Bidirectional translational research: Progress in understanding addictive diseases

Abstract

The focus of this review is primarily on recent developments in bidirectional translational research on the addictions, within the Laboratory of the Biology of Addictive Diseases at The Rockefeller University. This review is subdivided into major interacting aspects, including: a) Investigation of neurobiological and molecular adaptations (e.g., in genes for the opioid receptors or endogenous neuropeptides) in response to cocaine or opiates, administered under laboratory conditions modeling chronic patterns of human self-exposure (e.g., chronic escalating "binge"). b) The impact of such drug exposure on the hypothalamic-pituitary-adrenal (HPA) axis and interacting neuropeptidergic systems (e.g., opioid, orexin and vasopressin). c) Molecular genetic association studies using candidate gene and whole genome approaches, to define particular systems involved in vulnerability to develop specific addictions, and response to pharmacotherapy. d) Neuroendocrine challenge studies in normal volunteers and current addictive disease patients along with former addicts in treatment, to investigate differential pharmacodynamics and responsiveness of molecular targets, in particular those also investigated in the experimental and molecular genetic approaches described above. KeywordsCocaine; heroin; methadone; opioid; dynorphin; beta-endorphin; addiction; mu-opioid; kappaopioid; molecular genetics; HPA axis As the Laboratory of the Biology of Addictive Diseases at The Rockefeller University, and as an NIH-NIDA P60 Research Center, we are honored and delighted to join in the celebration of the 35 th Anniversary of NIDA. Our report herein will focus on some accomplishments of our scientists over the last five years, since we were privileged also to write a scientific tribute to the 30th Anniversary of NIDA . Selected topics only will be covered herein, primarily ones of interest both from the standpoint of basic science findings, with potential implications not only for the addictive diseases, but also for the molecular neurobiological mechanisms underlying many other human disorders, including Parkinsonism, Alzheimer's and Huntington's disease, as well as many which further elucidate normal physiology. In addition, our studies, of course, have significant implications for specific addictive diseases.

Clonidine Maintenance Prolongs Opioid Abstinence and Decouples Stress From Craving in Daily Life: A Randomized Controlled Trial With Ecological Momentary Assessment

“…The ecological momentary assessment results allow this clinical trial to have a bidirectional translational impact (19, 40). First, for clinicians, the ecological momentary assessment results identify the subpopulation of patients who would benefit most from clonidine maintenance: those who are susceptible to stress-induced lapses and those who have persistent though moderate stress.…”

Next generation effects of female adolescent morphine exposure

“…However, in addition to the well-known effects on pain transmission and reward processes, endogenous opioids are critical regulators of the neuroendocrine axis. Exposure to opiates can alter both the hypothalamic–pituitary–gonadal (HPG) and the HPA axes (Morley, 1981; Little and Kuhn, 1995; Zhou et al, 1999; Kreek et al, 2009). Modifications in either of these systems can induce persistent neural plasticity in various brain regions (Conrad and Bimonte-Nelson, 2010; Levy and Tasker, 2012).…”

Measuring the incentive value of escalating doses of heroin in heroin-dependent Fischer rats during acute spontaneous withdrawal

“…The schedule of heroin administration was designed to mimic patterns of heroin use often observed in human addicts (e.g., Dole et al 1966; Kreek et al 2009; Hser et al 2008; e.g. Zhou et al 2008) with continued, intermittent administration of escalating doses of heroin across the active period and into the inactive period of the circadian cycle (Table 1).…”

“…Rats received frequent, intermittent homecage injections of heroin at doses that increased progressively (to 75mg/kg/day) over a prolonged (10-day) period, mimicking the progressive increases in heroin consumption that characterize human addiction (e.g., Dole et al 1966; Haertzen and Hooks 1969; Kreek et al 2009). In parallel to this chronic homecage exposure to heroin, rats learned to associate regularly scheduled injections of heroin with a unique context.…”