Jean Lud Cadet

Dose-related neurocognitive effects of marijuana use

Background: Although about 7 million people in the US population use marijuana at least weekly, there is a paucity of scientific data on persistent neurocognitive effects of marijuana use. Objective: To determine if neurocognitive deficits persist in 28-day abstinent heavy marijuana users and if these deficits are dose-related to the number of marijuana joints smoked per week. Methods: A battery of neurocognitive tests was given to 28-day abstinent heavy marijuana abusers. Results: As joints smoked per week increased, performance decreased on tests measuring memory, executive functioning, psychomotor speed, and manual dexterity. When dividing the group into light, middle, and heavy user groups, the heavy group performed significantly below the light group on 5 of 35 measures and the size of the effect ranged from 3.00 to 4.20 SD units. Duration of use had little effect on neurocognitive performance. Conclusions: Very heavy use of marijuana is associated with persistent decrements in neurocognitive performance even after 28 days of abstinence. It is unclear if these decrements will resolve with continued abstinence or become progressively worse with continued heavy marijuana use.

Methamphetamine causes differential regulation of pro-death and anti-death Bcl-2 genes in the mouse neocortex

Bcl‐2, an inner mitochondrial membrane protein, inhibits apoptotic neuronal cell death. Expression of Bcl‐2 inhibits cell death by decreasing the net cellular generation of reactive oxygen species. Studies by different investigators have provided unimpeachable evidence of a role for oxygen‐based free radicals in methamphetamine (METH) ‐induced neurotoxicity. In addition, studies from our laboratory have shown that immortalized rat neuronal cells that overexpress Bcl‐2 are protected against METH‐induced apoptosis in vitro. Moreover, the amphetamines can cause differential changes in the expression of Bcl‐X splice variants in primary cortical cell cultures. These observations sug‐gested that METH might also cause perturbations of Bcl‐2‐related genes when administered to rodents. Thus, the present study was conducted to determine whether the use of METH might indeed be associated with transcriptional and translational changes in the expression of Bcl‐2‐related genes in the mouse brain. Here we report that a toxic regimen of METH did cause significant increases in the pro‐death Bcl‐2 family genes BAD, BAX, and BID. Concomitantly, there were significant decreases in the anti‐death genes Bcl‐2 and Bcl‐XL. These results thus support the notion that injections of toxic doses of METH trigger the activation of the programmed death pathway in the mammalian brain.—Jayanthi, S., Deng, X., Bordelon, M., McCoy, M. T., Cadet, J. L. Methamphetamine causes differential regulation of pro‐death and anti‐death Bcl‐2 genes in the mouse neocortex. FASEB J. 15, 1745–1752 (2001)

Sertraline slows disease progression and increases neurogenesis in N171-82Q mouse model of Huntington's disease

Huntingtons disease (HD) is an inherited progressive neurodegenerative disorder resulting from CAG repeat expansion in the gene that encodes for the protein huntingtin. To identify neuroprotective compound (s) that can slow down disease progression and can be administered long term with few side effects in Huntingtons disease, we investigated the effect of sertraline, a selective serotonin reuptake inhibitor (SSRI) which has been shown to upregulate BDNF levels in rodent brains. We report here that in HD mice sertraline increased BDNF levels, preserved chaperone protein HSP70 and Bcl-2 levels in brains, attenuated the progression of brain atrophy and behavioral abnormalities and thereby increased survival. Sertraline also enhanced neurogenesis, which appeared to be responsible for mediating the beneficial effects of sertraline in HD mice. Additionally, the effective levels of sertraline are comparable to the safe levels achievable in humans. The findings suggest that sertraline is a potential candidate for treatment of HD patients.

Fatty acid amide hydrolase (FAAH) inhibition enhances memory acquisition through activation of PPAR-alpha nuclear receptors.

Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of anandamide (a cannabinoid CB(1)-receptor ligand) and oleoylethanolamide and palmitoylethanolamide (OEA and PEA, ligands for alpha-type peroxisome proliferator-activated nuclear receptors, PPAR-alpha) when and where they are naturally released in the brain. Using a passive-avoidance task in rats, we found that memory acquisition was enhanced by the FAAH inhibitor URB597 or by the PPAR-alpha agonist WY14643, and these enhancements were blocked by the PPAR-alpha antagonist MK886. These findings demonstrate novel mechanisms for memory enhancement by activation of PPAR-alpha, either directly by administering a PPAR-alpha agonist or indirectly by administering a FAAH inhibitor.

A factor analysis of the Fagerström Test for Nicotine Dependence (FTND).

Psychometric study of the Fagerström Test for Nicotine Dependence (FTND) provides insight into its structure and the dimensions of nicotine addiction it assesses. We evaluated the factor structure of the FTND in 541 research volunteers, most with histories of polysubstance use. Tetrachoric and phi correlation techniques were utilized and promax- and varimax-rotated solutions are reported. Two factors were found. Factor 1 was defined by questions regarding time to first cigarette in after waking, which cigarette is most preferred, and prominence of morning smoking. Factor 2 was defined by questions regarding difficulty refraining from smoking, amount smoked, and smoking while ill. The question How soon on waking do you smoke your first cigarette? loaded substantially on both Factor 2 and Factor 1. Repeating the analyses after stratification by gender did not change the results. The factor structure from our sample population was similar to results reported by previous studies with different types of populations. We propose that Factor 1 assesses the degree of urgency to restore nicotine levels to a given threshold after nighttime abstinence, whereas Factor 2 reflects the persistence with which nicotine levels are maintained at about that threshold during waking hours. Thus, the FTND may assess distinguishable self-reportable pharmacological dimensions of nicotine addiction. These two dimensions may provide indirect assessment of a smokers daily nicotine intake. Testing this hypothesis requires correlation of biomarkers and responses to specific items of the FTND.

