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BACKGROUND: Nearly 2 million U.S. veterans live with co-occurring alcohol use disorder and posttraumatic stress disorder (AUD/PTSD). Extant AUD/PTSD treatments emphasize symptom reduction, sometimes overlooking psychosocial functioning improvements, and have dropout rates as high as 50â¯%. Additionally, current approaches to measuring psychosocial functioning are limited to self-report. This study protocol describes a 1:1 parallel, two-arm, pilot randomized controlled trial comparing Behavioral Activation (BA) psychotherapy to Relapse Prevention (RP) psychotherapy for veterans with AUD/PTSD. METHODS: Forty-six veterans with AUD/PTSD will be block-randomized to eight weekly, virtual, hour-long individual sessions of BA or RP. Clinical interview, self-report, and geospatial assessments will be administered at pre- and post-treatment. Select outcome and exploratory measures will be administered during treatment. Analyses will focus on trial feasibility, BA acceptability, and preliminary efficacy. Geospatial analyses will explore whether pre- to post-treatment changes in geospatial movement can be used to objectively measure treatment response. The study site and an independent Data and Safety Monitoring Board will monitor trial progress, safety, and quality. De-identified data from consenting participants will be submitted to a sponsor-designated data repository. CONCLUSION: If successful, this trial could help to provide veterans with AUD/PTSD with a more acceptable treatment option. Positive findings would also lay groundwork for testing BA in civilians with AUD/PTSD. Finally, by incorporating novel geospatial methods and technologies, this study could potentially yield a new approach to objectively measuring AUD/PTSD recovery that could be used in other clinical trials. This study was registered in ClinicalTrials.gov (NCT06249386).
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BACKGROUND: Human exposures to organophosphate flame retardants result from their use as additives in numerous consumer products. These agents are replacements for brominated flame retardants but have not yet faced similar scrutiny for developmental neurotoxicity. We examined a representative organophosphate flame retardant, triphenyl phosphate (TPP) and its potential effects on behavioral development and dopaminergic function. METHODS: Female Sprague-Dawley rats were given low doses of TPP (16 or 32 mg kg-1 day-1 ) via subcutaneous osmotic minipumps, begun preconception and continued into the early postnatal period. Offspring were administered a battery of behavioral tests from adolescence into adulthood, and littermates were used to evaluate dopaminergic synaptic function. RESULTS: Offspring with TPP exposures showed increased latency to begin eating in the novelty-suppressed feeding test, impaired object recognition memory, impaired choice accuracy in the visual signal detection test, and sex-selective effects on locomotor activity in adolescence (males) but not adulthood. Male, but not female, offspring showed marked increases in dopamine utilization in the striatum, evidenced by an increase in the ratio of the primary dopamine metabolite (3,4-dihydroxyphenylacetic acid) relative to dopamine levels. CONCLUSIONS: These results indicate that TPP has adverse effects that are similar in some respects to those of organophosphate pesticides, which were restricted because of their developmental neurotoxicity.
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Retardadores de Llama , Humanos , Animales , Ratas , Masculino , Retardadores de Llama/toxicidad , Dopamina , Ratas Sprague-Dawley , Pez Cebra , Organofosfatos/toxicidadRESUMEN
BACKGROUND: Cannabis legalization is expanding and men are the predominant users. We have limited knowledge about how cannabis impacts sperm and whether the effects are heritable. RESULTS: Whole genome bisulfite sequencing (WGBS) data were generated for sperm of rats exposed to: (1) cannabis extract (CE) for 28 days, then 56 days of vehicle only (~ one spermatogenic cycle); (2) vehicle for 56 days, then 28 days of CE; or (3) vehicle only. Males were then mated with drug-naïve females to produce F1 offspring from which heart, brain, and sperm tissues underwent analyses. There were 3321 nominally significant differentially methylated CpGs in F0 sperm identified via WGBS with select methylation changes validated via bisulfite pyrosequencing. Significant methylation changes validated in F0 sperm of the exposed males at the gene 2-Phosphoxylose Phosphatase 1 (Pxylp1) were also detectable in their F1 sperm but not in controls. Changes validated in exposed F0 sperm at Metastasis Suppressor 1-Like Protein (Mtss1l) were also present in F1 hippocampal and nucleus accumbens (NAc) of the exposed group compared to controls. For Mtss1l, a significant sex-specific relationship between DNA methylation and gene expression was demonstrated in the F1 NAc. Phenotypically, rats born to CSE-exposed fathers exhibited significant cardiomegaly relative to those born to control fathers. CONCLUSIONS: This is the first characterization of the effect of cannabis exposure on the entirety of the rat sperm methylome. We identified CE-associated methylation changes across the sperm methylome, some of which persisted despite a "washout" period. Select methylation changes validated via bisulfite pyrosequencing, and genes associated with methylation changes were involved in early developmental processes. Preconception CE exposure is associated with detectable changes in offspring DNA methylation that are functionally related to changes in gene expression and cardiomegaly. These results support that paternal preconception exposure to cannabis can influence offspring outcomes.
