Cocaine abuse is a major medical and public health concern in the United States, with approximately 2.1 million people dependent on cocaine. Pharmacological approaches to the treatment of cocaine addiction have thus far been disappointing, and new therapies are urgently needed. This paper describes an immunological approach to cocaine addiction. Antibody therapy for neutralization of abused drugs has been described previously, including a recent paper demonstrating the induction of anti-cocaine antibodies. However, both the rapidity of entry of cocaine into the brain and the high doses of cocaine frequently encountered have created challenges for an antibody-based therapy. Here we demonstrate that antibodies are efficacious in an animal model of addiction. Intravenous cocaine self-administration in rats was inhibited by passive transfer of an anti-cocaine monoclonal antibody. To actively induce anti-cocaine antibodies, a cocaine vaccine was developed that generated a high-titer, long-lasting antibody response in mice. Immunized mice displayed a significant change in cocaine pharmacokinetics, with decreased levels of cocaine measured in the brain of immunized mice only 30 seconds after intravenous (i.v.) administration of cocaine. These data establish the feasibility of a therapeutic cocaine vaccine for the treatment of cocaine addiction.

Cocaine addiction is a chronically relapsing brain disease, but its neural basis is not yet well understood. Clinical reports underscore the possible importance of associative processes for regulating at least some aspects of cocaine addiction. The present study reports the effects of reversible lidocaine-induced inactivation of rostral basolateral amygdala (rBLA) and caudal basolateral amygdala (cBLA) regions on the maintenance and reinstatement of drug-seeking behavior in rats trained to selfadminister 1 mg/kg cocaine under a second order schedule of drug delivery. Both regions of the basolateral amygdala were investigated because they have dissociable effects on cognitive task performance. Results demonstrated that after selfadministration training and a period of extinction and abstinence, lidocaine inactivation of the rBLA and cBLA attenuated the reinstatement of drug-seeking behavior induced by cocaine-associated cues examined in conjunction with a single priming injection of cocaine. In contrast, lidocaine inactivation of only the rBLA blocked reinstatement of drug-seeking behavior induced by cocaine-associated cues examined alone. Additional differences were shown during cocaine maintenance testing where inactivation of only the cBLA attenuated drugseeking behavior. Drug intake was not altered. Thus, the rBLA and cBLA appear to selectively and dissociably regulate drugseeking behavior under conditions of cocaine abstinence (cue-induced reinstatement) and repeated cocaine use (maintenance), respectively. These findings suggest that the basolateral amygdala may be more functionally heterogeneous than commonly thought for regulating drug-seeking behavior. The basis for this dissociation might be related to neuroanatomical connections of the rBLA and cBLA with segregated, but parallel, corticostriatalpallidothalamic circuits.Key words: caudal basolateral amygdala; cocaine; drug cues; drug prime; lidocaine; maintenance; reinstatement; rostral basolateral amygdala Cocaine addiction is a chronically relapsing brain disease. Clinical reports suggesting a link between limbic and cortical structures in mediating drug use and craving underscore the possible importance of associative processes for regulating some aspects of drug addiction. Imaging studies demonstrate that craving induced by cocaine-associated cues in abstinent addicts produces specific changes in patterns of activation in the amygdala, anterior cingulate, basal ganglia, dorsolateral prefrontal cortex, and cerebellum (Grant et al., 1996;Maas et al., 1998;Childress et al., 1999;Wang et al., 1999). Furthermore, Breiter et al. (1997) showed that craving and rush induced by a cocaine priming injection also modulate patterns of activation in memory circuits important for regulating cognitive functions. Animal studies examining cognitive aspects of addiction-related behavior are emerging, particularly in reference to the basolateral amygdala.An associative conditioning process involving mechanisms within the basolateral amygdala is thought to underlie the...

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.

Appropriate animal models of Attention Deficit/Hyperactivity Disorder (ADHD) and drug reinforcement allow investigation of possible underlying biological bases of ADHD and its co-morbidity with cocaine addiction. Toward this end, Spontaneously Hypertensive Rats (SHR) exhibiting an ADHD phenotype were compared to Wistar-Kyoto (WKY) and Wistar (WIS) rats. Initially, 1.5 mg/kg oral methylphenidate or vehicle was administered between post-natal days 28–55 and acquisition of visual discrimination learning was examined. After discontinuing adolescent treatments, adult rats were evaluated for cocaine self-administration and dopamine transporter (DAT) function in prefrontal cortex and striatum. During adolescence, SHR showed deficits in visual discrimination relative to WKY and WIS when non-medicated. Methylphenidate improved visual discrimination only in SHR. Compared to WKY and WIS, SHR with prior methylphenidate treatment acquired cocaine self-administration fastest, identified cocaine as a highly efficacious reinforcer by displaying an upward shift in the cocaine dose-response function, and showed the greatest motivation to self-administer cocaine by exhibiting the highest progressive ratio breakpoints. In prefrontal cortex, maximal dopamine uptake (Vmax) at DAT was decreased in SHR and increased in WKY and WIS by prior methylphenidate treatment. Affinity (Km) for dopamine at DAT in prefrontal cortex was not different between strains, nor was Vmax or Km altered in striatum by prior methylphenidate treatment in any strain. Methylphenidate-induced decreases in dopamine clearance by DAT in prefrontal cortex may underlie increased cocaine self-administration in SHR. These preclinical findings suggest that caution should be exercised when methylphenidate is prescribed for first-time treatment of ADHD in adolescent patients, as cocaine addiction vulnerability may be augmented.

Evidence of stimulus attribute-specificity within the prefrontal cortex (PFC) suggests that different prefrontal subregions may contribute to cocaine addiction in functionally distinct ways. Thus, the present study examined the effects of lidocaine-induced inactivation of two distinct PFC subregions, the prelimbic (PL) or dorsal agranular insular (AId) cortices, on drug-seeking and drug-taking behaviors under cocaine maintenance and reinstatement testing conditions in rats trained to self-administer 1 mg/kg cocaine under a second-order schedule of drug delivery. Throughout maintenance and reinstatement phases, rats were exposed to conditioned light cues and contextual odor or sound cues. Results showed that PL inactivation during maintenance test sessions significantly reduced drug-seeking and drug-taking behaviors, and disrupted patterns of responding in rats exposed to light-sound, but not light-odor, cues. Moreover, lidocaine-induced inactivation of the PL significantly attenuated drug-seeking behavior during cue-induced and cocaine prime-induced reinstatement in rats exposed to light-sound cues only. In contrast, AId inactivation significantly attenuated cue-induced reinstatement of drug-seeking behavior in rats exposed to light-odor cues only. Drug-seeking and drug-taking behaviors in these rats were not disrupted during maintenance and cocaine prime-induced reinstatement testing regardless of the type of contextual cues used. Together, these data suggest that PL and AId subregions play separate yet overlapping roles in regulating cocaine addiction in rats in ways that are dependent on the presence or absence of cocaine and on the types of contextual cues present in the cocaine self-administration environment.