Buspirone maintenance does not alter the reinforcing, subjective, and cardiovascular effects of intranasal methamphetamine

Abstract

Background Medications development efforts for methamphetamine-use disorder have targeted central monoamines because these systems are directly involved in the effects of methamphetamine. Buspirone is a dopamine autoreceptor and D3 receptor antagonist and partial agonist at serotonin 1A receptors, making it a logical candidate medication for methamphetamine-use disorder. Buspirone effects on abuse-related behaviors of methamphetamine have been mixed in clinical and preclinical studies. Experimental research using maintenance dosing, which models therapeutic use, is limited. This study evaluated the influence of buspirone maintenance on the reinforcing effects of methamphetamine using a self-administration procedure, which has predictive validity for clinical efficacy. The impact of buspirone maintenance on the subjective and cardiovascular response to methamphetamine was also determined. Methods Eight research participants (1 female) reporting recent illicit stimulant use completed a placebo-controlled, crossover, double-blind protocol in which the pharmacodynamic effects of intranasal methamphetamine (0, 15, and 30 mg) were assessed after at least 6 days of buspirone (0 and 45 mg/day) maintenance. Results Intranasal methamphetamine functioned as a reinforcer and produced prototypical stimulant-like subjective (e.g., increased ratings of Good Effects and Like Drug) and cardiovascular (e.g., elevated blood pressure) effects. These effects of methamphetamine were similar under buspirone and placebo maintenance conditions. Maintenance on buspirone was well tolerated and devoid of effects when administered alone. Conclusions These data suggest that buspirone is unlikely to be an effective pharmacotherapy for methamphetamine-use disorder. Given the central role of monoamines in methamphetamine-use disorder, it is reasonable for future studies to continue to target these systems.

Using a dependent schedule to measure risky choice in male rats: Effects of d-amphetamine, methylphenidate, and methamphetamine.

“…Methylphenidate and methamphetamine were included because these drugs have been used in commonly used delay-discounting tasks (e.g., Adriani et al, 2004; Evenden & Ryan, 1996; Pardey, Kumar, Goodchild, & Cornish, 2013; Paterson, Wetzler, Hackett, & Hanania, 2012; Pitts & Febbo, 2004; Richards, Sabol, & de Wit, 1999; Siemian, Xue, Blough, & Li, 2017; Slezak & Anderson, 2011; Tanno, Maguire, Henson, & France, 2014; van Gaalen, van Koten, Schoffelmeer, & Vanderschuren, 2006; Wade, de Wit, & Richards, 2000) as well as in concurrent-chains procedures (Maguire et al, 2009; Pitts et al, 2016; Ta et al, 2008) but have not been tested in probability discounting. Also, using these drugs is important as they are known to have high abuse potential in both preclinical (Baladi, Nielsen, Umpierre, Hanson, & Fleckenstein, 2014; Balster & Schuster, 1973; Collins, Weeks, Cooper, Good, & Russell, 1983; Harrod, Dwoskin, Crooks, Klebaur, & Bardo, 2001; Marusich & Bardo, 2009; Munzar, Baumann, Shoaib, & Goldberg, 1999; Pickens, 1968) and clinical populations (Reynolds, Strickland, Stoops, Lile, & Rush, 2017; Rush, Essman, Simpson, & Baker, 2001; Rush, Stoops, Lile, Glaser, & Hays, 2011; Stoops, Glaser, Fillmore, & Rush, 2004; see Stoops, 2008 for a review) and are known to alter risky decision making in humans (e.g., Campbell-Meiklejohn et al, 2012) or alter neural circuits related to risky decision making (Bischoff-Grethe et al, 2017; Ersche et al, 2005; Kohno, Morales, Ghahremani, Hellemann, & London, 2014). The results of the current experiment can provide further insights into how psychostimulants affect choice between reinforcers that differ in magnitude and probability, which may allow us to better understand the relationship between risky decision making and substance abuse.…”

GZ-11608, a Vesicular Monoamine Transporter-2 Inhibitor, Decreases the Neurochemical and Behavioral Effects of Methamphetamine

“…Substantial effort has been directed toward discovering a pharmacotherapeutic for MUD (see reviews: Ballester et al, 2017;Dwoskin et al, 2017;Reynolds et al, 2017). Methamphetamine redistributes dopamine from synaptic vesicles into the cytosol by interacting with the vesicular monoamine transporter-2 (VMAT2) and disrupting the vesicular pH gradient (Sulzer and Rayport, 1990;Sulzer et al, 1995;Dwoskin and Crooks, 2002).…”