Ruben D Baler

• Ph.D. Molecular Biology
• Researcher at National Institute on Drug Abuse, National Institutes of Health

The tobacco epidemic has been one of the biggest public health threats, and smoking is one of the world's largest preventable causes of premature death. An estimated 15.4% of all deaths in the world are attributable to tobacco smoking. The present review aims to describe addiction to tobacco smoking and vaping. Tobacco and vaping devices contain ni...

The persistent difficulty in conceptualizing the relationship between addictive and other mental disorders stands out among the many challenges faced by the field of Psychiatry. The different philosophies and schools of thought about, and the sheer complexity of these highly prevalent clinical conditions make progress inherently difficult, not to m...

Consumed by an estimated 2.5% of the world’s population, cannabis is the most popular illicit drug. Depending on age of onset, frequency, duration, and other variables, cannabis use can be associated with a broad spectrum of medical consequences, the range of which mirrors the physiological ubiquity and versatility of the endocannabinoid system. Im...

Informing physicians who prescribe opioids about opioid-linked deaths in their practice reduces future opioid prescribing.

The World Association on Dual Disorders (WADD), the World Psychiatric Association (WPA) (Section on Dual Disorders), and the Sociedad Española de Patología Dual (SEPD) have joined forces to clarify that: Addiction is a mental disorder, not a voluntary, self-indulgent act. • Dual disorder is a term applied to people who have an addictive disorder an...

Behaviours such as eating, copulating, defending oneself or taking addictive drugs begin with a motivation to initiate the behaviour. Both this motivational drive and the behaviours that follow are influenced by past and present experience with the reinforcing stimuli (such as drugs or energy-rich foods) that increase the likelihood and/or strength...

• Dual disorders is a term applied to people who have an addictive disorder and another co-occurring mental illness. It is related to interacting neurobiological and environmental processes involved in behaviors of substance and non-substance related disorders. Nobody chooses to become addicted, and addictions do not develop in “weak” people or tho...

Cannabis enables and enhances the subjective sense of well-being by stimulating the endocannabinoid system (ECS), which plays a key role in modulating the response to stress, reward, and their interactions. However, over time, repeated activation of the ECS by cannabis can trigger neuroadaptations that may impair the sensitivity to stress and rewar...

The use of Positron emission tomography (PET) to study the effects of acute and chronic alcohol on the human brain has enhanced our understanding of the mechanisms underlying alcohol's rewarding effects, the neuroadaptations from chronic exposure that contribute to tolerance and withdrawal, and the changes in fronto-striatal circuits that lead to l...

With a political debate about the potential risks and benefits of cannabis use as a backdrop, the wave of legalization and liberalization initiatives continues to spread. Four states (Colorado, Washington, Oregon, and Alaska) and the District of Columbia have passed laws that legalized cannabis for recreational use by adults, and 23 others plus the...

Balancing behaviors that provide a reward NOW versus behaviors that provide an advantage LATER is critical for survival. We propose a model in which dopamine (DA) can favor NOW processes through phasic signaling in reward circuits or LATER processes through tonic signaling in control circuits. At the same time, through its modulation of the orbitof...

It is widely believed that substance use disorder (SUD) results from both pre-alterations (vulnerability) and/or post-alterations (drug effects) on cortico-striatal circuits. These circuits are essential for cognitive control, motivation, reward dependent learning, and emotional processing. As such, dysfunctions in cortico-striatal circuits are tho...

The prevention and treatment of substance use disorders (SUD), including addiction would benefit from having better biomarkers for the classification of patients into categories that are reproducible and have predictive validity. Direct measurement of drugs or their metabolites in various body fluids constitutes a clinically valuable biomarker, but...

Convergent neurobiological studies of value-based learning, and the computational models that flow from them, have long pointed to the existence of a reciprocal relationship between dopamine and beliefs. The complex interactions between the pharmacological (reinforcing) effects of addictive drugs and the conditioned responses (expectations) engende...

As marijuana use becomes legal in some states, the dominant public opinion is that marijuana is a harmless source of mood alteration. Although the harms associated with marijuana use have not been well studied, enough information is available to cause concern.

Modern imaging techniques have allowed researchers to noninvasively peer into the human brain and investigate, among many other things, the acute effects and long-term consequences of drug abuse. Here, we review the most commonly used and some emerging imaging techniques in addiction research, explain how the various techniques generate their chara...

Until very recently addiction-research was limited by existing tools and strategies that were inadequate for studying the inherent complexity at each of the different phenomenological levels. However, powerful new tools (e.g., optogenetics and designer drug receptors) and high throughput protocols are starting to give researchers the potential to s...

