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By P. Owen. Judson College, Marion AL.

A recent report of desipramine in depressed cocaine cocaine abuse discount arcoxia 60 mg without prescription psoriatic arthritis in the knee, and others do not specify patient diagnosis). Thus, these tricyclic anti- these patients tend to be more available for follow-up be- depressants do not have well-demonstrated utility even in cause of their need to report to a clinic daily for methadone the depressed cocaine abusers, who can be a substantial treatment, it is likely that they are different from patients subgroup comprising up to 40% of those presenting for with primary cocaine use disorders. Outcome clinical trials with fluoxetine have been conducted in pa- variables differ among clinical trials, making it difficult to tients with cocaine use disorders. Studies that utilized controlled, cocaine administration study examined the in- self-reports without confirmation by urine toxicology screen teraction of cocaine with fluoxetine at 0, 20, 40, or 60 mg may not be reflective of cocaine use by study participants. Fluoxetine has been utilized in outpatient clinical Antidepressants trials in both methadone-maintained, cocaine-dependent Desipramine, a tricyclic antidepressant agent, was one of patients and in patients with primary cocaine use disorders. It is one of the most extensively studied phar- dent patients found that fluoxetine at 45 mg daily signifi- macotherapies for cocaine dependence to date (4). The cantly reduced self-reported use and quantitative urine ben- initial study of desipramine suggested its efficacy based on zoylecgonine concentrations during 9 weeks of treatment self-report primarily, and two subsequent studies in metha- (39). More recently, fluoxetine has not reduced cocaine pos- done-maintained samples based on urine toxicology found itive urines more than placebo in either methadone-main- no difference from placebo (33–35). A large clinical trial tained or primary cocaine abusers (40). The consensus of examined the efficacy of desipramine and psychotherapy, these studies is that fluoxetine may not have a clinical role alone and in combination, as a treatment for ambulatory among unselected cocaine abusers, and side effects have lim- cocaine abusers (32). In this 12-week, double-blind, pla- ited its use in several studies. Al- vention plus placebo, and clinical management plus pla- though a pilot study suggested efficacy, a large multicenter cebo. The mean dose of desipramine was 200 mg daily and study in methadone-maintained patients showed little bene- was adjusted by a nonblinded psychiatrist in response to fit in cocaine dependence (41). All groups showed significant improvement in Dopaminergic Agents (DA) treatment retention and a reduction in cocaine use at 12 weeks, but there were no significant main effects for psycho- The most widely accepted explanation of cocaine-induced therapy, pharmacotherapy, or the combination. Lower se- euphoria is that dopamine reuptake inhibition results in verity patients (cocaine use 1 to 2. Desi- limbic and mesocortical reward pathways in the brain (42). Although a laboratory study suggested attenuation response among depressed patients was confirmed among of cocaine effects by the D1 antagonist Schering 39166, a the depressed patients on methadone. A subsequent study multisite outpatient trial found no dose response and no by Nunes et al. The D2 antagonists such as halo- imipramine, but not placebo. They did not find a significant peridol and flupenthixol have had minimal effects on eu- effect in the nondepressed patients. Finally, a recent study phoria in human cocaine administration studies (44), and with desipramine in methadone- and buprenorphine-main- flupenthixol has not been superior to placebo in an outpa- tained cocaine- and opioid-dependent patients found a re- tient trial (45). Bromocriptine is primarily used in the treatment of childhood attention-defi- an agonist with high affinity for the D2 receptor. MP is a DA agonist with pharma- studies, pretreatment with either bromocriptine 2. Although early work supported (55) have reported that it does not increase cocaine use and its use, even in an early double-blind clinical trial, bromo- retains patients better than placebo, but have not shown a criptine at 5 to 7. In another small double-blind, placebo- Mazindol is a DA reuptake inhibitor that is without controlled trial Moscovitz et al. A report on the patients presenting to an emergency room for minor medi- effects of cocaine alone and in combination with mazindol cal complaints. They found no difference in retention (bro- at 1 or 2 mg orally in cocaine abusing volunteers found mocriptine group 43%, placebo group 31%), but those ran- that the combination significantly increased heart rate and domized to bromocriptine had more urine toxicology blood pressure (56). Mazindol did not alter the subjective screens negative for cocaine (67%) than those randomized effects of cocaine. One 12-week, double-blind, placebo-con- to placebo (31%). Cocaine administration studies have trolled clinical trial of mazindol 2 mg daily in cocaine- found a lack of effects with pergolide (49).

