A Single Dose of Lysergic Acid Diethylamide Influences Gene Expression Patterns within the Mammalian Brain

Abstract

Hallucinogenic drugs such as lysergic acid diethylamide (LSD) have profound effects on humans including INTRODUCTIONLysergic acid diethylamide (LSD) is an hallucinogenic drug that transiently but powerfully alters human perception, behavior, and mood at extremely low doses. Certain aspects of the behavior elicited by acute doses of LSD closely resemble symptoms of mental disorders such as schizophrenia (Breier 1995). Despite extensive research over the past four decades, the mechanism of action of hallucinogenic drugs still largely remains a mystery. The behavioral effects of LSD are believed to arise in part from agonist activity at the 5-HT 2A , 5-HT 2C , and 5-HT 1A receptor subtypes (Burris et al. 1991; KrebsThomson et al. 1998;Titeler et al. 1988), but if, and how, these interactions affect cognitive functions remains unknown. In addition to actions at serotonin receptors, LSD has high affinity for dopamine receptors and has been shown to act as an agonist at these receptors (Giacomelli et al. 1998;Watts et al. 1995). Because LSD is a unique ligand that can simultaneously bind to serotonin and dopamine receptor subtypes implicated in both normal and abnormal human behaviors, it is an excellent tool for probing the biochemical basis for behavior.Simply increasing brain levels of serotonin, however, does not produce hallucinogenic effects. Recent work has demonstrated that while LSD binds to the same re- NO . 5 LSD-influenced Gene Expression 635 ceptor sites as the endogenous ligand serotonin, it has the capacity to activate different intracellular signaling cascades (Backstrom et al. 1999). Because intracellular signaling cascades influence gene expression, LSDinduced signaling events within cells may inappropriately alter gene expression, which in turn may lead to changes in the physiological status of the neurons, ultimately altering the processes of cognition. Certain behavioral effects of LSD resemble paranoid schizophrenia in humans. This particular subset of mood alterations occurs within the "second phase . . . of the LSD experience" as defined by Freedman, and may be specific for LSD (Freedman 1984). These delayed "second phase" effects could result from transient changes in gene expression. Thus, identifying and characterizing these genes could prove to be important in understanding mechanisms underlying how hallucinogens such as LSD alter behavior. In addition, understanding these mechanisms may lead to the identification of novel therapeutic targets for treatment of mental disorders.We took a broad approach to investigating and identifying genes that are altered by an acute dose of LSD in the mammalian brain. First, we investigated the expression of the mRNAs of the 5-HT receptor subtypes thought to mediate hallucinogenic effects in animal models (5-HT 1A,2A,2C ), as well as, specific gene expression of immediate early genes predicted to be affected by LSD. Next, we performed a DNA microarray screen to identify gene expression influenced by LSD at a more global level. For each gene identified,...

Homers regulate drug-induced neuroplasticity: Implications for addiction

“…145,146]. Homer1a or Ania-3 mRNA expression is increased within PFC and/or NAC upon acute injection of psychomotor stimulants [102,[159][160], the hallucinogen LSD [161,162], nicotine [163], and the dissociative anesthetic phencyclidine [164]. While the repeated administration of cocaine or nicotine induces a tolerance in the capacity of the drug to elevate NAC Homer1a levels [160,163], the capacity of methamphetamine to elevate mRNA levels persists within PFC with repeated drug treatment [159].…”

Homer Isoforms Differentially Regulate Cocaine-Induced Neuroplasticity

“…First described for acute cocaine (Brakeman et al, 1997), a growing number of studies demonstrate an enhancement within corticolimbic structures in the expression of mRNA encoding short Homer isoforms by acute exposure to psychoactive drugs Cochran et al, 2002;Fujiyama et al, 2003;Nichols et al, 2003;Nichols and Sanders-Bush, 2002;Polese et al, 2002). Although there is some evidence that the capacity of drugs of abuse to increase short Homer isoform expression is enduring (Ammon et al, 2003;Cochran et al, 2002) or persists throughout repeated drug administration (Ammon et al, 2003;Fujiyama et al, 2003), behavioral sensitization to methamphetamine is not coincident with an altered capacity of this drug to elevate the expression of short Homer isoforms (Fujiyama et al, 2003).…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Interestingly, the specific 5HT 2A receptor activation caused by hallucinogens seems to be of key importance in producing neuroplasticity. Hallucinogens Drug-Induced Neuroplasticity such as LSD induce brain-region dependent mRNA expression of various immediate early genes, such as c-Fos, arc, and homer1a splice isoform ania3 (Nichols and Sanders-Bush, 2002), that influence regulation of gene expression and synaptic responses, whereas DOI has been shown to produce changes in dendritic spine morphology on cortical neurons . Chronic LSD administration to rats causes a persistent increase in synthesis and turnover of 5-HT as well as downregulation of cortical 5HT 2A receptors (Diaz and Huttunen, 1971;Lee and Geyer, 1980;Gresch et al, 2005), and a 2-week LSD treatment followed by 14 days of abstinence still showed an augmented 5-HT level in the midbrain and cerebral cortex (Peters and Tang, 1977).…”