Biology subjects

Grant, Y.

Publications and source records attributed to Grant, Y..

6 recordsLinked to original sources

bioRxiv2017

Δ9-tetrahydrocannabinol Attenuates Oxycodone Self-Administration Under Extended Access Conditions

Growing nonmedical use of prescription opioids is a global problem, motivating research on ways to reduce use and combat addiction. Medical cannabis (\"medical marijuana\") legalization has been associated epidemiologically with reduced opioid harms and cannabinoids have been shown to modulate effects of opioids in animal models. This study was conducted to determine if {Delta}9-tetrahydrocannabinol (THC) enhances the behavioral effects of oxycodone.\n\nMale rats were trained to intravenously self-administer (IVSA) oxycodone (0.15 mg/kg/infusion) during 1 h, 4 h or 8 h sessions. Following acquisition rats were exposed to THC by vapor inhalation (1 h and 8 h groups) or injection (0-10 mg/kg, i.p.; all groups) prior to IVSA sessions. Fewer oxycodone infusions were obtained by rats following vaporized or injected THC compared with vehicle treatment prior to the session. Follow-up studies demonstrated parallel dose-dependent effects of THC, i.p., on self-administration of different per-infusion doses of oxycodone and a preserved loading dose early in the session. These patterns are inconsistent with behavioral suppression. Additional groups of male and female Wistar rats were assessed for nociception following inhalation of vaporized THC (50 mg/mL), oxycodone (100 mg/mL) or the combination. Tail withdrawal latency was increased more by the THC/oxycodone combination compared to either drug alone. Similar additive antinociceptive effects were produced by injection of THC (5.0 mg/kg, i.p.) and oxycodone (2.0 mg/kg, s.c.). Together these data demonstrate additive effects of THC and oxycodone and suggest the potential use of THC to enhance therapeutic efficacy, and to reduce the abuse, of opioids.

neuroscience↗

bioRxiv2017

Prophylactic vaccination protects against the development of oxycodone addiction

Abuse of prescription opioids is a growing public health crisis in the United States, with drug overdose deaths increasing dramatically over the past 15 years. Few preclinical studies exist on the reinforcing effects of oxycodone or on the development of therapies for oxycodone abuse. This study was conducted to determine if immunopharmacotherapy directed against oxycodone would be capable of altering oxycodone-induced antinociception and intravenous self-administration. Male Wistar rats were administered a small-molecule immunoconjugate vaccine (Oxy-TT) or the control carrier protein, tetanus toxoid (TT), and trained to intravenously self-administer oxycodone (0.06 or 0.15 mg/kg/infusion). Brain oxycodone concentrations were 50% lower in Oxy-TT rats compared to TT rats 30 minutes after injection (1 mg/kg, s.c.) whereas plasma oxycodone was 15-fold higher from drug sequestration by circulating antibodies. Oxy-TT rats were also less sensitive to 1-2 mg/kg, s.c. oxycodone on a hot water nociception assay. Half of the Oxy-TT rats failed to acquire intravenous self-administration under the 0.06 mg/kg/infusion training dose. Oxycodone self-administration of Oxy-TT rats trained on 0.15 mg/kg/infusion was higher than controls; however under progressive ratio (PR) conditions the Oxy-TT rats decreased their oxycodone intake, unlike TT controls. These data demonstrate that active vaccination provides protection against the reinforcing effects of oxycodone. Anti-oxycodone vaccines may entirely prevent repeated use in some individuals who otherwise would become addicted. Vaccination may also reduce dependence in those who become addicted and therefore facilitate the effects of other therapeutic interventions which either increase the difficulty of drug use or incentivize other behaviors.

neuroscience↗

bioRxiv2017

Binge-like Acquisition of α-pyrrolidinopentiophenone (α-PVP) Self-Administration in Female Rats

The synthetic cathinone -pyrrolidinopentiophenone (-PVP) has been associated with violent and/or bizarre public behavior in users. Association of such behavior with extended binges of drug use motivates additional investigation, particularly since a prior study found that half of male rats experience a binge of exceptionally high intake, followed by sustained lower levels of self-administration during the acquisition of intravenous self-administration (IVSA) of a closely related drug, 3,4-methylenedioxypyrovalerone. The binge-like acquisition pattern appeared to be novel for rat IVSA, thus the present study was designed to determine if this effect generalizes to IVSA of -PVP in female rats. Female Wistar rats were trained in IVSA of -PVP (0.05 mg/kg/inf) in experimental chambers that contained an activity wheel. Groups of animals were trained with the wheels fixed (No-Wheel group), fixed for the initial 5 days of acquisition or free to move throughout acquisition (Wheel group). The groups were next subjected to a wheel-access switch and then all animals to dose-substitution (0.0125-0.3 mg/kg/inf) with the wheels alternately fixed and free to move. Approximately half of the rats initiated their IVSA pattern with a binge day of exceptionally high levels of drug intake, independent of wheel access condition. Wheel activity was much lower in the No-Wheel group in the wheel switch post-acquisition. Dose-effect curves were similar for wheel-access training groups, for binge/no binge phenotypic subgroups and were not altered with wheel access during the dose-substitution. This confirms the high reinforcer efficacy of -PVP in female rats and the accompanying devaluation of wheel activity as a naturalistic reward.