Nearly 15 million Americans 12 years of age and older were dependent on or abused alcohol in 2010.¹ The high prevalence of problem alcohol use worldwide has been estimated to cause 2.5 million deaths each year,² not to mention the exorbitant costs associated with excess morbidity³ and loss of productivity.⁴ The chronic and relapsing nature of alcoh...

Our brains are hardwired to respond and seek immediate rewards. Thus, it is not surprising that many people overeat, which in some can result in obesity, whereas others take drugs, which in some can result in addiction. Though food intake and body weight are under homeostatic regulation, when highly palatable food is available, the ability to resis...

Drug addiction and obesity appear to share several properties. Both can be defined as disorders in which the saliency of a specific type of reward (food or drug) becomes exaggerated relative to, and at the expense of others rewards. Both drugs and food have powerful reinforcing effects, which are in part mediated by abrupt dopamine increases in the...

Drug addiction and obesity appear to share several properties. Both can be defined as disorders in which the saliency of a specific type of reward (food or drug) becomes exaggerated relative to, and at the expense of others rewards. Both drugs and food have powerful reinforcing effects, which are in part mediated by abrupt dopamine increases in the...

The traffic light turns from green to yellow. With just one car between you and the intersection, your brain sprints into action, calculating distances and relative velocities; checking for hurried pedestrians; simulating the mental processes of the driver in front of you; and readying every muscle in preparation for a split-second decision that co...

Both drug addiction and obesity can be defined as disorders in which the saliency value of one type of reward (drugs and food, respectively) becomes abnormally enhanced relative to, and at the expense of others. This model is consistent with the fact that both drugs and food have powerful reinforcing effects-partly mediated by dopamine increases in...

The stubbornly high incidence of new HIV infections belies the overwhelming evidence showing that sustained highly active antiretroviral therapy (HAART) has the power to dramatically reduce the spread of HIV infection and forever change the face of this devastating epidemic. One of the main contributors to this public health paradox is the ongoing...

Scientific advances in the field of addiction have forever debunked the notion that addiction reflects a character flaw under voluntary control, demonstrating instead that it is a bona fide disease of the brain. The aim of this review is to go beyond this consensus understanding and explore the most current evidence regarding the vast number of gen...

As I sit to compose this plea I can't say with any amount of certainty that my son is alive. My son discovered narcotics at the age of 13. He experienced a severe orthopedic sports injury. There seems to be nothing that can induce him to stop for any appreciable length of time. I had him arrested May of 2006 for heroin possession and identity fraud...

The ability to resist the urge to eat requires the proper functioning of neuronal circuits involved in top-down control to oppose the conditioned responses that predict reward from eating the food and the desire to eat the food. Imaging studies show that obese subjects might have impairments in dopaminergic pathways that regulate neuronal systems a...

While it is well known that osmotic stimulation induces the expression of Fos family members in the supraoptic nucleus (SON), it is unclear whether the induced protein products are involved in the regulation of the gene transcription of arginine vasopressin (AVP). In the present study, we examined the in vivo correlation between changes in AVP gene...

Based on brain imaging findings, we present a model according to which addiction emerges as an imbalance in the information processing and integration among various brain circuits and functions. The dysfunctions reflect (a) decreased sensitivity of reward circuits, (b) enhanced sensitivity of memory circuits to conditioned expectations to drugs and...

The use of stimulant drugs for the treatment of children with attention-deficit hyperactivity disorder (ADHD) is one of the most widespread pharmacological interventions in child psychiatry and behavioral pediatrics. This treatment is well grounded on controlled studies showing efficacy of low oral doses of methylphenidate and amphetamine in reduci...

The discovery of dopamine in 1957-8 was one of the seminal events in the development of modern neuroscience, and has been extremely important for the development of modern therapies of neurological and psychiatric disorders. Dopamine has a fundamental role in almost all aspects of behavior — from motor control to mood regulation, cognition and addi...

Receptor heteromers constitute a new area of research that is reshaping our thinking about biochemistry, cell biology, pharmacology and drug discovery. In this commentary, we recommend clear definitions that should facilitate both information exchange and research on this growing class of transmembrane signal transduction units and their complex pr...

Molecular Psychiatry publishes work aimed at elucidating biological mechanisms underlying psychiatric disorders and their treatment

The pineal gland plays an essential role in vertebrate chronobiology by converting time into a hormonal signal, melatonin, which is always elevated at night. Here we have analyzed the rodent pineal transcriptome using Affymetrix GeneChip(R) technology to obtain a more complete description of pineal cell biology. The effort revealed that 604 genes (...

