Christopher S. Freet

The suppressive effects of sucrose and cocaine, but not lithium chloride, are greater in lewis than in Fischer rats: Evidence for the reward comparison hypothesis

Rats suppress intake of a saccharin conditioned stimulus (CS) when it is paired with an aversive unconditioned stimulus (US), an appetitive US, or a drug of abuse such as morphine or cocaine. It is unclear, however, whether the reduction in intake induced by these drugs is mediated by their aversive or their rewarding properties. The present set of experiments addressed this question by comparing the suppressive effects of a known aversive US (LiCl), a known reinforcing US (sucrose), and a drug of abuse (cocaine) in two strains of rats (i.e., Lewis and Fischer 344 rats) that differ in their preference for rewarding stimuli. The results show that, although both strains readily acquired a LiCl-induced conditioned taste aversion (CTA), the suppressive effects of sucrose and cocaine were robust in the drug-preferring Lewis rats and absent in the Fischer rats. These data argue against a CTA account and in favor of the reward comparison hypothesis.

Baroreflex and chemoreflex controls of sympathetic activity following intermittent hypoxia

There is a large amount of evidence linking obstructive sleep apnea (OSA), and the associated intermittent hypoxia that accompanies it, with the development of hypertension. For example, cross-sectional studies demonstrate that the prevalence of hypertension increases with the severity of OSA (Bixler et al., 2000; Grote et al., 2001) and an initial determination of OSA is associated with a three-fold increase for future hypertension (Peppard et al., 2000). Interestingly, bouts of intermittent hypoxia have also been shown to affect sympathetic output associated with the baroreflex and chemoreflex, important mechanisms in the regulation of arterial blood pressure. As such, the possibility exists that changes in the baroreflex and chemoreflex may contribute to the development of chronic hypertension observed in OSA patients. The aim of the current article is to briefly review the response of the baroreflex and chemoreflex to intermittent hypoxic exposure and to evaluate evidence for the hypothesis that modification of these autonomic reflexes may, at least in part, support the comorbidity observed between chronic hypertension and OSA.

Lewis rats are more sensitive than Fischer rats to successive negative contrast, but less sensitive to the anxiolytic and appetite-stimulating effects of chlordiazepoxide.

Lewis rats show greater anticipatory contrast effects than Fischer 344 rats. Specifically, relative to Fischer rats, Lewis rats exhibit greater avoidance of a saccharin cue when it predicts the future availability of a preferred sucrose reward [Grigson, P.S., Freet, C.S. The suppressive effects of sucrose and cocaine, but not lithium chloride, are greater in Lewis than in Fischer rats: evidence for the reward comparison hypothesis. Behav Neurosci 2000;114:353-363.]. Experiment 1 was designed to determine whether Lewis rats also would demonstrate greater contrast in another paradigm, successive negative contrast (SNC). The results demonstrated a tendency for greater SNC in Lewis rats and then slower recovery from the unexpected loss of reward relative to the Fischer rats. Pretreatment with the anxiolytic agent, chlordiazepoxide (CDP), effectively eliminated contrast in the Fischer rats, but served to prolong recovery from contrast in the Lewis rats. Finally, the results of Experiment 2 demonstrated that Fischer rats, but not Lewis rats, increase consumption of a 0.1 M sucrose solution following pretreatment with CDP. Together, the results show that, while both Lewis and Fischer rats demonstrate SNC, the effect is more sustained in the Lewis rats and these rats are insensitive to both the anxiolytic and the appetite-stimulating effects of CDP.

Compared with DBA/2J mice, C57BL/6J mice demonstrate greater preference for saccharin and less avoidance of a cocaine-paired saccharin cue.

