Elsevier

Physiology & Behavior

Volume 161, 1 July 2016, Pages 104-115
Physiology & Behavior

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

https://doi.org/10.1016/j.physbeh.2016.03.037Get rights and content

Highlights

  • We analyzed the effect of restriction state on drug-induced suppression.

  • Cocaine efficacy was decreased by water and food restriction.

  • Morphine efficacy was decreased by water and food restriction.

  • LiCl was the most resistant to the disruptive effects of water or food restriction.

Abstract

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.

Introduction

In aversive conditioning, rats decrease intake of a saccharin conditioned stimulus (CS) when paired with unconditioned stimuli (US) that cause gastrointestinal distress such as LiCl or X-radiation [22], [48], [53], [67]. The magnitude of such conditioned taste aversions (CTA) increases with the intensity of the aversive US [28], [50], [69]. In a somewhat similar appetitive conditioning paradigm, rats decrease intake of a saccharin CS when it is paired with consumption of a highly preferred concentration of sucrose. This phenomenon is termed anticipatory contrast and is thought to occur because rats avoid intake of the lesser valued saccharin CS in anticipation of the availability of the preferred high concentration of sucrose [15], [16]. Rats also decrease intake of a saccharin CS when paired with the administration of a psychoactive drug such as morphine, cocaine, or amphetamine [4], [5], [14], [45]. This finding has been traditionally interpreted as a CTA induced by the aversive properties of drugs of abuse and, as such, as evidence that similar mechanisms mediate the suppressive effects of both drugs of abuse and LiCl [26], [27], [39], [51].

There is much evidence, however, that points to a distinct mechanism for taste avoidance induced by drugs of abuse compared with that induced by LiCl [28], [30], [33], [34], [37], [54], [55], [56], [65], [72]. For example, the suppressive effects of a rewarding sucrose US and drugs of abuse, but not LiCl, are similarly affected by manipulations of the intensity and palatability of the CS [3], [19], [28], [63], selectively bred strains [44], [12], bilateral lesions of the gustatory thalamus [20], [61], [64], [65], as well as exaggeration of the suppressive effects by chronic morphine treatment [37].

Indeed, more recent data have made it clear that LiCl and drugs of abuse do not merely differ in their drug properties, but in the nature of the conditioning process that is engaged in anticipation of their delivery. For example, when using intake tests that necessitate voluntarily consumption of the saccharin CS, the suppressive effects of LiCl, but not drugs of abuse, elicit aversive orofacial responses [38], [55], [56], [57]. When the CS is intraorally infused, however, we now know that both LiCl and cocaine can support the onset of conditioned aversive taste reactivity (i.e., gapes) to the CS [36], [71], [72]. The underlying mechanism in these cases is, nevertheless, distinct. For LiCl, the taste (CS) merely predicts nausea (US); for cocaine, the taste cue elicits a conditioned compensatory response (CCR) to the physiological and neurochemical impact of cocaine delivery. The CCR occurs during the waiting period, prior to cocaine consumption, and is, by definition, opposite to the drug's rewarding effects and likely contributes to tolerance [1], [43], [60]. Along these lines, avoidance of the drug-paired taste cue also is associated with elevated corticosterone levels [25] and blunted or even reduced levels of dopamine in the nucleus accumbens [31], [71]. Finally, as evidence that the CCR involves a negative affective and physiological state, greater avoidance of the taste cue and/or aversive taste reactivity is associated with a shorter latency to the first infusion of cocaine, a greater number of infusions of cocaine self-administered in the first 10 min of access (i.e., greater “load-up” behavior), a greater willingness to work for cocaine on a progressive ratio schedule, and more rapid acquisition of cocaine self-administration across trials [34], [36], [70], [72].

Another variable that may dissociate the suppressive effects of LiCl from drugs of abuse is restriction state. For example, when using a sucrose CS, food restriction exerts a greater disruption on the suppressive effects of a sucrose US and a drug of abuse than the suppressive effect of LiCl [18], [24]. Similarly, water restriction also prevents the avoidance of a sucrose CS when paired with morphine, but not LiCl [33]. Finally, when using a saccharin CS, food restriction disrupts the suppressive effects of amphetamine and chlordiazepoxide, while leaving those of a standard dose of LiCl intact [2]. Food- and water restriction, then, can attenuate avoidance of a taste cue and these effects might be greater when a drug of abuse, rather than the aversive agent, LiCl, serves as the US.

Since drugs of abuse and LiCl can vary in intensity, it is critical that the reduction in CS intake is compared across a range of doses. Dose effects, however, also can vary greatly across laboratories using slightly different testing regimens. For example, some have reported no differences in the magnitude of morphine-induced suppression of saccharin intake across a range of doses (9, 10, 20, 17, 50, and 80 mg/kg) of the drug [46], [62]. Others have reported greater suppressive effects with the lower doses [13], while others have reported greater suppressive effects with the higher doses of the drug [66]. Given conflicting reports of this nature, and the marked effect that restriction state can have on the willingness to avoid intake of an otherwise palatable gustatory cue [29], [35], a full, systematic investigation is warranted. To this end, the current series of experiments was designed to evaluate suppression of intake of a saccharin CS following pairings with morphine, cocaine, and LiCl across a range of doses in non-restricted, food restricted, and water restricted rats.

Section snippets

Subjects

The subjects were 695 male Sprague-Dawley rats (Charles Rivers Laboratories) weighing between 250 and 350 g (mean: ~ 290 g) at the beginning of the experiment. All rats were housed individually in stainless steel hanging cages in a temperature-controlled (21°) animal care facility with a 12:12 h light:dark cycle (lights on at 7:00 a.m.). All experimental manipulations were conducted approximately 3 h into the light phase of the cycle. The rats were maintained with free access to dry Harlan Teklad

Experiment 1A. Water restricted

An 8 × 8 mixed factorial ANOVA varying drug (saline, 0.002, 0.004, 0.009, 0.018, 0.037, 0.075, 0.15) and trials (1–8) was conducted on the data. Newman-Keuls post hoc tests of a significant Drug × Trials interaction, F(49, 448) = 11.49 p < 0.0001, indicated that suppression of the saccharin CS occurred in the later trials at lower doses and in the earliest trials at higher doses (see Fig. 1).

Specifically, at the three lowest doses, significant suppression began at the sixth, fifth, and third pairing,

Discussion

The current set of experiments was designed to compare LiCl-, morphine-, and cocaine-induced avoidance of a preferred 0.15% saccharin solution in rats that were water restricted, food restricted, or non-restricted using an extensive dose-response analysis. Importantly, all of the doses employed for each of the three drugs produced significant conditioned avoidance of the saccharin CS when taste-drug pairings were evaluated in a non-restricted state. However, this avoidance was disrupted when

Acknowledgements

The research was supported by the National Institutes of Health, National Institute of Drug Addiction [Grant DA009815].

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