Dopamine is involved in drug reinforcement but its role in addiction is less clear. Here we describe PET imaging studies that investigate dopamine's involvement in drug abuse in the human brain. In humans the reinforcing effects of drugs are associated with large and fast increases in extracellular dopamine, which mimic those induced by physiologic...

Smoking is the leading cause of preventable illness in the world today. Prenatal cigarette smoke exposure (PCSE) is a particularly insidious form because so many of its associated health effects befall the unborn child and produce behavioural outcomes that manifest themselves only years later. Among these are the associations between PCSE and condu...

Arylalkylamine N-acetyltransferase (Aanat) is the penultimate enzyme in the serotonin-N-acetylserotonin-melatonin pathway. It is nearly exclusively expressed in the pineal gland and the retina. A marked rhythm of Aanat gene expression in the rat pineal is mediated by cyclic AMP response elements located in the promoter and first intron. Intron 1 al...

The nature of addiction is often debated along moral versus biological lines. However, recent advances in neuroscience offer insights that might help bridge the gap between these opposing views. Current evidence shows that most drugs of abuse exert their initial reinforcing effects by inducing dopamine surges in limbic regions, affecting other neur...

The ELOVL3 protein is a very long-chain fatty acid elongase found in liver, skin, and brown adipose tissues. Circadian expression of the Elovl3 gene in the liver is perturbed in mutant CLOCK mice but persists in mice with severe hepatic dysfunction. A reliance on an intact clock, combined with the refractoriness to liver decompensation and the find...

The interaction between the BMAL1/CLOCK transcription factor and the cis-acting element known as the E-Box is a key event in the regulation of clock and clock-controlled gene expression. However, the fact that the ubiquitous E-Box element sits at the center of a presumably highly discriminating control system generates a certain level of puzzlement...

X-irradialed (250 rad), cyelophosphamide-treated or ATx A miceinjected with syngeneic trinitrophenylated spleen cells (TNP-SC) and footpad challenged with syngencic lymphoblasts generated delayed-type hypersensitivity (DTH) responses 24, 48 and 72 h after challenge. The syngeneic-DTH (syn-DTM) response was mediated by Lyt-l+ cells and suppressed wi...

The act of feeding in mammals can generate such powerful cues for peripheral organs that, under certain conditions, they can override the entraining signals coming from the clock in the brain. Restricting the feeding time to the inactivity period, for example, can completely and quickly reverse the rhythms of gene expression in the liver. This mani...

In non-mammalian vertebrates, the pineal gland is photoreceptive and contains an intrinsic circadian oscillator that drives rhythmic production and secretion of melatonin. These features require an accurate spatiotemporal expression of an array of specific genes in the pineal gland. Among these is the arylalkylamine N-acetyltransferase, a key enzym...

NGFI-B (Nur77/Nr4a1) is a member of a nuclear steroid receptor subgroup that includes the related factors Nurr1 (Nr4a2) and NOR-1 (Nr4a3). These proteins do not have recognized ligands and in fact function independently as orphan receptors with transcriptional regulatory activity. In the present study, expression of the NGFI-B gene in the rat pinea...

Pineal function is defined by a set of very narrowly expressed genes that encode proteins required for photoperiodic transduction and rhythmic melatonin secretion. One of these proteins is serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT), which controls the daily rhythm in melatonin production. Here, pineal-specific express...

The mammalian circadian timing system is composed of countless cell oscillators distributed throughout the body and central pacemakers regulating temporal physiology and behavior. Peripheral clocks display circadian rhythms in gene expression both in vivo and in culture. We examined the biosynthesis of phospholipids as well as the expression of the...

Life on earth has evolved on a photic carousel, spinning through alternating periods of light and darkness. This playful image belies the fact that only those organisms that learned how to benefit from the recurring features in their environment were allowed to ride on. This selection process has engendered many daily rhythms in our biosphere, most...

The E-Box is a widely used DNA control element. Despite its brevity and broad distribution the E-Box is a remarkably versatile sequence that affects many different genetic programs, including proliferation, differentiation, tissue-specific responses, and cell death. The circadian clock is one of the latest pathways shown to employ this element. In...

The pineal gland is a major output of the endogenous vertebrate circadian clock, with melatonin serving as the output signal. In many species, elevated nocturnal melatonin production is associated with changes in pineal gene expression. In the current study, cDNA array analysis was used in an attempt to identify additional genes that exhibit day/ni...