Rats avoid intake of a saccharin cue when paired with a drug of abuse. While this is true for most subjects, the degree of avoidance of the drug-paired cue depends upon many factors including an individual rats preference for rewards. That said, the direction of this effect is complex. For example, reward-preferring Lewis rats exhibit greater cocaine-induced avoidance of a saccharin cue relative to Fischer 344 rats; while reward-preferring mice that overexpress ΔFosB (NSE-tTA × TetOp-ΔFosB) exhibit less avoidance of the drug-paired taste cue compared to controls. The aim here was to use two strains of commonly used mice, C57BL/6J and DBA/2J, to determine whether known differences in sensitivity to rewards will facilitate or attenuate drug-induced suppression of intake of a drug-paired taste cue. The results of Experiment 1 demonstrate that C57BL/6J mice, compared with DBA/2J mice, exhibit attenuated suppression of saccharin intake when it is paired with cocaine. The results of Experiment 2 demonstrate that strain differences in impulsivity are not likely to account for these differences. It is proposed that, while the C57BL/6J mice typically are more responsive to drug, they also are more responsive to natural rewards (in this case saccharin), and the stronger preference for saccharin serves to militate against drug.

Increased intravenous morphine self-administration following Roux-en-Y gastric bypass in dietary obese rats.

Roux-en-Y gastric bypass (RYGB) surgery is a commonly performed and very effective method to achieve significant, long-term weight loss. Opioid analgesics are primarily used to manage postoperative pain as fewer alternative medication options are available for bariatric surgery patients than for the general population. Recent clinical studies support a greater risk for substance use following bariatric surgery, including an increased use of opioid medications. The present study is the first to study morphine self-administration in a rat model of RYGB. High fat diet-induced obese (HFD-DIO) rats underwent RYGB (n=14) or sham-surgery with ad libitum HFD (SHAM, n=14) or a restricted amount that resulted in weight matched to the RYGB cohort (SHAM-WM, n=8). An additional normal-diet (ND, n=7), intact (no surgery) group of rats was included. Two months after the surgeries, rats were fitted with jugular catheters and trained on a fixed ratio-2 lick task to obtain morphine intravenously. Both morphine-seeking (number of licks on an empty spout to obtain morphine infusion) and consumption (number of infusion) were significantly greater in RYGB than any control group beginning on day 3 and reached a two-fold increase over a period of two weeks. These findings demonstrate that RYGB increases motivation for taking morphine and that this effect is independent of weight loss. Further research is warranted to reveal the underlying mechanisms and to determine whether increased morphine use represents a risk for opioid addiction following RYGB. Identifying risk factors preoperatively could help with personalized postoperative care to prevent opioid abuse and addiction.

Fischer rats are more sensitive than Lewis rats to the suppressive effects of morphine and the aversive kappa-opioid agonist spiradoline.

Data have suggested that rats avoid intake of an otherwise palatable saccharin cue when paired with a drug of abuse, at least, in part, because the value of the taste cue pales in anticipation of the availability of the highly rewarding drug. Earlier support for this hypothesis was provided by the finding that, relative to the less sensitive Fischer rats, Lewis rats exhibit greater avoidance of a saccharin cue when paired with a rewarding sucrose or cocaine unconditioned stimulus (US), but not when paired with the aversive agent, lithium chloride. More recent data, however, have shown that Fischer rats actually exhibit greater, not less, avoidance of the same saccharin cue when morphine serves as the US. Therefore, Experiment 1 evaluated morphine-induced suppression of intake of the taste cue in Lewis and Fischer rats when the morphine US was administered subcutaneously, rather than intraperitoneally. Experiment 2 examined the effect of strain on the suppression of intake of the saccharin cue when paired with spiradoline, a selective kappa-opioid receptor agonist. The results confirmed that Fischer rats are more responsive to the suppressive effects of morphine than Lewis rats, and that Fischer rats also exhibit greater avoidance of the saccharin cue when paired with spiradoline, despite the fact that spiradoline is devoid of reinforcing properties. Taken together, the data suggest that the facilitated morphine-induced suppression observed in Fischer rats, compared with Lewis rats, may reflect an increased sensitivity to the aversive, kappa-mediated properties of opiates.

