Current Psychopharmacology - Volume 1, Issue 4, 2012

Antipsychotic medications remain the first-line treatment for several psychiatric disorders. These compounds, classified as typical or atypical antipsychotics, have well-established neurotransmitter receptor binding profiles; however, long-term therapeutic benefits likely result from molecular changes in the brain occurring downstream from receptor blockade. In the past decade, researchers have utilized high-throughput gene expression approaches to study post-receptor mechanisms of antipsychotic drug function and have implicated several systems, including synaptic- and ubiquitinationrelated pathways, in the mechanisms of actions of antipsychotic drugs. In recent years, additional transcriptome data from updated and improved microarray platforms have been published. The most widely studied antipsychotics have been haloperidol, olanzapine and clozapine, representing both typical and atypical drugs, and several studies have highlighted both the similarities and differences in the transcriptome profiles associated with both classes of drugs. Furthermore, some studies have additionally investigated the effects of antipsychotic drugs in combination with psychostimulant exposure to rodents, in order to identify convergent gene expression alterations. This review will summarize recent transcriptomewide studies that have investigated differential gene expression in response to antipsychotic drug treatment in rodent brain, highlighting the most reproducible findings across studies. Emerging evidence has also suggested that epigenetic mechanisms of gene regulation are associated with antipsychotic drug action; this will also be reviewed herein. Examination of transcriptomic profiles of antipsychotic drug action should reveal key information regarding the beneficial mechanisms associated with drug treatment and may reveal gene ‘signatures’ for known drugs, which could be used to develop improved therapeutics.

Over the last decade, major depressive disorder (MDD) has attracted great attention in the Western societies for mainly two reasons. First, epidemiological studies demonstrate a steady increase in the number of affected patients so that MDD will be one of the most disabling conditions worldwide in the near future. Second, preclinical and clinical science has early recognized the need for elaborating the cause and progression of MDD in order to improve treatment strategies. Progress in developing advanced technologies such as DNA microarrays and next-generation sequencing has allowed for rapidly acquiring detailed biochemical information about DNA polymorphisms and transcriptome profiles. These studies collectively show profound biochemical changes in affected individuals, and animal studies partly corroborate or complement the alterations identified in patients. In this review, we survey transcriptional changes in the course of MDD and the effects of antidepressant drugs on multiple disease-related transcriptional pathways. The combination of both potentially unravels additional mechanisms of disease aetiology which eventually represents a bottom-up approach for the discovery of newly-acting antidepressant drugs.

Sensitivity to ethanol intoxication, propensity to drink ethanol and vulnerability to develop alcoholism are all influenced by genetic factors. Conversely, exposure to ethanol or subsequent withdrawal produce gene expression changes, which, in combination with environmental variables, may participate in the emergence of compulsive drinking and relapse. The present review offers an integrated perspective on brain gene expression profiling in rodent models of predisposition to differential ethanol sensitivity or consumption, in rats and mice subjected to acute or chronic ethanol exposure, as well as in human alcoholics. The functional categories over-represented among differentially expressed genes suggest that the transcriptional effects of chronic ethanol consumption contribute to the neuroplasticity and neurotoxicity characteristic of alcoholism. Importantly, ethanol produces distinct transcriptional changes within the different brain regions involved in intoxication, reinforcement and addiction. Special emphasis is put on recent profiling studies that have provided some insights into the molecular mechanisms potentially mediating genome-wide regulation of gene expression by ethanol. In particular, current evidence for a role of transcription factors, chromatin remodeling and microRNAs in coordinating the expression of large sets of genes in animals predisposed to excessive ethanol drinking or exposed to protracted abstinence, as well as in human alcoholics, is presented. Finally, studies that have compared ethanol with other drugs of abuse have highlighted common gene expression patterns that may play a central role in drug addiction. The availability of novel technologies and a focus on mechanistic approaches are shaping the future of ethanol transcriptomics.

