Substance abuse dopamine

Fuxe K, Andersson K, Nilsen OG, et al Toluene and telencephalic dopamine selective reduction of amine mrnover in discrete DA nerve terminal systems of the anterior caudate nucleus by low concentrations of toluene. Toxicol Lett 12 115—123,1982 Cause EM, Mendez V, Geller I Exploratory smdies of a rodent model for inhalant abuse. Neurobehav Toxicol Teratol 7 143—148, 1985 Gentry JR, Hill C, Malcolm R New anticonvulsants a review of applications for the management of substance abuse disorders. Ann Clin Psychiatry 14 233—245, 2002 Gerasimov MR, Ferrieri RA, Schiffer WK, et al Smdy of brain uptake and biodistribution of [llCjtoluene in non-human primates and mice. Life Sci 70 2811 — 2828, 2002... 

Slow-onset, long duration dopamine reuptake inhibitors with reduced potential for substance abuse have been suggested as therapies for psychostimulant addiction [33-35]. A series of slow-onset, long duration N-alkyl analogues of methylphenidate were recently reported to have enhanced selectivity for the dopamine transporter [34]. A representative compound is 13, an RR/SS diastereomer (DAT K, = 16nM, SERT K = 5900 nM, NET K-, = 840 nM). In a locomotor activity assay in mice, 13 has a slow onset of activity (20-30 min) with peak activity occurring between 90 and 120 min. In contrast, both methylphenidate and cocaine are active within 10 min and reach peak activity within 30 min. 

Reward Therapy. A similar (yet nonspecific) approach is to use a medication that stimulates the brain s reward centers. Reward medications usually do not work in quite the same way as the substance of abuse however, the net effect in the final common pathway (i.e., the reward centers) may be the same. For the most part, these reward centers are activated by either dopamine or endogenous opioid agonists. One common feature of most abused drugs is that they stimulate these reward centers. This lies at the heart of their addictive potential. Some attempts have been made to use medications that activate these reward centers in place of the abused substance. The hypothesis is that the addict will have less intense craving for his/her preferred substance of abuse in the presence of these other agents. This is, of course, a relatively nonspecific approach that could theoretically be used to treat the abuse of many different substances. It has not yet, however, demonstrated any utility in the treatment of substance abuse. 

Dopamine-Stimulating Medications. A variety of drugs that increase the availability of dopamine have been studied in cocaine addicts including L-DOPA, bupropion, amantadine, and methylphenidate. In small uncontrolled trials, these have shown some benefit, but definitive studies have yet to be performed. In addition, some dopamine-stimulating medications (in particular, the stimulants like methylphenidate or the amphetamines) are themselves subject to abuse, though, of note, this is typically not a problem when they are prescribed to patients who do not have a history of substance abuse such as, for example, in the treatment of attention deficit-hyperactivity disorder. 

Jeffrey W. Dailey and his colleagues use animal models and imaging to show that the physiological state of dopamine neurotransmission may be an important factor in substance abuse problems. 

Dailey, Jeffrey W., Tim D. Fryer, Laurent Brichard, Emma S. J. Robinson, David E. H. Theobald, Kristjan La e, et al. Nucleus Accumbens D2/3 Receptors Predict Trait Impulsivity and Cocaine Reinforcement. Science 315 (March 2,2007) 1,267-1,270. The researchers report on evidence that indicates the state of dopamine neurotransmission may be an important factor leading to substance abuse problems. 

Ebstein, Richard P.,and Robert H. Belmaker. 1997. "Saga of an Adventure Gene Novelty Seeking, Substance Abuse, and the Dopamine D4 Receptor (D4DR) Exon 111 Repeat Polymorphism." Molecular Psychiatry 2 381-84. 

Nicotine enhances dopamine release by acting on presynaptic facilitatory heteroreceptors located on the terminal regions of dopaminergic neurons (Marshall et al. 1997). It is tempting to associate these effects of nicotine and the fact that tobacco dependence, the most common substance abuse disorder, is due to nicotine. Nicotine... 

Increases in norepinephrine and dopamine centrally can cause CNS side effects such as insomnia, agitation, psychosis and substance abuse... 

Is the nicotine patch an effort to modify human mental activity Will a brain Polypill be developed to treat persons susceptible to substance abuse, such as cocaine We now know that cocaine and methamphetamine flood the brain with dopamine and other neurotransmitters,producing a"high. Methamphetamine (meth),prescribed for patients with severe attention-deficit hyperactivity disorder or narcolepsy, is widely abused. Crystal meth is the crystalline form of the drug that is smoked. It is difficult to imagine that there will ever be supplementation of a communal water supply, but we should remember that salt is iodized, there is fluoride in water and iron and folic acid are supplements in many foods. 

O Virtually all abused substances appear to activate the same brain reward pathway. Key components of the reward pathway are the dopamine (DA) mesocorticolimbic system that projects from the ventral tegmental area (VTA) and the nucleus accumbens (NA) to the prefrontal cortex, the amygdala, and the olfactory tubercle (Figs. 33-3 and 33-4).5 Animal studies... 

Alterations in dopamine (DA) levels are associated with the rewarding effects of abused substances including cigarettes. Specifically, the mesolimbic DA pathway, which originates in the... 

Given the low incidence of severe withdrawal symptoms and the modest effects on the mesolimbic dopamine (reward) system, most investigators have found that cannabis has a low abuse or addiction potential. However, it has been argued that if cannabis is a non-addictive substance, why is its use so widespread and why are there so many longterm and heavy users Finally, contrary to the evidence that cannabis can produce chronic tolerance, some regular users report that they require less drug to achieve the same high, or sensitisation (Chapter 3). Three possible explanations may account for this. First, chronic users may focus on the effects that they wish to achieve. Second, the... 

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