The role of dose and restriction state on morphine-, cocaine-, and LiCl-induced suppression of saccharin intake: A comprehensive analysis
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].
References (74)
- et al.
Effects of food deprivation on conditioned taste aversions in rats
Pharmacol. Biochem. Behav.
(1998) Augmentation of drug reward by chronic food restriction: behavioral evidence and underlying mechanisms
Physiol. Behav.
(2002)- et al.
Prior access to a sweet is more protective against cocaine self-administration in female rats than in male rats
Physiol. Behav.
(2013) - et al.
Morphine-induced place conditioning in Fischer and Lewis rats: acquisition and dose-response in a fully biased procedure
Pharmacol. Biochem. Behav.
(2007) - et al.
Cocaine-induced taste aversions: effect of route of administration
Pharmacol. Biochem. Behav.
(1991) - et al.
Relative hedonic value modulates anticipatory contrast
Physiol. Behav.
(1994) - et al.
The suppressive effects of LiCl, sucrose, and drugs of abuse are modulated by sucrose concentration in food-deprived rats
Physiol. Behav.
(1999) - et al.
Morphine-induced suppression of saccharin intake is correlated with elevated corticosterone levels
Brain Res.
(2000) Aversive stimulus properties of drugs
Neuropharmacology
(1979)- et al.
Cocaine-induced conditioned taste aversions in rats
Pharmacol. Biochem. Behav.
(1978)
The suppressive effects of intraperitoneal cocaine are augmented when evaluated in nondeprived rats
Pharmacol. Biochem. Behav.
Bilateral lesions of the gustatory thalamus disrupt morphine- but not LiCl-induced intake suppression in rats: evidence against the conditioned taste aversion hypothesis
Brain Res.
Water-deprivation prevents morphine-, but not LiCl-induced, suppression of sucrose intake
Physiol. Behav.
Heroin-induced suppression of saccharin intake in water-deprived and water-replete rats
Pharmacol. Biochem. Behav.
The taste reactivity test. I. Mimetic responses to gustatory stimuli in neurologically normal rats
Brain Res.
Conditioned taste aversion induced by self-administered drugs: paradox revisited
Neurosci. Biobehav. Rev.
Opioid modulation of taste hedonics within the ventral striatum
Physiol. Behav.
Antagonism of morphine-induced aversive conditioning by naloxone
Pharmacol. Biochem. Behav.
Conditioned sucrose aversions produced by naloxone-precipitated withdrawal from acutely administered morphine
Pharmacol. Biochem. Behav.
Learned taste aversions in rats as a function of dosage, concentration, and route of administration of LiCl
Physiol. Behav.
Positively reinforcing drugs may produce a different kind of CTA than drugs which are not positively reinforcing
Learn. Motiv.
Orofacial and somatic responses elicited by lithium-, nicotine- and amphetamine-paired sucrose solution
Pharmacol. Biochem. Behav.
Morphine-induced taste avoidance is attenuated with multiple conditioning trials
Pharmacol. Biochem. Behav.
Cocaine cues drive opposing context-dependent shifts in reward processing and emotional state
Biol. Psychiatry
Behavioral and electrophysiological indices of negative affect predict cocaine self-administration
Neuron
Pre-drug cues modulate morphine tolerance, striatal c-Fos, and AP-1 DNA binding
Neuroreport
Second order conditioning detects unexpressed morphine-induced salt aversion
Anim. Learn. Behav.
Conditioned aversion to saccharin by single administrations of mescaline and d-amphetamine
Psychopharmacologia
Aversive conditioning by psychoactive drugs: effects of morphine, alcohol and chlordiazepoxide
Psychopharmacologia
Chronic food restriction in rats augments the central rewarding effect of cocaine and the delta1 opioid agonist, DPDPE, but not the delta2 agonist, deltorphin-II
Psychopharmacology
Ketoconazole suppresses food restriction-induced increases in heroin self-administration in rats: sex differences
Exp. Clin. Psychopharmacol.
Conditioned aversion for a cocaine-predictive cue is associated with cocaine seeking and taking in rats
International journal of comparative psychology/ISCP
Once is too much: conditioned aversion develops immediately and predicts future cocaine self-administration behavior in rats
Behav. Neurosci.
Morphine injections in the taste aversion paradigm
Physiol. Psychol.
Anticipation of incentive gain
Anim. Learn. Behav.
From contrast to reinforcement: role of response contingency in anticipatory contrast
J Exp Psychol Anim Behav Process
Incentive Relativity
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