The molecular mechanisms underlying neuroprotective effect of valproate, a widely used antiepileptic and mood stabilizing drug, are not clearly understood. The acute biochemical effects of valproate on neurotransmitter systems and ion channels do not provide simple mechanistic interpretation of its long-term neuroprotective action. The latter is instead considered to result from drug induced gene expression changes. To this end, expression profiles of mouse and rat brain, and cultured rat cortical neurons and human neuroblastoma cells following valproate treatment have previously been analyzed. The present review aims to examine if there exists converging evidence of genes and pathways in valproate action. A synthesis of the available transcriptomic data revealed enrichment of processes related to cell death/apoptosis, learning or memory, and antigen processing and presentation of peptide antigen via MHC class I in valproate regulated genes. An independent set of valproate regulated genes described in diverse non-transcriptomic studies also enriched these processes. Further, previously identified differentially expressed genes in multiple transcriptomic studies in epilepsy and bipolar disorder showed enrichment of apoptosis. Literature search also revealed that several apoptotic pathways targeting drugs possess therapeutic potential in epilepsy or bipolar disorder. The present analysis therefore implicates apoptosis in the neuroprotective mechanism of valproate. This is consistent with a recently described interaction network analysis of valproate responsive transcriptome, genes and enzymes reported in a variety of cell/tissue types in different organisms.

In the present review we integrated findings from microarray analyses of anticonvulsant treatment, discussing the replicability of the findings and their corroboration with data obtained from patients and with information from other fields of study. We further relate to the duality of several antiepileptic drugs exhibiting both anticonvulsant and moodstabilizing effects in the treatment of epilepsy and bipolar disorder, respectively.

Cocaine, like most other drugs of abuse, exerts long lasting changes in gene expression in the reward circuitry of the brain. This resultant remodelled reward circuitry is considered to underlie drug addiction and relapse. In recent years, genome-wide expression studies and epigenomic analysis of the affected regions in the reward circuitry have identified molecular changes associated with the structural remodeling of the circuitry. In particular, application of gene expression microarray and chromatin immunoprecipitation (ChIP) coupled to microarray (ChIP-chip) or sequencing (ChIP-seq) has provided unprecedented insights into the neural and behavioral adaptations in nucleus accumbens (NAc), the critical substrate of the reward circuitry, in cocaine addiction. Genome level expression profiling and epigenomic analysis leading to the recent advances in our understanding of cocaine-induced neural and behavioral adaptations are reviewed here. We examine the convergence of transcriptomic and epigenomic evidence, and discuss about emerging drug target candidates in cocaine-addiction.

Ethanol is one of the most common teratogens, causing a broad range of physiological, neuronal and behavioral problems, named as fetal alcohol spectrum disorder (FASD). Expression of various molecules involved in apoptosis, signaling pathways, and innate immune system, has been shown to change upon acute ethanol exposure. Gene expression profiling has been attempted by several groups, but comprehensive understanding is required, considering different experimental protocols used by each group. In this review, we summarize previously published reports of transcriptome analyses and our own previously unpublished results of cDNA microarray, according to developmental stages of brain and discuss about what we have learned from the results.

The importance of omega-3 poly-unsaturated fatty acids (PUFAs) to improve several medical conditions is well recognized. More recently, these agents, because of their role of stabilization of neuronal membranes, have been considered in the treatment of various psychiatric disorders. The aim of this review is to provide a complete account of the empirical evidences of efficacy and safety for eicosapentaenoic acid (EPA), docosaexaenoic acid (DHA) and other less used PUFAs in the management of mental illness. There is little evidence to support the use of omega-3 fatty acids in the treatment of schizophrenia and of conditions characterized by high level of impulsivity and aggression. The most convincing findings are in favour of the use of PUFAs for mood disorders, especially unipolar and bipolar depression (but not mania). Concerning ADHD, trials are characterized by considerable heterogeneity in methods and omega-3 fatty acids supplementation exhibits modest benefits compared with traditional pharmacotherapy. On the basis of available data, omega-3 PUFAs cannot be unequivocally recommended as a monotherapy or adjunctive-therapy in any mental disorder. Although these compounds represent a novel and attractive modality of treatment, also considering good tolerability and safety, further studies are required to confirm omega-3 fatty acids supplementation as an effective intervention in psychiatric disorders.

Pathological Gambling (PG) is characterized by “the failure to resist gambling impulses despite severe personal, family or occupational consequences”. PG estimated prevalence ranges between 0.4% and 3.4% within the adult population. PG seems to be more common in patients with Parkinson's disease (PD) than in the general population. In the past few years, PG has been reported as a side effect of dopamine agonist (DA) therapy used in PD. This association has aroused great interest for the dramatic impact PG has on patients' quality of life. Management of PG in patients with PD could be demanding. It is based on patient and caregiver education, modification of dopamine replacement therapy, and in some cases psychoactive drug administration. This review describes possible pathogenesis of PG associated with DA therapy, available pharmacological treatments and management approaches that may increase the likelihood of satisfactory treatment outcomes in PD patients.