In spite of its apparent weakness as a clock model, the budding yeast has spawned a technique that has revolutionized our ability to study specific protein-protein interactions like those at the core of the molecular timekeeping mechanisms. Here, the author will summarize the evolution, power, and limitations of this technique and highlight its pot...

Fos-related antigen 2 (Fra-2) is a member of the Fos family of immediate-early genes, most of which are rapidly induced by second messengers. All members of this family act by binding to AP-1 sites as heterodimeric complexes with other proteins. However, each appears to have a distinct role. The role and biology of Fra-2 are less well understood th...

The rat arylalkylamine N-acetyltransferase (AA-NAT) gene encodes the key enzyme whose rhythmic expression drives the nocturnal production of melatonin. It is of interest that this enzyme is expressed virtually exclusively in two phylogenetically related tissues: retinal photoreceptors, which harbor an endogenous clock, and pinealocytes which, in hi...

The bacterial gene chloramphenicol acetyltransferase (CAT) is a widely used reporter in both in-vitro and in-vivo studies of genetic regulation. We have recently generated novel rat transgenic lines carrying an arylalkylamine N-acetyltransferase (AA-NAT) promoter-reporter construct in which CAT (with associated SV40 small-t antigen sequence) is the...

Extensive studies have established that light regulates c-fos gene expression in the suprachiasmatic nucleus, the site of an endogenous circadian clock, but relatively little is known about the expression of genes structurally related to c-fos, including fra-1, fra-2 and fosB. We analysed the photic and temporal regulation of these genes at the mes...

The daily rhythm in the activity of arylalkylamine N-acetyltransferase (AA-NAT) controls the rhythm in melatonin synthesis in the pineal gland. In the rat, transcriptional regulatory mechanisms play a major role in determining the observed pattern of AA-NAT gene expression. Remarkably, high levels of AA-NAT transcripts can only be detected in the n...

The arylalkylamine N-acetyltransferase (AA-NAT) gene is strongly expressed in the rat primarily in the pineal gland; low levels of expression are also found in the retina. AA-NAT catalyzes the key regulatory step controlling rhythmic melatonin output: the acetylation of serotonin. In the rat, the AA-NAT gene is expressed at night. This is controlle...

Abstract : The arylalkylamine N-acetyltransferase (AA-NAT) gene is strongly expressed in the rat primarily in the pineal gland ; low levels of expression are also found in the retina. AA-NAT catalyzes the key regulatory step controlling rhythmic melatonin output : the acetylation of serotonin. In the rat, the AA-NAT gene is expressed at night. This...

A 10-100-fold rhythm in the activity of arylalkylamine N-acetyltransferase (AA-NAT; EC 2.3.1.87) controls the rhythm in melatonin synthesis in the pineal gland. In some mammals, including the rat, the high nocturnal level of AA-NAT activity is preceded by an approximately 100-fold increase in AA-NAT mRNA. The increase in AA-NAT mRNA is generated by...

A 10-100-fold rhythm in the activity of arylalkylamine N-acetyltransferase (AA-NAT; EC 2.3.1.87) controls the rhythm in melatonin synthesis in the pineal gland. In some mammals, including the rat, the high nocturnal level of AA-NAT activity is preceded by an ∼100-fold increase in AA-NAT mRNA. The increase in AA-NAT mRNA is generated by norepinephri...

A remarkably constant feature of vertebrate physiology is a daily rhythm of melatonin in the circulation, which serves as the hormonal signal of the daily light/dark cycle: melatonin levels are always elevated at night. The biochemical basis of this hormonal rhythm is one of the enzymes involved in melatonin synthesis in the pineal gland-the melato...

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In vertebrates, the circadian rhythm in the activity of serotonin N-acetyltransferase [arylalkylamine N-acetyltransferase (AA-NAT); EC 2.3.1.87] drives the daily rhythm in circulating melatonin. We have discovered that expression of the AA-NAT gene in the rat pineal gland is essentially turned off during the day and turned on at night, resulting in...

Heat and other environmental insults (stress) cause unfolding of proteins, triggering the activation of heat shock transcription factor HSF (HSF1 in vertebrates) that, in higher eukaryotes, involves trimerization of the factor and acquisition of heat shock element (HSE) DNA-binding ability. Interaction of activated HSF1 with HSEs in promoters of ge...

The nuclear orphan receptor RZRbeta is highly expressed in the rat pineal gland. Recent studies proposed that melatonin, the pineal hormone which regulates a wide variety of circadian-linked phenomena, may be the natural ligand of this receptor. These provocative reports prompted us to learn more about RZRbeta and how it might function in circadian...

