User:Nuklear/Indatraline

(Eliot L. Gardner, et al. 2006)

Illicit cocaine use is a major medical, public health problem, and economic problem, with approximately 2 million chronic users in the US alone. Among addictive drugs, the medical and social impact of cocaine is disproportionately large. The lives of chronic cocaine addicts often become dominated by the drug use habit, with addicts losing jobs and families and turning to crime or prostitution to support their habits. Approximately 25% of problem users seek treatment yearly, but the retention rate in therapy is low, and releapse rates are typically greater than 50%. Currently, no pharmacotherapies have been shown to be clinically effective, although the need is great. As with other drugs of abuse, cocaines addictive action derives from its enhancement of DA in reward-related neural circuits originating in the midbrain VTA, and projecting to the forebrain NAcc. Cokes specific action is DARI, sharply enhancing synaptic DA in the forebrain reward loci—esp. NAcc—and producing the euphoria associated with coke use. With chronic use however, synaptic DA appears to become depleted during abstinence periods, and the resulting reduced levels of synaptic DA in reward-related brain loci may be a mechanistic substrate of drug craving and drug-seeking behavior. Also, it has been suggested that the genetic vulnerability to addiction shown by some individuals may result from a deficit of DA neuronal function within reward-related brain loci such as the NAcc. In turn, this deficit in DA neuronal function has been hypothesized to underlie some of the co-morbid illness with which drug addiction is associated, such as depression and ADHD. This has led led to the suggestion that some instances of drug abuse may be triggered by attempts of self-medication for co-morbid illness in susceptible individuals. For all these reasons, and by analogy to the use of methadone for the treatment of H addicts and nicotine patches to help fob smokers off tobacco, a nonaddictive and nonabusable DA reuptake inhibitor may be useful in the pharmaceutical treatment of cocaine dependence. Indeed, this notion has been in the forefront of medication development for the treatment of cocaine addiction for more than a decade. Also, it has become increasing clear that the speed with which the addictive drug reaches the brain and elevates NAcc DA levels appears to correlate +vely with addictive efficacy.<> Conversely, slow onset and/or prolonged duration of action appear to confer lower reinforcing efficacy. For example, simulating the kinetics of abusable drugs with electric brain-stimulation reward results in self-administration patterns similar to the self-administration of abused drugs, and electrical trains with slow decay parameters produce decreased response rates. Even more significantly, electrical reward trains with slow onsets and slow rise times produce a decrease in break-point on a progressive ratio reinforcement schedule, suggesting that brain-reward of equivalent efficacy loses appetitiveness with slow onset kinetics. On the basis of these concepts, a number of approaches have been taken for discovery and develpment of compounds that raise brain reward loci DA levels in a slow-onset, long-lasting manner, and could thus serve as development templates for anti-cocaine addiction pharmacotherapeutic agents. A wide variety of structural clauses have served as such templates, including benztropines, mazindol, substituted piperazines, tropanes, and other structural entities.

Discussion
The present findings show that the N,N-dimethyl analog produces the characteristic neurochemical, electrophysiological, and behavioral properties of cocaine-like monoamine reuptake inhibitor, but with a pronounced slow-onset, long-lasting profile.

In the in-vivo brain microdialysis experiments, DiMe produced a slow-onset, long-lasting increase of extracellular NAcc DA levels, coupled with pronouned slow-onset, long-lasting decreases of the DA metabolites, DOPAC and HVA, and of the serotonin metabolite 5HIAA. This profile of increased extracellular NAcc DA couplde with decreased extracellular DOPAC, HVA, and 5HIAA has been repeatedly reported to be characteristic of NAcc extracellular neurochemistry following acute administration of cocaine. Thus DiMe showed a cocaine-like profile with regard to its effect on NAcc extracellular neurochemistry, but with slow-onset, long-lasting profile.

It is well established that absolute values of DA, DOPAC, HVA, and 5HIAA measured during in vivo brain imaging are affected by the chemical composition of the dialysate fluid. Dialysates that differ in chemical composition from the brains extracellular fluid, as in the present experiments, yield DA, DOPAC, HVA, and 5HIAA values that are useful only on a relative basis, i.e., for determining relative changes produced by drug treatments from pre-drug baselines. Thus, the absolute values for NAcc DA, DOPAC, HVA and 5HIAA measured in the present study are presented as percentage changes from pre-drug baseline levels. This, however does not invalidate the present data

==Indatraline ==

Interestingly sertraline has cis-diastereochemistry whereas Indatraline is trans.

Effects of indatraline and buprenorphine on self-administration of speedball combinations of cocaine and heroin by rhesus monkeys.

Effects of the Long-Acting Monoamine Reuptake Inhibitor Indatraline on Cocaine Self-Administration in Rhesus Monkeys