent evidence indicates that a sensible approach for treatment of cocaine abuse could be to interfere with cocaine pharmacokinetics, i.e. by preventing the drug from reaching the receptors responsible for its biological effects. Administration of cocaine binding antibodies as well as catalytic antibodies and enzymes that hydrolyze cocaine represent potential alternative therapeutic approach(es). The discovery of the cocaine esterase from the strain MB1 of the bacterium Rhodococcus sp. (cocE) could be a major breakthrough in this field; cocE hydrolyzes cocaine faster than any known cocaine esterase and catalytic antibody. IUBMB Life, 55: 397-402, 2003 Keywords Rhodococcus sp. esterase; human plasma butyrylcholinesterase; human liver carboxylesterase-1; human liver carboxylesterase-2; cocaine binding antibodies; cocaine binding catalytic antibodies; cocaine metabolism.

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“…However, these studies have raised concerns regarding the efficacy of the conjugate (12), antibody surmountability (13,14), and the choice of schedules of reinforcement (14). Recently, these concerns were addressed in the report of a series of studies from this laboratory, where both active (GNC-KLH) and passive (mAb GNC92H2) immunization were tested in a rat model of cocaine relapse (15). It was found that immunization with GNC-KLH or GNC92H2 significantly inhibited the reinforcing value and, when combined, the intake of self-administered cocaine.…”

mentioning

confidence: 99%

A second-generation vaccine protects against the psychoactive effects of cocaine

Carrera¹

2001

Proceedings of the National Academy of Sciences

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The effects of immunization with the second-generation cocaine immunoconjugate GND-keyhole limpet hemocyanin (KLH) or with the anti-cocaine mAb GNC92H2 were assessed in a model of acute cocaine-induced locomotor activity. After i.p. administration of cocaine⅐HCl (15 mg͞kg), rats were tested in photocell cages, and stereotypy was rated to determine preimmunization drug response (baseline). Experimental animals were subjected to an immunization protocol with GND-KLH or treated with the mAb GNC92H2. Rats were then challenged with systemic cocaine, and their locomotor responses were again measured. Active immunization with GND-KLH produced a 76% decrease in the ambulatory measure (crossovers) in the experimental group and a 12% increase in the control group compared with baseline values. Also, stereotypic behavior was significantly suppressed in the vaccinated animals. Decreases in both measures were seen in the experimental group on two subsequent challenges. The maximum effect was observed at the time of the second challenge with a dramatic 80% decrease in crossovers. Treatment with GNC92H2 resulted in a 69% decrease in crossovers compared with baseline. This effect persisted across two additional challenges over 11 days with decreases of 46 -47%. In contrast, the control group showed increases of up to 28%. Significant differences between groups were observed in the stereotypic measure in all three challenges. The results indicate that these immunopharmacotherapeutic agents have significant cocaine-blockade potential and therefore may offer an effective strategy for the treatment of cocaine abuse.T he abuse of cocaine (structure 1 in Fig. 1) has reached epidemic proportions in the United States, representing a major and increasing threat to public health (1). At present, there is no suitable medication for the treatment of this illness. Despite the many advances in the understanding of the biochemistry of action of cocaine, the development of antagonists, agonists, and antidepressants for pharmacotherapeutic and psychotherapeutic interventions has had limited success in both animal models and clinical studies (2-4). Because these therapeutic means are designed to block the central neurochemical effects of cocaine, their actions are nonselective and thus generate unwanted secondary effects (5). Immunopharmacotherapy, wherein antibodies are used to neutralize the drug, offers a possible alternative. Rather than targeting the receptors in the brain, antibodies obstruct partitioning of cocaine from the blood. This approach has the advantage of operating by means of an endogenous response that is independent of the central nervous system, thus circumventing the problem of neurotoxicity.Earlier studies showed that anti-morphine (6) and anti-heroin (7) antibodies could suppress opiate-induced effects. In the last decade, this strategy has been explored as a possible treatment for cocaine abuse. Work from this laboratory demonstrated that active immunization with a keyhole limpet hemocyanin (KLH) immunoconjugate derived ...

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Cocaine vaccines: Antibody protection against relapse in a rat model

Cited by 149 publications

References 26 publications

Novel Cocaine Vaccine Linked to a Disrupted Adenovirus Gene Transfer Vector Blocks Cocaine Psychostimulant and Reinforcing Effects

Novel Cocaine Vaccine Linked to a Disrupted Adenovirus Gene Transfer Vector Blocks Cocaine Psychostimulant and Reinforcing Effects

The Rhodococcus sp. Cocaine Esterase: A Bacterial Candidate for Novel Pharmacokinetic‐based Therapies for Cocaine Abuse

A second-generation vaccine protects against the psychoactive effects of cocaine

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