Pontine and thalamic influences on fluid rewards: I. Operant responding for sucrose and corn oil

The reward strength of orosensory sucrose and corn oil was measured using fixed and progressive ratio operant schedules. Because the orosensory effects of the stimuli were of interest, Experiment 1 compared operant responses for sucrose in sham and real feeding rats. The results demonstrated that rats would work for sucrose solutions without the accompanying postingestive effects. Furthermore, the break points for high concentrations of sucrose (1.0 M or 2.0 M) were significantly higher in sham feeding rats than in real feeding controls. Experiment 2 investigated the role of the parabrachial nucleus (PBN) and of the thalamic orosensory area (TOA) in sucrose and corn oil reward. During free access, rats with PBN lesions (PBNx) licked significantly less sucrose solution than their controls, but both groups ingested a similar volume of corn oil emulsion. When an operant was imposed, these same PBNx rats failed to respond for sucrose and continued only modestly for corn oil. In contrast, the TOA lesioned rats (TOAx) showed no impairment in responding for sucrose or corn oil during either the free access or operant sessions. Furthermore, rats with TOA lesions demonstrated significantly higher break points for sucrose than did their controls. Together, the data imply that the PBN but not the TOA is critical for the perception of, or responding to the reward value of sucrose and corn oil.

The role of dose and restriction state on morphine-, cocaine-, and LiCl-induced suppression of saccharin intake: A comprehensive analysis

Rats avoid intake of a taste cue when paired with a drug of abuse or with the illness-inducing agent, lithium chloride (LiCl). Although progress has been made, it is difficult to compare the suppressive effects of abused agents and LiCl on intake of a gustatory conditioned stimulus (CS) because of the cross-laboratory use of different CSs, different unconditioned stimuli (USs), and different doses of the drugs, different conditioning regimens, and different restriction states. Here we have attempted to unify these variables by comparing the suppressive effects of a range of doses of morphine, cocaine, and LiCl on intake of a saccharin CS using a common regimen in non-restricted, food restricted, or water restricted male Sprague-Dawley rats. The results showed that, while the putatively aversive agent, LiCl, was effective in suppressing intake of the taste cue across nearly all doses, regardless of restriction state, the suppressive effects of both morphine and cocaine were greatly reduced when evaluated in either food or water restricted rats. Greater sensitivity to drug was revealed, at very low doses, when testing occurred in the absence of need (i.e., when the rats were non-restricted). Together, these results provide the first uniform and comprehensive analysis of the suppressive effects of morphine, cocaine, and LiCl as a function of dose and restriction state. In the present case, the suppressive effects of morphine and cocaine are found to differ from those of LiCl and, in some respects, from one another as well.

Ceftriaxone attenuates acquisition and facilitates extinction of cocaine-induced suppression of saccharin intake in C57BL/6J mice.

Growing evidence implicates glutamate homeostasis in a number of behaviors observed in addiction such as acquisition of drug taking, motivation, and reinstatement. To date, however, the role of glutamate homeostasis in the avoidance of natural rewards due to exposure to drugs of abuse has received little attention. The aim of the current study was to evaluate the beta-lactam antibiotic, ceftriaxone, which has been shown to normalize disrupted glutamate homeostasis associated with exposure to drugs of abuse, in cocaine-induced suppression of saccharin intake in C57BL/6J mice. Briefly, C57BL/6J mice received daily injections of either 200mg/kg ceftriaxone or saline. Mice were then given access to 0.15% saccharin for 1h and immediately injected intraperitoneally with either saline or 30 mg/kg cocaine; taste-drug pairings occurred every 24h for 5 trials followed by a final CS only trial. One week following taste-drug pairings, extinction was evaluated in a series of one- and two-bottle saccharin intake tests. Individual differences in cocaine-induced suppression were observed (i.e., low and high suppressors) with differential effects of ceftriaxone. Ceftriaxone delayed suppression of saccharin intake in high suppressors but prevented suppression in low suppressors. In addition, ceftriaxone history facilitated extinction in the high suppressors. These data suggest that changes in glutamate homeostasis may be involved in the formation and expression of cocaine-induced suppression of saccharin intake in mice.