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result(s) for
"Vann, Robert E"
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Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo
Δ⁹-Tetrahydrocannabinol (THC), the psychoactive component of marijuana, and other direct cannabinoid receptor (CB1) agonists produce a number of neurobehavioral effects in mammals that range from the beneficial (analgesia) to the untoward (abuse potential). Why, however, this full spectrum of activities is not observed upon pharmacological inhibition or genetic deletion of either fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), enzymes that regulate the two major endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), respectively, has remained unclear. Here, we describe a selective and efficacious dual FAAH/MAGL inhibitor, JZL195, and show that this agent exhibits broad activity in the tetrad test for CB1 agonism, causing analgesia, hypomotilty, and catalepsy. Comparison of JZL195 to specific FAAH and MAGL inhibitors identified behavioral processes that were regulated by a single endocannabinoid pathway (e.g., hypomotility by the 2-AG/MAGL pathway) and, interestingly, those where disruption of both FAAH and MAGL produced additive effects that were reversed by a CB1 antagonist. Falling into this latter category was drug discrimination behavior, where dual FAAH/MAGL blockade, but not disruption of either FAAH or MAGL alone, produced THC-like responses that were reversed by a CB1 antagonist. These data indicate that AEA and 2-AG signaling pathways interact to regulate specific behavioral processes in vivo, including those relevant to drug abuse, thus providing a potential mechanistic basis for the distinct pharmacological profiles of direct CB1 agonists and inhibitors of individual endocannabinoid degradative enzymes.
Journal Article
Genome-Wide Pharmacogenomic Study of Neurocognition As an Indicator of Antipsychotic Treatment Response in Schizophrenia
Neurocognitive deficits are a core feature of schizophrenia and, therefore, represent potentially critical outcome variables for assessing antipsychotic treatment response. We performed genome-wide association studies (GWAS) with 492K single nucleotide polymorphisms (SNPs) in a sample of 738 patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness study. Outcome variables consisted of a neurocognitive battery administered at multiple time points over an 18-month period, measuring processing speed, verbal memory, vigilance, reasoning, and working memory domains. Genetic mediation of improvements in each of these five domains plus a composite neurocognitive measure was assessed for each of five antipsychotics (olanzapine, perphenazine, quetiapine, risperidone, and ziprasidone). Six SNPs achieved genome-wide significance using a pre-specified threshold that ensures, on average, only 1 in 10 findings is a false discovery. These six SNPs were located within, or in close proximity to, genes
EHF
,
SLC26A9
,
DRD2
,
GPR137B
,
CHST8
, and
IL1A
. The more robust findings, that is those significant across multiple neurocognitive domains and having adjacent SNPs showing evidence for association, were rs286913 at the
EHF
gene (
p
-value 6.99 × 10
−8
,
q
-value 0.034, mediating the effects of ziprasidone on vigilance), rs11240594 at
SLC26A9
(
p
-value 1.4 × 10
−7
,
q
-value 0.068, mediating the effects of olanzapine on processing speed), and rs11677416 at
IL1A
(
p
-value 6.67 × 10
−7
,
q
-value 0.081, mediating the effects of olanzapine on working memory). This study has generated several novel candidate genes for antipsychotic response. However, our findings will require replication and functional validation. To facilitate replication efforts, we provide all GWAS
p
-values for download.
Journal Article
The Gut-brain Connection and Episodic Migraine: an Update
Purpose of review
Historical evidence suggests a shared underlying etiology for migraine and gastrointestinal (GI) disorders that involves the gut-brain axis. Here we provide narrative review of recent literature on the gut-brain connection and migraine to emphasize the importance of tailoring treatment plans for patients with episodic migraine who experience GI comorbidities and symptoms.
Recent findings
Recent population-based studies report the prevalence of migraine and GI disorders as comorbidities as well as overlapping symptomology. American Headache Society (AHS) guidelines have integrated GI symptoms as part of migraine diagnostic criteria and recommend nonoral therapies for patients with GI symptoms or conditions. Nasal delivery is a recommended nonoral alternative; however, it is important to understand potential adverse events that may cause or worsen GI symptoms in some patients due to the site of drug deposition within the nasal cavity with some nasal therapies. Lastly, clinical perspectives emphasize the importance of identifying GI symptoms and comorbidities in patients with episodic migraine to best individualize migraine management.
Summary
Support for an association between the gut-brain axis and migraine continues to prevail in recent literature; however, the relationship remains complex and not well elucidated. The presence of GI comorbidities and symptoms must be carefully considered when making treatment decisions for patients with episodic migraine.
