Effective active vaccination against methamphetamine in female rats

Abstract

Background Immunotherapies directed against methamphetamine (MA) abuse have shown success in rodent models, however only a limited number of studies have investigated active vaccination in female mice and none in female rats. It is critical to determine if potential immunotherapeutic strategies generalize across sex, particularly for drugs that may produce significant sex-differences on behavioral or physiological endpoints. Methods Female Wistar rats were initially vaccinated with keyhole-limpet hemocyanin (KLH) or an anti-methamphetamine-KLH conjugate (MH6-KLH) three times over five weeks and implanted with radiotelemetry devices to assess locomotor activity and body temperature responses to MA. Rats were first exposed to MA via vapor inhalation (100mg/mL in propylene glycol) and then by injection (0.25–1.0 mg/kg, i.p.) and vapor after a final vaccine boost. Results The MH6-KLH vaccine generated an increase in antibody titers across the initial 6-week, 3 immunization protocol and a restoration of titer after a week 14 booster. Locomotor stimulation induced by 0.25 mg/kg MA, i.p, in the KLH group was prevented in the MH6-KLH group. MH6-KLH animals also exhibited an attenuated locomotor stimulation produced by 0.5 mg/kg MA, i.p. No group differences in locomotion induced by vapor inhalation of MA were observed and body temperature was not differentially affected by MA across the groups, most likely because vapor inhalation of MA that produced similar locomotor stimulation resulted in ~10-fold higher plasma MA levels. Conclusions This study confirms the efficacy of the MH6-KLH vaccine in attenuating the effects of MA in female rats.

Effects of Nicotine and THC Vapor Inhalation Administered by An Electronic Nicotine Delivery System (ENDS) in Male Rats

“…Injected nicotine has previously been shown to reduce body temperature and increase spontaneous locomotion in rats (Bryson et al 1981;Clemens et al 2009;Green et al 2003;Levin et al 2003), thus these measures were selected for initial validation. These have the additional advantages of supporting indirect crossdrug comparison with our prior reports on the effects of inhaled THC (Javadi-Paydar et al 2018a;Nguyen et al 2016b;Nguyen et al 2018) and psychomotor stimulants (Nguyen et al 2016a;Nguyen et al 2017). As in those prior studies, it was further important to contextualize some of the inhaled effects, including plasma nicotine and cotinine levels, with those produced by parenteral nicotine injection.…”

“…This relative paucity of information means that it is of pressing and significant interest to develop and validate experimental methods that can support a range of ENDS studies. We have recently developed a system capable of delivering behaviorally significant doses of THC (Javadi-Paydar et al 2018a;Nguyen et al 2016b;Nguyen et al 2018), as well as methamphetamine, mephedrone and 3,4-methylenedioxypyrovalerone (Nguyen et al 2016a;Nguyen et al 2017) to rats via the inhalation of ENDS vapor. This system has also been shown to support the self-administration of sufentanil with rats reaching dependence-inducing levels of drug intake via inhalation (Vendruscolo et al 2018).…”

Δ9-tetrahydrocannabinol attenuates oxycodone self-administration under extended access conditions

“…Oxy-TT (1.0 mg/ml in PBS) or control TT (1.0 mg/ml in PBS), CpG ODN 1826 (5 mg/ml in PBS), and Alhydrogel ® (alum, 10 mg/ml, InvivoGen) and administered intraperitoneally. Rats were administered the conjugate vaccine (Oxy-TT; N=12) or tetanus toxoid only (TT; N=10) on Weeks 0, 2, and 4, adapted from a vaccination protocol previously reported (Nguyen et al, 2016c;Nguyen et al, 2017a). Rats were prepared with chronic intravenous catheters on week 7 of the vaccination protocol and allowed one week of recovery prior to the start of self-administration experiments.…”

Female rats self-administer heroin by vapor inhalation

“…The present study was therefore designed to assess the effects of heroin delivered by ENDS vapor inhalation on measures of reinforcement, withdrawal-like behavior, and nociception. The approach adapted a technique we have shown delivers behaviorally active, non-contingent doses of drugs as varied as methamphetamine and MDPV (Nguyen et al, 2016a;Nguyen et al, 2017), Δ 9 -tetrahydrocannabinol and cannabidiol (Nguyen et al, 2016b;Javadi-Paydar et al, 2018;Javadi-Paydar et al, 2019a), oxycodone and sufentanil, (Vendruscolo et al, 2018;Nguyen et al, 2019b) and nicotine (Javadi-Paydar et al, 2019b). To determine behavioral efficacy of inhaled heroin, we first assessed anti-nociception by measuring tail withdrawal latency from a hot water bath after non-contingent opioid vapor exposure and compared this with the effects of subcutaneous opioid injection.…”