neuroscience↗

bioRxiv2017

Withdrawal-induced escalated oxycodone self-administration is mediated by kappa opioid receptor function

BackgroundPrescription opioid addiction is a significant health problem characterized by compulsive drug seeking, withdrawal and chronic relapse. We investigated the neurobiological consequences of escalation of prescription opioid use using extended access to intravenous oxycodone self-administration in rats.\n\nMethodsMale Wistar rats acquired oxycodone self-administration (0.15 mg/kg/infusion, i.v.) in 1h or 12h access sessions. Electrophysiological and immunohistochemical studies investigated the effects of oxycodone self-administration on kappa opioid receptor (KOR) regulation of GABAergic signaling and dynorphin expression in the central nucleus of the amygdala (CeA).\n\nResultsRats given 12h access to oxycodone for 5 sessions/week (LgA) escalated their responding more than rats given 1h oxycodone (ShA) or 12h saline access. Slowed escalation of responding was found in rats given 12h access for 7 sessions/week (LgA-7day) or rats pretreated with the KOR antagonist nor-binaltorphamine dihydrochloride (norBNI) before LgA (norBNI+LgA). The KOR agonist U-50488 decreased GABA release in CeA neurons of all groups except LgA. norBNI increased GABA release in control group neurons, suggesting tonic KOR activity. This activity was abolished in ShA, norBNI+LgA, and LgA-7day rat neurons, consistent with decreased CeA dynorphin immunoreactivity observed in LgA-7day rats. However, norBNI effects were reversed (decreased CeA GABA release) in LgA rat neurons.\n\nConclusionsThe experience of intermittent extended withdrawal periods accelerates the escalation of oxycodone self-administration and causes greater dysregulation of CeA KOR-mediated GABAergic signaling. A KOR agonist/antagonist switch effect seen with other drugs of abuse was absent, which suggests that oxycodone-induced neuroadaptations may be distinct from those resulting from other drugs of abuse.

neuroscience↗

bioRxiv2017

Repeated vapor inhalation of Δ9-tetrahydrocannabinol induces tolerance to hypothermia in female rats

RationaleA reduced effect of a given dose of {Delta}9-tetrahydrocannabinol (THC) emerges with repeated exposure to the drug. This tolerance can vary depending on THC dose, exposure chronicity and the behavioral or physiological measure of interest. A novel THC inhalation system based on e-cigarette technology has been recently shown to produce the hypothermic and antinociceptive effects of THC in rats.\n\nObjectiveTo determine if tolerance to these effects can be produced with repeated vapor inhalation.\n\nMethodsGroups of male and female Wistar rats were exposed to 30 minutes of inhalation of the propylene glycol (PG) vehicle or THC (200 mg/mL in PG) two or three times per day for four days. Rectal temperature changes and nociception were assessed after the first exposure on the first and fourth days of repeated inhalation.\n\nResultsFemale, but not male, rats developed tolerance to the hypothermic and antinociceptive effects of THC after four days of twice-daily THC vapor inhalation. Thrice daily inhalation for four days resulted in tolerance in both male and female rats. The plasma THC levels reached after a 30 minute inhalation session did not differ between the male and female rats.\n\nConclusionsRepeated daily THC inhalation induces tolerance in female and male rats, providing further validation of the vapor inhalation method for preclinical studies.\n\nAbbreviationsPG, propylene glycol; THC; {Delta}9tetrahydrocannabinol;

neuroscience↗

bioRxiv2017

Effects Of Δ9-THC And Cannabidiol Vapor Inhalation In Male And Female Rats

Previous studies report sex differences in some, but not all, responses to cannabinoids in rats. The majority of studies use parenteral injection, however most human use is via smoke inhalation and, increasingly, vapor inhalation. The aim of this study was to compare thermoregulatory and locomotor responses to inhaled {Delta}9-tetrahydrocannabinol (THC), cannabidiol (CBD) and their combination using an e-cigarette based model in male and female rats.\n\nGroups of male and female Sprague-Dawley rats (N=8 per group) were implanted with radiotelemetry devices for the assessment of body temperature and locomotor activity. Animals were then exposed to THC or CBD vapor (4 puffs/5 minutes) using a propylene glycol (PG) vehicle. THC dose was adjusted via the concentration in the vehicle (12.5-200 mg/ml) and CBD (100, 400 mg/mL) dose was also adjusted by varying the inhalation duration (10-40 minutes). Anti-nociception was evaluated using a tail-withdrawal assay following vapor inhalation.\n\nTHC inhalation reduced body temperature and increased tail-withdrawal latency in both sexes equivalently and in a concentration-dependent manner. Female temperature, activity and anti-nociceptive responses to THC did not differ between the estrus and diestrus phases. CBD inhalation alone induced hypothermia and suppressed locomotor activity in both males and females. Co-administration of THC with CBD, in a 1:4 ratio, significantly decreased temperature and activity in an approximately additive manner and to similar extent in each sex.\n\nIn summary the inhalation of THC or CBD, alone and in combination, produces approximately equivalent effects in male and female rats. Sex differences were subtle and mostly reflected in a more prolonged body temperature disruption in females.

pharmacology and toxicology↗