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Cannabis , Animales , Cardiomegalia , Metilación de ADN , Femenino , Humanos , Masculino , Extractos Vegetales , Ratas , Semillas , EspermatozoidesRESUMEN
Maternal toxicant exposure during gestation can have deleterious effects on neurobehavioral development of the offspring. The potential risks engendered by paternal toxicant exposure prior to conception have been largely understudied. Recently, we found that chronic THC exposure prior to conception in male rats causes long-lasting behavioral impairment in their offspring. The current study examined the effects of chronic preconception exposure to cannabis smoke extract in Sprague-Dawley rats at two different phases in sperm development. One group received daily subcutaneous (sc) injections of THC in cannabis extract at 4 mg/kg/day for 28 days until three days prior to mating with untreated females (late exposure group). Another group received the same regimen except they underwent 56 days of drug abstinence prior to mating (early exposure group). These were compared with a control group treated with vehicle. The offspring underwent a battery of tests for behavioral function to assess motor, emotional and cognitive function. On the elevated plus maze test, the offspring of both paternal cannabis smoke extract (CSE) exposure groups had significantly more time on the open arms than control offspring, indicative of greater risk-taking behavior. No significant main effects of CSE exposure were seen on adolescent or adult locomotor activity in the figure-8 apparatus. In the novel object recognition test, there was a significantly greater drop-off in novel object preference across the session in the male, but not female offspring of the late exposure group. There was also a sex-selective effect of paternal CSE treatment in the 16-arm radial maze test of memory function. Female offspring of the late exposure group had significantly more working memory errors than control females in the first half of the 12-session training sequence. No significant effects were seen in the operant visual signal sustained detection test of attention. This study shows that there are long-lasting behavioral consequences of preconception CSE exposure through the paternal lineage in rats.
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Conducta Animal/efectos de los fármacos , Dronabinol/toxicidad , Alucinógenos/toxicidad , Exposición Paterna/efectos adversos , Espermatogénesis/efectos de los fármacos , Animales , Cognición/efectos de los fármacos , Prueba de Laberinto Elevado , Emociones/efectos de los fármacos , Femenino , Locomoción , Masculino , Actividad Motora/efectos de los fármacos , Prueba de Campo Abierto , Ratas Sprague-Dawley , Factores SexualesRESUMEN
A variety of neural systems are involved in the brain bases of tobacco addiction. Animal models of nicotine addiction have helped identify a variety of interacting neural systems involved in the pathophysiology of tobacco addiction. We and others have found that drug treatments affecting many of those neurotransmitter systems significantly decrease nicotine self-administration. These treatments include dopamine D1 receptor antagonist, histamine H1 antagonist, serotonin 5HT2C agonist, glutamate NMDA antagonist, nicotinic cholinergic α4ß2 partial agonist and nicotinic cholinergic α3ß4 antagonist acting drugs. It may be the case that combining treatments that affect different neural systems underlying addiction may be more efficacious than single drug treatment. In the current study, we tested the interactions of the D1 antagonist SCH-23390 and the serotonin 5HT2c agonist lorcaserin, both of which we have previously shown to significantly reduce nicotine self-administration. In the acute interactions study, both SCH-23390 and lorcaserin significantly reduced nicotine self-administration when given alone and had additive effects when given in combination. In the chronic study, each drug alone caused a significant decrease in nicotine self-administration. No additive effect was seen in combination because SCH-23390 given alone chronically was already highly effective. Chronic administration of the combination was not seen to significantly prolong reduced nicotine self-administration into the post-treatment period. This research shows that unlike lorcaserin and SCH-23390 interactions when given acutely, when given chronically in combination they do not potentiate or prolong each other's effects in reducing nicotine self-administration.