Journal Article
Neurochemical Metabolomics Reveals Disruption to Sphingolipid Metabolism Following Chronic Haloperidol Administration
Haloperidol is an effective antipsychotic drug for treatment of schizophrenia, but prolonged use can lead to debilitating side effects. To better understand the effects of long-term administration, we measured global metabolic changes in mouse brain following 3 mg/kg/day haloperidol for 28 days. These conditions lead to movement-related side effects in mice akin to those observed in patients after prolonged use. Brain tissue was collected following microwave tissue fixation to arrest metabolism and extracted metabolites were assessed using both liquid and gas chromatography mass spectrometry (MS). Over 300 unique compounds were identified across MS platforms. Haloperidol was found to be present in all test samples and not in controls, indicating experimental validity. Twenty-one compounds differed significantly between test and control groups at the
p
< 0.05 level. Top compounds were robust to analytical method, also being identified via partial least squares discriminant analysis. Four compounds (sphinganine, N-acetylornithine, leucine and adenosine diphosphate) survived correction for multiple testing in a non-parametric analysis using false discovery rate threshold < 0.1. Pathway analysis of nominally significant compounds (
p
< 0.05) revealed significant findings for sphingolipid metabolism (
p
= 0.015) and protein biosynthesis (
p
= 0.024). Altered sphingolipid metabolism is suggestive of disruptions to myelin. This interpretation is supported by our observation of elevated N-acetyl-aspartyl-glutamate in the haloperidol-treated mice (
p
= 0.004), a marker previously associated with demyelination. This study further demonstrates the utility of murine neurochemical metabolomics as a method to advance understanding of CNS drug effects.
Journal Article
Large-scale neurochemical metabolomics analysis identifies multiple compounds associated with methamphetamine exposure
Methamphetamine (MA) is an illegal stimulant drug of abuse with serious negative health consequences. The neurochemical effects of MA have been partially characterized, with a traditional focus on classical neurotransmitter systems. However, these directions have not yet led to novel drug treatments for MA abuse or toxicity. As an alternative approach, we describe here the first application of metabolomics to investigate the neurochemical consequences of MA exposure in the rodent brain. We examined single exposures at 3 mg/kg and repeated exposures at 3 mg/kg over 5 days in eight common inbred mouse strains. Brain tissue samples were assayed using high-throughput gas and liquid chromatography mass spectrometry, yielding quantitative data on >300 unique metabolites. Association testing and false discovery rate control yielded several metabolome-wide significant associations with acute MA exposure, including compounds such as lactate (
p
= 4.4 × 10
−5
,
q
= 0.013), tryptophan (
p
= 7.0 × 10
−4
,
q
= 0.035) and 2-hydroxyglutarate (
p
= 1.1 × 10
−4
,
q
= 0.022). Secondary analyses of MA-induced increase in locomotor activity showed associations with energy metabolites such as succinate (
p
= 3.8 × 10
−7
). Associations specific to repeated (5 day) MA exposure included phosphocholine (
p
= 4.0 × 10
−4
,
q
= 0.087) and ergothioneine (
p
= 3.0 × 10
−4
,
q
= 0.087). Our data appear to confirm and extend existing models of MA action in the brain, whereby an initial increase in energy metabolism, coupled with an increase in behavioral locomotion, gives way to disruption of mitochondria and phospholipid pathways and increased endogenous antioxidant response. Our study demonstrates the power of comprehensive MS-based metabolomics to identify drug-induced changes to brain metabolism and to develop neurochemical models of drug effects.
Journal Article
Kappa opioid mediation of cannabinoid effects of the potent hallucinogen, salvinorin A, in rodents
Rationale
Salvinorin A, the primary psychoactive derivative of the hallucinogenic herb
Salvia divinorum
, is a potent and highly selective kappa-opioid receptor (KOR) agonist. Several recent studies, however, have suggested endocannabinoid system mediation of some of its effects.
Objectives
This study represents a systematic examination of this hypothesis.
Methods
Salvinorin A was isolated from
S. divinorum
and was evaluated in a battery of in vitro and in vivo procedures designed to detect cannabinoid activity, including CB
1
receptor radioligand and [
35
S]GTPγS binding, calcium flux assay, in vivo cannabinoid screening tests, and drug discrimination.
Results
Salvinorin A did not bind to nor activate CB
1
receptors. In vivo salvinorin A produced pronounced hypolocomotion and antinociception (and to a lesser extent, hypothermia). These effects were blocked by the selective KOR antagonist, JDTic, but not by the CB
1
receptor antagonist rimonabant. Interestingly, however, rimonabant attenuated KOR activation stimulated by U69,593 in a [
35
S]GTPγS assay. Salvinorin A did not substitute for Δ
9
-tetrahydrocannabinol (THC) in mice trained to discriminate THC.
Conclusions
These findings suggest that similarities in the pharmacological effects of salvinorin A and those of cannabinoids are mediated by its activation of KOR rather than by any direct action of salvinorin A on the endocannabinoid system. Further, the results suggest that rimonabant reversal of salvinorin A effects in previous studies may be explained in part by rimonabant attenuation of KOR activation.
