Differential effects of acute and chronic treatment with the α2-adrenergic agonist, lofexidine, on cocaine self-administration in rhesus monkeys

Kohut, Stephen J.; Fivel, Peter A.; Mello, Nancy K.

doi:10.1016/j.drugalcdep.2013.07.032

Cited by 20 publications

(22 citation statements)

References 43 publications

(62 reference statements)

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“…After initial training to respond for food pellets, subjects were surgically prepared with chronic indwelling double-lumen catheters as described previously (Kohut et al 2013). Monkeys responded during daily 120-min sessions that consisted of components of food and nicotine availability.…”

Section: Methodsmentioning

confidence: 99%

“…Finally, similar procedures were conducted to evaluate the reinforcing strength of the unit dose of 0.01 mg/kg cocaine and, separately, 1 g banana-flavored food pellets (described below). The unit dose of cocaine was chosen because we previously found that it produced peak levels of IV self-administration behavior under similar schedule conditions (see Bergman et al 2012; Kohut et al 2013). A limit of 200 inj was placed on self-administration of 0.01 mg/kg/inj cocaine to reduce the likelihood of toxic effects.…”

Section: Methodsmentioning

confidence: 99%

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Reinforcing effectiveness of nicotine in nonhuman primates: effects of nicotine dose and history of nicotine self-administration

Kohut

Bergman

2016

Psychopharmacology

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Rationale Despite the high prevalence of nicotine use in humans, robust nicotine self-administration has been difficult to demonstrate in laboratory animals. Objectives A parametric analysis of nicotine self-administration was conducted to study its reinforcing effects in non-human primates. Methods Adult rhesus macaques (N=6) self-administered intravenous (IV) nicotine (0.001-0.1 mg/kg) under a fixed ratio (FR) 1 schedule of reinforcement during daily 90-min sessions. Next, the demand function relating drug intake and response cost was determined by increasing the FR across sessions during the availability of each of several unit doses of nicotine (0.0032-0.032 mg/kg/inj). The reinforcing effects of 0.01 mg/kg/inj cocaine and 1-g banana-flavored food pellets were also determined under similar testing conditions. Finally, the nicotine demand function was re-determined after approximately 8 months of daily IV nicotine self-administration. Results IV nicotine self-administration followed an inverted-U shaped pattern, with the peak number of injections maintained by 0.0032 mg/kg/inj. Self-administration of each reinforcer (food pellets, IV cocaine, and IV nicotine) decreased as FR size increased. Application of the exponential model of demand showed that the demand elasticity for nicotine was: 1) dose-dependent and lowest for 0.0032 mg/kg/inj); 2) for 0.0032 mg/kg/inj, similar to that of food pellets and significantly higher than cocaine; and 3) decreased after 8 months of daily nicotine self-administration. Conclusions These data show that, though high levels of nicotine self-administration can be achieved under simple FR schedules in nonhuman primates, its reinforcing effectiveness is dose-related but limited, and may increase over time.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Reinforcing effectiveness of nicotine in nonhuman primates: effects of nicotine dose and history of nicotine self-administration

Kohut

Bergman

2016

Psychopharmacology

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“…A newer α-2R agonist, lofexidine, also attenuates stress-induced reinstatement of cocaine-seeking in rats (Erb et al 2000; Highfield et al 2001) and decreases drug withdrawal and stress-induced craving in humans (Sinha et al 2007; Yu et al 2008). Recently, acute treatment with lofexidine was shown to significantly reduced cocaine self-administration in rhesus monkeys, however, chronic treatment produced a leftward shift in the cocaine self-administration dose-effect curve (Kohut et al 2013). Taken together, available evidence appears to support the notion that lofexidine may attenuate cocaine’s effects in humans.…”

Section: Introductionmentioning

confidence: 99%

Assessment of safety, cardiovascular and subjective effects after intravenous cocaine and lofexidine