An In Vitro Model of Human Dopaminergic Neurons Derived from Embryonic Stem Cells: MPP+ Toxicity and GDNF Neuroprotection

Human embryonic stem cells (hESCs) can proliferate indefinitely yet also differentiate in vitro, allowing normal human neurons to be generated in unlimited numbers. Here, we describe the development of an in vitro neurotoxicity assay using human dopaminergic neurons derived from hESCs. We showed that the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP+), which produces features of Parkinsons disease in humans, was toxic for hESC-derived dopaminergic neurons. Treatment with glial cell line-derived neurotrophic factor protected tyrosine hydroxylase-positive neurons against MPP+-induced apoptotic cell death and loss of neuronal processes as well as against the formation of intracellular reactive oxygen species. The availability of human dopaminergic neurons, derived from hESCs, therefore allows for the possibility of directly examining the unique features of human dopaminergic neurons with respect to their responses to pharmacological agents as well as environmental and chemical toxins.

Epigenetics of Stress, Addiction, and Resilience: Therapeutic Implications.

Substance use disorders (SUDs) are highly prevalent. SUDs involve vicious cycles of binges followed by occasional periods of abstinence with recurrent relapses despite treatment and adverse medical and psychosocial consequences. There is convincing evidence that early and adult stressful life events are risks factors for the development of addiction and serve as cues that trigger relapses. Nevertheless, the fact that not all individuals who face traumatic events develop addiction to licit or illicit drugs suggests the existence of individual and/or familial resilient factors that protect these mentally healthy individuals. Here, I give a brief overview of the epigenetic bases of responses to stressful events and of epigenetic changes associated with the administration of drugs of abuse. I also discuss the psychobiology of resilience and alterations in epigenetic markers that have been observed in models of resilience. Finally, I suggest the possibility that treatment of addiction should involve cognitive and pharmacological approaches that enhance resilience in at risk individuals. Similar approaches should also be used with patients who have already succumbed to the nefarious effects of addictive substances.

Epigenetic landscape of amphetamine and methamphetamine addiction in rodents

Amphetamine and methamphetamine addiction is described by specific behavioral alterations, suggesting long-lasting changes in gene and protein expression within specific brain subregions involved in the reward circuitry. Given the persistence of the addiction phenotype at both behavioral and transcriptional levels, several studies have been conducted to elucidate the epigenetic landscape associated with persistent effects of drug use on the mammalian brain. This review discusses recent advances in our comprehension of epigenetic mechanisms underlying amphetamine- or methamphetamine-induced behavioral, transcriptional, and synaptic plasticity. Accumulating evidence demonstrated that drug exposure induces major epigenetic modifications—histone acetylation and methylation, DNA methylation—in a very complex manner. In rare instances, however, the regulation of a specific target gene can be correlated to both epigenetic alterations and behavioral abnormalities. Work is now needed to clarify and validate an epigenetic model of addiction to amphetamines. Investigations that include genome-wide approaches will accelerate the speed of discovery in the field of addiction.

Neurophysiological signs of cocaine dependence: Increased electroencephalogram beta during withdrawal

To determine whether a central nervous system marker of cocaine dependence might exist, the resting electroencephalogram (EEG) of 33 drug-free, cocaine-dependent men (DSM-III-R criteria) was compared with two control groups [nondrug group (n = 10) and drug group who abused drugs, but were not cocaine dependent (n = 20)]. The EEG was recorded from eight sites after about 10 days of monitored abstinence (range 4-15 days) on a closed research ward for the drug-using individuals. The EEG was recorded for the nondrug control group as outpatients. The drug history was determined by the drug history questionnaire and a medical screening interview. The percent of EEG beta activity for the cocaine-dependent subjects was greater than that of both control groups (p < .05) as well as a normative database (HZI: Tarrytown, NY). The percent of EEG beta in frontal and central areas of the cocaine-dependent individuals was correlated with the frequency of cocaine use during the last 30 days. High levels of EEG beta may be a neurophysiological withdrawal sign in cocaine-dependent men.

Clonidine and prazosin block the iminodipropionitrile (IDPN)-induced spasmodic dyskinetic syndrome in mice

The effects of drugs with selective action on alpha 1- or alpha 2-adrenoceptors were investigated on persistent head twitches, vertical neck dyskinesia, and the random circling behaviors induced by chronic intraperitoneal injections of IDPN. The alpha agonist clonidine and the alpha antagonist prazosin inhibited the IDPN-induced behavioral syndrome whereas the alpha antagonist yohimbine had no significant effect. These results suggest that dysregulation of a facilitatory noradrenergic input to cortical and/or subcortical motor areas may be involved in the abnormal movements caused by chronic treatment with IDPN.