Association between initial morphine intake and body weight change, acoustic startle reflex and drug seeking in rats

Nishida

Wilson

et al. 2017

Eur J of Neuroscience

Self Cite

Although certain drugs of abuse are known to disrupt brain glucose metabolism (BGluM), the effects of opiates on BGluM are not well characterized. Moreover, preclinical positron emission tomography (PET) studies anesthetize animals during the scan, which limits clinical applications. We investigated the effects of (i) isoflurane anesthesia and (ii) intravenous morphine self-administration (MSA) on BGluM in rats. Jugular vein cannulated adult male Sprague-Dawley rats self-administered either saline (SSA) or morphine (0.5 mg/kg/infusion, 4 h/day for 12 days). All animals were scanned twice with [ 18 F]-fluoro-deoxyglucose (FDG)-PET/CT at a baseline and at 2-day withdrawal from self-administration. After the IV injection of FDG, one batch of animals (n = 14) was anesthetized with isoflurane and the other batch (n = 16) was kept awake during the FDG uptake (45 min). After FDG uptake, all animals were anesthetized in order to perform a PET/CT scan (30 min). Isoflurane anesthesia, as compared to the awake condition, reduced BGluM in the olfactory, cortex, thalamus, and basal ganglia, while increasing BGluM in the midbrain, hypothalamus, hippocampus, and cerebellum. Morphine self-administered animals exhibited withdrawal signs (piloerection and increased defecation), drug seeking, and locomotor stimulation to morphine (0.5 mg/kg) during the 2 day withdrawal. The BGluM in the striatum was increased in the MSA group as compared to the SSA group; this effect was observed only in the isoflurane anesthesia, not the awake condition. These findings suggest that the choice of the FDG uptake condition may be important in preclinical PET studies and increased BGluM in the striatum may be associated with opiate seeking in withdrawal.

Section: Methodsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Effects of isoflurane anesthesia and intravenous morphine self‐administration on regional glucose metabolism ([¹⁸F]FDG‐PET) of male Sprague‐Dawley rats

Nishida

Wilson

et al. 2017

Eur J of Neuroscience

Self Cite

“…System as previously described (Le et al , 2014) for the bolus and infusion experiments. The ASR system consisted of 4 weight-sensitive platforms in 4 sound-attenuated chambers (Coulbourn Instruments, Columbus, OH).…”

Section: Sensorimotor Gating Asr Was Measured With a Startle Responsmentioning

confidence: 99%

Dose-response characteristics of intravenous ketamine on dissociative stereotypy, locomotion, sensorimotor gating, and nociception in male Sprague-Dawley rats

Radford

Pharmacology Biochemistry and Behavior

Lee

et al. 2017

Self Cite

Clinicians administer subanesthetic intravenous (IV) ketamine infusions for treatment of refractory depression, chronic pain, and post-traumatic stress disorder in humans. However, ketamine is administered via the subcutaneous (SC) or intraperitoneal (IP) routes to rodents in most pre-clinical research, which may limit translational application. The present study characterized the dose-response of a subanesthetic IV ketamine bolus (2 and 5mg/kg) and 1-h infusion (5, 10, and 20mg/kg/h) on dissociative stereotypy, locomotion, sensorimotor gating, and thermal nociception in male Sprague-Dawley rats. The secondary aim was to measure ketamine and norketamine plasma concentrations following IV ketamine bolus at 1, 20, and 50min and at the conclusion of the 1-h infusion using liquid chromatography/mass spectrometry. The results showed that ketamine bolus and infusions produced dose-dependent dissociative stereotypy. Bolus (2 and 5mg/kg) and 20mg/kg/h infusion increased locomotor activity while 5mg/kg/h infusion decreased locomotor activity. Both 10 and 20mg/kg/h infusions reduced the acoustic startle reflex, while 5mg/kg bolus and 20mg/kg/h infusion impaired pre-pulse inhibition. Ketamine 5mg/kg bolus and the 10 and 20mg/kg/h infusions induced significant and prolonged antinociception to the hotplate test. Plasma concentrations of ketamine decreased quickly after bolus while norketamine levels increased from 1 to 20min and plateaued from 20 to 50min. The peak ketamine plasma concentrations [ng/ml] were similar between 5mg/kg bolus [4100] vs. 20mg/kg/h infusion [3900], and 2mg/kg bolus [1700] vs. 10mg/kg/h infusion [1500]. These results support the findings from previous ketamine injection studies and further validate the feasibility of administering subanesthetic doses of IV ketamine infusion to rats for neuropharmacological studies.

“…In addition, spontaneous self-administration is believed to have a better validity when translating the reported results to human studies (Mello and Negus, 1996). Recently, there has been a study that examined the effects of chronic morphine self-administration (MSA) on the ASR and PPI (Le et al, 2014). However, the study investigated the effects of MSA in longer withdrawal (1 day and 1 week), and it is still unknown whether acute withdrawal from MSA alters ASR and PPI following MSA.…”

Section: Introductionmentioning

confidence: 99%

Altered Acoustic Startle Reflex, Prepulse Inhibition, and Peripheral Brain-Derived Neurotrophic Factor in Morphine Self-Administered Rats

Lee

Lin

et al. 2016

IJNPPY

Self Cite

Background:Previous studies suggested that opiate withdrawal may increase anxiety and disrupt brain-derived neurotrophic factor function, but the effects of i.v. morphine self-administration on these measures remain unclear.Methods:Adult male Sprague-Dawley rats were implanted with a catheter in the jugular vein. After 1 week of recovery, the animals were allowed to self-administer either i.v. morphine (0.5 mg/kg per infusion, 4 h/d) or saline in the operant conditioning chambers. The acoustic startle reflex and prepulse inhibition were measured at a baseline and on self-administration days 1, 3, 5, and 7 (1- and 3-hour withdrawal). Blood samples were collected on self-administration days 3, 5, and 7 from separate cohorts of animals, and the levels of brain-derived neurotrophic factor and corticosterone were assayed using the enzyme-linked immunosorbent assay method.Results:Compared with the saline group, the morphine self-administration group showed hyper-locomotor activity and reduced defecation during the self-administration. The morphine self-administration increased acoustic startle reflex at 1-hour but not 3-hour withdrawal from morphine and disrupted prepulse inhibition at 3-hour but not 1-hour withdrawal. The blood brain-derived neurotrophic factor levels were decreased in the morphine self-administration group at self-administration days 3 and 5, while the corticosterone levels remained unchanged throughout the study.Conclusions:The current findings suggest that spontaneous withdrawal from i.v. morphine self-administration may have transient effects on acoustic startle, sensorimotor gating, and peripheral brain-derived neurotrophic factor levels, and these changes may contribute to the adverse effects of opiate withdrawal.