Garza

Newton

Mendelson

et al. 2014

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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The primary objective of this study was to determine the safety of lofexidine, an α2 receptor agonist, alone and concurrent with cocaine in non-treatment seeking cocaine-dependent or cocaine-abusing participants. After screening, eligible participants received double-blind, randomized infusions of saline and 20 mg of cocaine on Day 1, and saline and 40 mg of cocaine on Day 2. Subjects were randomized and started receiving daily administration of placebo (N=4) or lofexidine on Day 3 and continued on this schedule until Day 7. Two dosing regimens for lofexedine were investigated: 0.8 QID (N=3) and 0.2 mg QID (N=11). On Days 6 and 7, subjects received double-blind infusions of saline and 20 mg of cocaine on Day 6, and saline and 40 mg of cocaine on Day 7. The data reveal a notable incidence of hemodynamic-related AEs over the course of the study. Two of the three participants at the 0.8 mg dose level discontinued, and five of 11 participants at the 0.2 mg dose level were withdrawn (or voluntarily discontinued) after hemodynamic AEs. Subjective effects and cardiovascular data were derived from all participants who were eligible to receive infusions (i.e., did not meet stopping criteria) on Days 6 and 7 (6 received lofexidine 0.2 mg, QID and 4 received placebo, QID). As expected, cocaine significantly increased heart rate and blood pressure, as well as several positive subjective effects. There was a trend for lofexidine to decrease cocaine-induced cardiovascular changes and cocaine-induced ratings for "Any Drug Effect", "Good Effects", and “Desire Cocaine”, but sample size issues limit the conclusions that can be drawn. Despite the trends to reduce cocaine-induced subjective effects, cardiovascular AEs may limit future utility of lofexidine as a treatment for this population.

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“…Rather, these findings are consistent with neuropharmacological data showing l-MA to be 15-20 fold less potent than d-MA in stimulating DA release in vitro (Rothman and Baumann 2003) and in vivo (Kuczenski et al 1995; Melega et al 1999) and similarly potent in stimulating norepinephrine release in vitro (Rothman et al 2001). Notwithstanding such differences in relative potency, the cocaine-like discriminative stimulus effects of varying relative potency for releasing DA and NE and that the ability of l-MA, like other monoaminergic stimulants, to mimic the discriminative-stimulus effects of cocaine resides primarily in its dopaminergic actions (Spealman 1995; Czoty et al 2004a; Czoty et al 2004b; Kohut et al 2013b). Nevertheless, differences in the relative potency with which l-MA and d-MA release monoamines may contribute to other aspects of their behavioral and pharmaceutical profiles that contribute to their dissimilar DEA scheduling (see Rothman et al 2001).…”

Section: Discussionmentioning

confidence: 99%

Effects of l-methamphetamine treatment on cocaine- and food-maintained behavior in rhesus monkeys

2015

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Rationale Monoamine releasers with prominent dopaminergic actions, e.g., d-methamphetamine (d-MA), significantly reduce cocaine use and craving in clinical and preclinical laboratory studies. However, d-MA and related drugs also display high abuse potential, which limits their acceptability as agonist replacement medications for the management of Cocaine Use Disorder. Objectives The l-isomer of methamphetamine (l-MA), unlike d-MA, has preferential noradrenergic actions and is used medicinally with low, if any, abuse liability. The present study was conducted to determine whether l-MA could serve as an agonist replacement medication by both mimicking interoceptive effects of cocaine and decreasing intravenous (IV) cocaine self-administration. Methods Separate groups (N=4-5) of rhesus monkeys were studied to determine whether l-MA could (1) substitute for cocaine in subjects that discriminated intramuscular (IM) cocaine (0.4 mg/kg) from saline and, (2) decrease IV cocaine self-administration under a second-order FR2(VR16:S) schedule of reinforcement. Results l-MA, like d-MA but with approximately 5-fold lesser potency, substituted for cocaine in drug discrimination experiments in a dose-dependent manner. In IV self-administration studies, 5-10 day treatments with continuously infused l-MA (0.032-0.32 mg/kg/hr, IV) dose-dependently decreased cocaine-maintained responding; the highest dosage reduced cocaine intake to levels of saline self-administration without appreciable effects on food-maintained responding. Conclusions These results indicate that l-MA both shares discriminative-stimulus effects with cocaine and reduces cocaine self-administration in a behaviorally selective manner. l-MA and other compounds with a similar pharmacological profile deserve further evaluation for the management of Cocaine Use Disorder.

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Differential effects of acute and chronic treatment with the α2-adrenergic agonist, lofexidine, on cocaine self-administration in rhesus monkeys

Cited by 20 publications

References 43 publications

Reinforcing effectiveness of nicotine in nonhuman primates: effects of nicotine dose and history of nicotine self-administration

Reinforcing effectiveness of nicotine in nonhuman primates: effects of nicotine dose and history of nicotine self-administration

Assessment of safety, cardiovascular and subjective effects after intravenous cocaine and lofexidine

Effects of l-methamphetamine treatment on cocaine- and food-maintained behavior in rhesus monkeys

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