PRECLINICAL STUDY: Route of administration affects the ability of naltrexone to reduce amphetamine‐potentiated brain stimulation reward in rats

Abstract

Opioid receptor antagonism has been shown to attenuate behavioral and neurochemical effects of amphetamine in humans and rodents. The effects of acute (oral or subcutaneous) or extended-release naltrexone (XR-NTX) were tested on the reward-enhancing effects of amphetamine using the intracranial self-stimulation (ICSS) paradigm. Acute exposure to drugs of abuse reduces the locus of rise (LOR) in the ICSS procedure, reflecting enhanced brain stimulation reward (BSR). Rats were treated once a day with naltrexone orally (PO; 5.0 mg/kg) or subcutaneously (SC; 0.5 mg/kg) for four consecutive days and tested with D-amphetamine (0.5 mg/kg, intraperitoneal) in the ICSS paradigm 30 minutes later on days 1 and 4. Separate groups of rats received XR-NTX (50 mg/kg, SC) or placebo microspheres (similar mass to XR-NTX, SC) on day 0 and tested with D-amphetamine in the ICSS paradigm on days 4, 14, 21, 28 and 41 after administration. Naltrexone plasma concentrations were determined for each amphetamine testing session using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). In rats pretreated with naltrexone acutely, amphetamine-potentiated BSR did not differ from vehicle-pretreated rats on either day 1 or day 4 (25-30% decrease in LOR). In XR-NTX-pretreated rats, amphetamine-potentiated BSR was reduced by 64 and 70% on days 4 and 14, respectively, compared to placebo microsphere-treated controls. This effect dissipated by day 21. Naltrexone plasma concentrations were comparable across all treatment groups (14-30 ng/ml) on days 1, 4 and 14. In summary, an extended-release formulation of naltrexone results in significant attenuation of psychostimulant-enhanced BSR that is not observed with acute naltrexone.

Effects of Acute Oral Naltrexone on the Subjective and Physiological Effects of Oral D-Amphetamine and Smoked Cocaine in Cocaine Abusers

“…Furthermore, a randomized clinical trial of oral NTX (50 mg) for treating AMPH dependence demonstrated that treatment outcomes (number of AMPH-negative urine samples, rate of continuous abstinence, craving, and self-reported consumption of AMPH) were significantly improved in NTX compared with placebo-treated patients (N ¼ 40 per group; JayaramLindstrom et al, 2008a). Consistent with the clinical data, preclinical studies have demonstrated that NTX reduces the reinforcing effects of intravenous AMPH (Jimenez-Gomez et al, 2011), AMPH-induced decreases in the threshold for intracranial brain stimulation reward (Todtenkopf et al, 2009), and reinstatement of AMPH seeking (Haggkvist et al, 2009). The exact mechanism by which NTX altered AMPHinduced responses remains unclear.…”

Using a rate-frequency curve method to assess the rewarding properties of morphine in the intracranial self-stimulation paradigm in rats

“…Beginning approximately 6-7 days after surgery, rats were trained on a continuous reinforcement schedule (FR1) to respond for rewarding brain stimulation in operant chambers interfaced with stimulators (Med Associates, St. Albans, VT) as previously described (Todtenkopf et al, 2009). Using customized software, each lever-press earned a 0.5-s train of square-wave cathodal pulses (0.1-ms pulse duration) at a set frequency (178 Hz).…”

“…To confirm electrode placements, rats were perfused with 4% paraformaldehyde and sections through the lateral hypothalamus were stained with cresyl violet as previously described (Todtenkopf et al, 2009). …”

“…Monopolar, stainless steel electrodes (0.25-mm diameter; Plastics One, Inc., Roanoke, VA) were implanted in the right medial forebrain bundle, at the level of the lateral hypothalamus (3.0 mm posterior to bregma, 1.6 mm lateral from midsaggital suture and 7.8 mm below dura) (Paxinos and Watson, 2005) as previously described (Todtenkopf et al, 2009). The portion of the electrode implanted is composed of benign stainless steel that is coated in polyamide acrylic insulation except at the flattened tip.…”

“…To characterize the functions relating response strength to reward magnitude, a non-linear regression analysis was done using the Gompertz model across the frequencies using customized analysis software (rfc ANA, v5.0) to calculate the locus of rise (LOR) as previously reported (Todtenkopf et al, 2009). LOR is defined as the frequency at the inflection point of the asymmetrical sigmoidal curve.…”