The dopaminergic system, and in particular the dopamine D2 receptor, has been implicated in reward mechanisms. The net effect of neurotransmitter interaction at the mesolimbic brain region induces “reward” when dopamine (DA) is released from the neuron at the nucleus accumbens and interacts with a dopamine D2 receptor. “The reward cascade” involves the release of serotonin, which in turn at the hypothalmus stimulates enkephalin, which in turn inhibits GABA at the substania nigra, which in turn fine tunes the amount of DA released at the nucleus accumbens or “reward site.” It is well known that under normal conditions in the reward site DA works to maintain our normal drives. In fact, DA has become to be known as the “pleasure molecule” and/or the “antistress molecule.” When DA is released into the synapse, it stimulates a number a DA receptors (D1-D5) which results in increased feelings of well-being and stress reduction. A consensus of the literature suggests that when there is a dysfunction in ...

Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors.

The vaccines developed over the first two hundred years since Jenner's lifetime have accomplished striking reductions of infection and disease wherever applied. Pasteur's early approaches to vaccine development, attenuation and inactivation, are even now the two poles of vaccine technology. Today, purification of microbial elements, genetic engineering and improved knowledge of immune protection allow direct creation of attenuated mutants, expression of vaccine proteins in live vectors, purification and even synthesis of microbial antigens, and induction of a variety of immune responses through manipulation of DNA, RNA, proteins and polysaccharides. Both noninfectious and infectious diseases are now within the realm of vaccinology. The profusion of new vaccines enables new populations to be targeted for vaccination, and requires the development of routes of administration additional to injection. With all this come new problems in the production, regulation and distribution of vaccines.

/pdf/vaccines-past-present-and-future-36dwlkvq5x.pdf

Vaccines: past, present and future.

Rationale and objectives: To review the literature on the use of second-order schedules of drug reinforcement in the context of experimental investigations of the neural and pharmacological mechanisms underlying addictive behaviour in general and drug-seeking behaviour in particular. Methods: Second-order schedules of drug reinforcement are described in which responding is maintained not only by the self-administered drug, but also by contingent presentation of drug-paired stimuli that serve as conditioned reinforcers of instrumental behaviour. Results: The behaviour of rats and monkeys responding under second-order schedules is discussed in relation to self-administered drug dose and the importance of drug-associated cues in maintaining responding for cocaine, morphine or heroin. Drug-seeking behaviour during the period before drug is self-administered is described and compared with drug-seeking behaviour derived from other procedures. In addition, results are summarised that demonstrate the differential involvement of the amygdala and prefrontal cortex in the acquisition of cue-controlled cocaine- and heroin-seeking behaviour, as well as the effects of drugs interacting with D3 dopamine, NMDA and AMPA receptors on drug-seeking behaviour and dopaminergic correlates of drug-paired stimuli presented non-contingently and during responding for cocaine under a second-order schedule. Conclusions: We argue that the first, drug-free interval (or other period) of responding under a second-order schedule of reinforcement has particular utility in that it provides a measure of drug-seeking behaviour and reinforcing efficacy that are not affected by the pharmacological effects of recently administered drug. It also provides a means of investigating the role of drug-paired stimuli in drug-seeking behaviour, including its behavioural, neural and neurochemical basis.

Second-order schedules of drug reinforcement in rats and monkeys: measurement of reinforcing efficacy and drug-seeking behaviour.

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 self-administer 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 self-administration 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 drug-seeking behavior. Drug intake was not altered. Thus, the rBLA and cBLA appear to selectively and dissociably regulate drug-seeking 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.

https://www.jneurosci.org/content/jneuro/22/3/1126.full.pdf

Dissociable effects of lidocaine inactivation of the rostral and caudal basolateral amygdala on the maintenance and reinstatement of cocaine-seeking behavior in rats.

Human therapeutic cocaine vaccine: safety and immunogenicity

Rationale: Previous pre-clinical studies with an anti-cocaine monoclonal antibody left open several issues critical to assessing the effectiveness of a vaccine for altering cocaine self-administration behavior. Objectives: The objectives of this study were to determine, first, whether changes in self-administration behavior would be systematically related to antibody level and, second, how the antibody affected the self-administration of different doses of cocaine. Methods: Two experiments were conducted using a second-order schedule of drug delivery in rats. The first was a passive-administration study using the anti-cocaine monoclonal antibody MO240 to examine the relationship between antibody level and cocaine self-administration behavior, and the second was an active-immunization study to examine the efficacy of the cocaine vaccine IPC-1010 for blocking various doses of self-administered cocaine. Results: The passive-administration experiment with control and 4-mg or 12-mg MO240 treatments showed that antagonism of the 1 mg/kg cocaine training dose was dependent on antibody level. In animals whose serum antibody levels were sustained above 0.05 mg/ml, there was a sufficient amount of antibody to reduce drug-seeking behavior and drug intake. In the active-immunization experiment, the cocaine vaccine IPC-1010 induced average serum antibody levels of 0.08 mg/ml and reduced the reacquisition of behavior by 1 mg/kg cocaine. Antagonism of cocaine self-administration after immunization was evident across a range of doses of cocaine and was only apparent in animals whose serum antibody levels exceeded 0.05 mg/ml. Furthermore, there was no evidence that the antagonism was surmountable within the dose range examined (up to 5.6 mg/kg). Conclusions: 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.

K. Giovanoni

Papers

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