Heat and other environmental insults (stress) cause unfolding of proteins, triggering the activation of heat shock transcription factor HSF (HSF 1 in vertebrates) that, in higher eukaryotes, involves trimerization of the factor and acquisition of heat shock element (HSE) DNA-binding ability. Interaction of activated HSF1 with HSEs in promoters of g...

Large circadian changes in the activity of serotonin N-acetyltransferase (AA-NAT) drive the daily rhythm in circulating melatonin in vertebrates. The recent cloning of AA-NAT reveals it is novel and representa a new family within an acetyltransferase superfamily. The enzyme is 23 kDa and has multiple putative phoaphorylation sites. There is a > 150...

Pineal serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, or AA-NAT) generates the large circadian rhythm in melatonin, the hormone that coordinates daily and seasonal physiology in some mammals. Complementary DNA encoding ovine AA-NAT was cloned. The abundance of AA-NAT messenger RNA (mRNA) during the day was high in the ovine pine...

Physiological changes in Fos-like immunoreactivity in the rat pineal gland are shown here to be due primarily to changes in a 42/46-kDa Fos-related antigen (Fra). Studies are presented that indicate this 42/46-kDa Fra is Fra-2, a poorly understood member of the Fos family of transcription factors. Both Fra-2 mRNA and protein are absent during the d...

Heat stress regulation of human heat shock genes is mediated by human heat shock transcription factor hHSF1, which contains three 4-3 hydrophobic repeats (LZ1 to LZ3). In unstressed human cells (37 degrees C), hHSF1 appears to be in an inactive, monomeric state that may be maintained through intramolecular interactions stabilized by transient inter...

Heat stress regulation of human heat shock genes is mediated by human heat shock transcription factor hHSF1, which contains three 4-3 hydrophobic repeats (LZ1 to LZ3). In unstressed human cells (37 degrees C), hHSF1 appears to be in an inactive, monomeric state that may be maintained through intramolecular interactions stabilized by transient inter...

Transcriptional activity of heat shock (hsp) genes is controlled by a heat-activated, group-specific transcription factor(s) recognizing arrays of inverted repeats of the element NGAAN. To date genes for two human factors, HSF1 and HSF2, have been isolated. To define their properties as well as the changes they undergo during heat stress activation...

Synergistic activation of transcription by Drosophila segmentation genes in tissue culture cells provides a model with which to study combinatorial regulation. We examined the synergistic activation of an engrailed-derived promoter by the pair-rule proteins paired (PRD) and fushi tarazu (FTZ). Synergistic activation by PRD requires regions of the h...

Transcriptional activity of heat shock (hsp) genes is controlled by a heat-activated, group-specific transcription factor(s) recognizing arrays of inverted repeats of the element NGAAN. To date genes for two human factors, HSF1 and HSF2, have been isolated. To define their properties as well as the changes they undergo during heat stress activation...

Synergistic activation of transcription by Drosophila segmentation genes in tissue culture cells provides a model with which to study combinatorial regulation. We examined the synergistic activation of an engrailed-derived promoter by the pair-rule proteins paired (PRD) and fushi tarazu (FTZ). Synergistic activation by PRD requires regions of the h...

Heat shock genes encode proteins (hsp's) that play important structural roles under normal circumstances and are essential to the cells' ability to survive environmental insults. Evidence is presented herein that transcriptional regulation of hsp gene expression is linked with the regulation of overall protein synthesis as well as with the accumula...

Heat shock genes encode proteins (hsp's) that play important structural roles under normal circumstances and are essential to the ceils' ability to survive environmental insults. Evidence is presented herein that transcriptional regulation of hsp gene expression is linked with the regulation of overall protein synthesis as well as with the accumula...

We have studied the cellular basis for differential expression of the Ly-6A/E alloantigen on T cells obtained from mice of the Ly-6 a (10–20% Ly-6A/E +) and Ly-6 b (50–60% Ly-6A/E +) haplotypes. During T-cell ontogeny only a small fraction (< 12 %) of thymocytes expressed Ly-6A/E. By 4 weeks of age adult levels of Ly-6A/E bearing lymphocytes were s...

Heat shock protein (hsp) genes are typically silent and are activated by various stresses including heat. As a first step toward understanding this activation event, a human factor, referred to here as human heat shock transcription factor (human HTF), has been purified approximately 14,000-fold from extracts of heat-treated HeLa cells by means of...