Evaluation of anti-cocaine antibodies and a cocaine vaccine in a rat self-administration model

Kantak, Kathleen M.; Collins, Stephanie L.; Lipman, E. G.; Bond, Julian F.; Giovanoni, K.; Fox, Barbara S.

doi:10.1007/s002130050049

Cited by 156 publications

(156 citation statements)

References 27 publications

(51 reference statements)

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“…However, vaccinated rats showed a downward shift of the cocaine dose-response function compared with control rats, similar to a previous observation with succinylnorcocaine attached to cholera B toxin (Kantak et al, 2000). Most importantly, vaccinated rats exhibited decreased motivation to self-administer cocaine compared with control rats when the cost (ie, PR requirement) for a cocaine injection increased.…”

Section: Discussionsupporting

confidence: 86%

“…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). Immunization with succinylnorcocaine attached to cholera B toxin (IPC-1010 or TA-CD) decreased responding for cocaine and cocaine intake in rats, with serum antibody concentrations 40.05-0.07 mg/ml (Kantak et al, 2000(Kantak et al, , 2001, and this vaccine was well tolerated and produced specific antibodies in a dosedependent manner in a Phase I clinical trial (Kosten et al, 2002). In a Phase II clinical trial, 38% of the participants treated with TA-CD evoked antibody titer levels that correlated with lower cocaine levels in the urine, as an indicator of reduced cocaine use (Martell et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…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%

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: 86%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…For intravenous delivery of cocaine or saline during self-administration sessions, surgical implant of jugular vein catheters was performed as previously described in detail (Kantak et al 2000). Children's Tylenol in the drinking water (5 ml/250 ml water) and subcutaneously administered Buprenorphine (0.05 mg/ kg) were provided to manage post-surgical pain and discomfort for 48 hr.…”

Section: Surgery and Histology Proceduresmentioning

confidence: 99%

Role of dopamine D1 receptors in the prefrontal dorsal agranular insular cortex in mediating cocaine self-administration in rats

et al. 2008

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Rationale-Orbital/insular areas of the prefrontal cortex (PFC) are implicated in cocaine addiction. However, the role of dopamine D 1 receptors in mediating cocaine self-administration in these subregions remains unknown.Objectives-To define the role of the dorsal agranular insular (AId) sub-region of the PFC, we investigated the effects of D 1 receptor manipulation on self-administration behavior maintained by cocaine and cocaine-related stimuli. Methods-Rats

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“…Although cocaine-specific antibodies have been shown to reduce the reinforcing and/or subjective effects of cocaine in both preclinical (Carrera et al, 2000;Fox et al, 1996;Kantak et al, 2000), and clinical studies (Haney et al, 2010;Martell et al, 2005), many of these studies also suggest that the protective effects of cocaine-specific antibodies are easily surmounted by increasing the rate and/or amount of cocaine intake. One approach to circumvent these stoichiometric limitations has been to develop catalytic antibodies, such as mAb 15A10, which not only sequester cocaine in the periphery, but also catalyze its breakdown (Landry et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Long-Lasting Effects of a PEGylated Mutant Cocaine Esterase (CocE) on the Reinforcing and Discriminative Stimulus Effects of Cocaine in Rats

Collins

Narasimhan

Cunningham

et al. 2011

Neuropsychopharmacol

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Recent mutagenesis studies have identified a mutant G4C/S10C/T172R/G173Q cocaine esterase (CCRQ CocE) with an in vitro duration of action of 440 days. Although the in vivo duration of CCRQ CocE's action was o24 h, modification of this enzyme with polyethylene glycol (PEG) polymers resulted in a CocE (PEG-CCRQ CocE) capable of preventing cocaine-induced lethality for up to 72 h. The current studies were aimed at providing a detailed characterization of the effectiveness, selectivity, and duration of PEG-CCRQ CocE's actions in cocaine self-administration and discrimination assays in rats. Pretreatment with PEG-CCRQ CocE produced dose-dependent rightward shifts in the dose-response curves for cocaine self-administration and discrimination, with the highest dose of PEG-CCRQ CocE capable of producing an initial shift of cocaine's reinforcing and interoceptive effects of 430-fold to the right, with significant inhibition of these effects observed for up to 72 h. Although PEG-CCRQ CocE also produced slight reductions in the rates of methylphenidate-and foodreinforced responding, these effects were short-lived, lasting o24 h. Finally, when taken together with the finding that PEG-CCRQ CocE failed to alter the cocaine-like interoceptive effects of either methylphenidate or d-amphetamine, these results suggest that PEG-CCRQ CocE possesses a high degree of pharmacologic specificity for cocaine and a prolonged in vivo duration of action. In conclusion, these studies provide strong evidence to support the further development of long-lasting, highly efficient CocEs, such as PEG-CCRQ CocE, as a potential therapeutic option for the treatment of cocaine abuse in humans.

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Evaluation of anti-cocaine antibodies and a cocaine vaccine in a rat self-administration model

Abstract: Antagonism of cocaine self-administration across a range of doses is feasible after immunization with a cocaine vaccine as long as antibody levels are of a sufficient concentration.

Cited by 156 publications

References 27 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

Role of dopamine D1 receptors in the prefrontal dorsal agranular insular cortex in mediating cocaine self-administration in rats

Long-Lasting Effects of a PEGylated Mutant Cocaine Esterase (CocE) on the Reinforcing and Discriminative Stimulus Effects of Cocaine in Rats

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