Journal Article
Dose, duration, and pattern of nicotine administration as determinants of behavioral dependence in rats
Relatively little is known about the role of dose, duration, and pattern of nicotine exposure in the development of dependence. Disruption of learned behavior during antagonist-precipitated withdrawal can be a sensitive, quantitative measure of behavioral dependence.
The present study sought to determine whether behavioral dependence upon nicotine could be induced in rats and, if so, what exposure conditions were essential for inducing it. Our primary focus was on whether continuous exposure over several days was necessary to produce dependence.
Male Sprague-Dawley rats were trained to lever press under fixed-ratio 10 schedules of food reinforcement during daily, 15-min experimental sessions. Nicotine was then administered s.c. via osmotic minipumps that delivered various nicotine dosage regimens, some including 24-h nicotine-free periods, to manipulate pattern of exposure. The presence of dependence was tested with challenges with the nicotinic acetylcholine receptor antagonist, mecamylamine, or during spontaneous withdrawal.
After 7 days of 3, 6, and 12 mg kg(-1) day(-1) nicotine administration, response rates were significantly reduced in nicotinized, but not in saline-treated rats following mecamylamine challenges. Subsequent studies demonstrated that 4 days, but not 3 days, of cumulative 3 mg kg(-1) day(-1) nicotine administration was sufficient to induce dependence. The induction of dependence could be prevented by imposing a nicotine-free period between the first and second days during these 4-day regimens but not at other times.
Behavioral dependence upon nicotine can be induced in the rat, and its induction is dependent upon its cumulative duration and pattern of exposure suggesting that tobacco dependencies could be controlled by similar determinants.
Journal Article
Evidence of cellular nicotinic receptor desensitization in rats exhibiting nicotine-induced acute tolerance
Individuals vary in their susceptibility to nicotine addiction. However, there is little evidence that behavioral sensitivity to nicotine is dependent upon the functional state of nicotinic cholinergic receptors (nAChRs).
To determine the relationship between in vivo pharmacological desensitization (in other words, acute tolerance) and brain regional nAChR function.
Male Sprague-Dawley rats, trained to discriminate nicotine (0.4 mg/kg free base) from saline in a two-lever drug discrimination task, were tested for the development of acute tolerance. Rats were injected with 0.4 mg/kg nicotine, tested for nicotine discrimination for 2 min, then injected with the same dose of nicotine 90 min, 180 min, and 270 min after the first injection and tested for nicotine discrimination after each injection. These subjects were separated into two groups, desensitizers (DZ) and nondesensitizers (NDZ), based upon performance in the repetitive dosing drug discrimination paradigm. The sensitivity of nAChRs in specific brain regions of these two groups was assessed by the use of an 86Rb+ efflux assay using synaptosomes prepared from the frontal cortex, hippocampus, striatum, and \"thalamus,\" which included the midbrain and hypothalamus as well as the thalamus.
The nicotine-induced increase in 86Rb+ efflux was significantly greater in NDZ as compared to DZ in the \"thalamus.\" There was no statistically significant difference in the effects of nicotine in the frontal cortex, hippocampus, and striatum of these two groups. A significant correlation was observed between thalamic 86Rb+ efflux and the rate of behavioral desensitization of individual rats.
These findings are consistent with the concept that the production of acute tolerance by nicotine in vivo correlates directly with its ability to induce nAChR desensitization at the cellular level.
Journal Article
Cellular nicotinic receptor desensitization correlates with nicotine-induced acute behavioral tolerance in rats
Individuals vary in their susceptibility to nicotine addiction. However, there is little evidence that behavioral sensitivity to nicotine is dependent upon the functional state of nicotinic cholinergic receptors (nAChRs).
This study aims to determine the relationship between in vivo behavioral desensitization and in vitro desensitization of nAChR function.
Male Sprague-Dawley rats trained to discriminate nicotine were tested for development of acute behavioral tolerance. The rats were injected with nicotine (0.4 mg/kg free base, s.c.), tested for nicotine discrimination for 2 min, then injected with the same dose of nicotine 90, 180, and 270 min after the first injection and tested for nicotine discrimination after each injection. Susceptibility of nAChRs of individual rats to desensitization was assessed by use of the (86)Rb(+) efflux assay using synaptosomes prepared from the \"thalamus,\" which included the hypothalamus and midbrain as well as the thalamic nuclei. To desensitize nAChRs, synaptsosomes were superfused with low concentrations of nicotine (5, 10, 20, and 30 nM) before stimulation of (86)Rb(+) efflux with nicotine (10 muM).
The slopes of the behavioral desensitization were plotted as a function of the decline of nicotine-stimulated (86)Rb(+) efflux after in vitro desensitization. A significant correlation was observed between the in vitro desensitization of thalamic (86)Rb(+) efflux and the extent of behavioral desensitization of individual rats.
These findings are consistent with the idea that production of acute behavioral tolerance by nicotine is related to its ability to induce nAChR desensitization at the cellular level.
Journal Article