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Novel labeling meth- ods can be tested using arrays and serially diluted RNA specific primers would confirm the identity of each clone discount arcoxia 120 mg visa arthritis in dogs nsaids, templates. Assuming we can obtain a reasonably At present investigators use Northern blotting, the Taq- well-validated clone set, the cheapest way to produce the Man system, or in situ hybridization histochemistry to weed 1. When ar- primers, and to analyze the products on agarose gels. The rays are no longer limiting, this could be accomplished by resulting cDNAs will include T-tails of varying lengths, and studying replicate samples, but the argument could be made repeat sequences. Hybridization of labeled probe to these that one should focus on variations in collections of genes sequences is prevented by addition of a blocking solution instead of single ones, and that looking at many conditions containing oligo (dA) 20-mers, yeast transfer RNA (tRNA), and (for human probes) Cot-1 DNA to the probe solution. These RNAs can be added in different concen- simply a matter of listing the names of transcripts that ap- trations to crude tissue extracts, total RNA samples, or puri- peared to increase or decrease from control levels (Fig. They should be used exclusively for quality permit the classification of genes on the basis of similarities control. The response of each gene in each experimental condition is color SMALL SAMPLES, FALSE NEGATIVES, AND coded—one color (red) indicating an increase and another FALSE POSITIVES (green) a decrease vs. The eye can readily detect patterns in complex images of the sort Failure to detect transcripts or changes in transcripts could described, and groups of genes can be identified that parallel result from low-quality arrays or poor labeling methods. Gene responses can be imposed on metabolic charts or on maps of chromosomes. In the former case, increases or decreases in the utilization of certain path- ways can be detected; in the latter, deletions or changes in copy number may be recognized, or strong positional candidates identified. INTERPRETING EXPERIMENTS Recent studies of changes in gene expression in yeast associ- FIGURE 23. After normalization, a scatter plot shows that ated with nutritional and environmental stresses, the cell most genes fall in a ratio 1space. Arrows above and below this space point at genes with altered expression. See color version of cycle, or genetic manipulations are examples of well planned figure. All of the 6,200 known and predicted protein-coding genes in the yeast ge- nome were arrayed on a single microscope slide, and suffi- cient numbers of cells were grown to make ample amounts In the hypothetical SSRI study described above, one group of RNA for labeling. Each experiment gave a richly detailed of genes may be increased or decreased in the raphe nuclei picture of molecular responses to a physiologic process or following chronic, but not acute, treatment with drug, and perturbation. It varies with age, and is composed of genes might respond to SSRI treatment when behaviorally hundreds of different sorts of cells that express, in aggregate, responsive mouse strains are compared to unresponsive as many as half of the genes in the genome in a highly ones, and the pattern of gene expression is different in regulated manner. To determine the properties of single knockout animals that do not respond to SSRIs as compared populations of cells in the context of the intact structure with animals that do. Each additional experiment may nar- will be difficult, but perhaps not impossible. Initially, it row (or broaden) the list of genes of interest. This, in fact, is one goal of the Brain Molecular Anatomy Project (BMAP) (57). In addition to cataloging the transcripts in the brain, it would be helpful to look at the reactions of isolated popula- tions of neurons or glia to specific signals or environmental alterations—e. Some responses may be of a global nature—increases or decreases in energy metabolism or protein biosynthesis—while others may be quite specific to the cell studied or the agent administered. For example, if it were possible to examine the responses of isolated raphe neurons to SSRI treatment in vitro, it might be easier to recognize similar responses in tissue samples. Bear in mind, however, that the majority of arrayed genes discovered by sequencing the human genome and large col- lections of cDNAs are of unknown function. The clustering algorithm has sorted the tifs may hint at the function of some gene products (58), genes that were studied in a series of experiments according to but the role of most will remain an enigma. Byconvention, redindi- studies may help solve this problem because genes with simi- cates an increase from the standard used, and green a decrease. The collections of genes that are moving up or down in parallel lar expression profiles often have related jobs. The combination of 296 Neuropsychopharmacology: The Fifth Generation of Progress two-dimensional gel electrophoresis, ultrasensitive detection method used, side of the brain sampled, specimen weight, methods, and mass spectroscopic analyses will permit re- microdissection procedure and cells selected, RNA extrac- searchers to map protein species to specific organelles or tion method and quality, and labeling method are all essen- macromolecular complexes (59). It would be useful to have quality scores ber that most proteins in a cell do not exist or act in isola- for some of these—e. Components of metabolic pathways and regulatory Short of a quality score for diagnosis, a detailed description cascades reside in protein communities.

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