Rats learn to like the taste of morphine.

When rats are forced to drink a morphine solution as their only source of fluid, they eventually reverse their initial preference and drink more morphine than water in a 2-bottle preference test. Two experiments with 13 male Holtzman rats examined the cause of this shift in preference using the taste reactivity test, which involves the analysis of fixed action patterns elicited by taste solutions infused into Ss' mouths. Three morphine concentrations (0.03, 0.6, and 1.5 mg/ml) and 2 levels of motivation (drug-replete and drug-withdrawal states) were studied. A greater percentage of ingestive taste reactivity responses occurred to the oral morphine infusion in morphine-raised than in water-raised Ss. Data are inconsistent with the idea that enhanced morphine ingestion is caused by anticipation of positive consequences. Instead, they support the idea that rats come to "like" the flavor of the morphine solution; in other words, the palatability evaluation of the morphine changes, possibly through an association between the flavor and the hedonically positive effects of the morphine. (33 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Altering dietary levels of protein or vitamins and minerals does not modify morphine-induced analgesia in male rats

Previous research has demonstrated that chronic intake of nutritive sweet solutions, but not nonnutritive sweet solutions, enhances morphine's analgesic potency. To separate out the effects of sweet taste from other changes in dietary intake, which result when rats consume a sucrose solution, the effects of altering dietary levels of protein, or vitamins and minerals on morphine-induced analgesia were examined. In Experiment 1, 40 male Long-Evans rats were fed standard chow or a semipurified diet containing either 10, 20, or 40% protein. Three weeks later, antinociceptive responses to morphine were examined using the tail flick procedure. Tail flick latencies were measured immediately prior to and 30, 60, and 90 min after the administration of morphine sulfate (0.0, 1.25, 2.5, and 5.0 mg/kg, SC). At all three measurement times, antinociceptive responses increased directly as a function of the dose of morphine, but did not differ as a function of diet. In Experiment 2, 24 rats were maintained on either standard laboratory chow or semipurified diets containing 20% protein and either 100% or 25% of the recommended levels of vitamins and minerals for 3 weeks. Tail flick latencies were measured immediately prior to and 30 min after injections (SC) of 2.5 mg/kg morphine sulfate. This procedure was repeated until a cumulative dose of 10.0 mg/kg was obtained. Tail flick latencies increased significantly as a function of drug dose, but did not differ across dietary conditions. These results demonstrate that the increase in morphine-induced analgesia seen in rats consuming a sucrose solution is not due to alterations in either protein or micronutrient intake.     

A quantitative comparison of taste reactivity behaviors to sucrose before and after lithium chloride pairings: A unidimensional account of palatability.

Alterations in the motivation to ingest sucrose can be quantified by measuring the number and type of oral motor and somatic responses (i.e., taste reactivity [TR]) that are elicited by sucrose. In 2 experiments, rats had intraorally infused sucrose paired with LiCl injections for several trials, or they were injected with LiCl and had sucrose infused every 5 min during the 30-min postinjection period (data from A. C. Spector et al, 1988). In both experiments, ingestive TR responses decreased, whereas aversive TR responses increased over trials. Individual response components that comprise the ingestive and aversive categories followed the same trends of increase or decrease but changed at different rates as a function of number of trials or exposures. Overall, the array of response components could be projected onto a single unidimensional scale of palatability to capture the motivational states that ranged from acceptance to rejection. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

"Taste reactivity responses elicited by cocaine-, phencyclidine-, and methamphetamine-paired sucrose solutions": Correction to Parker.

Reports an error in "Taste reactivity responses elicited by cocaine-, phencyclidine-, and methamphetamine-paired sucrose solutions" by Linda A. Parker (Behavioral Neuroscience, 1993[Feb], Vol 107[1], 118-129). Table 1, on page 119, contains two errors. In the first section, the dose/route for the agent nicotine should read as follows: 1.2-2.0 mg/kg sc. In the second section, the dose/route for the agent morphine should read as follows: 2-80 mg/kg ip. Also, on page 121, paragraph 3, line 14, the parenthetical information after 40 mg/kg cocaine should read (40C; 2 × 20 mg/kg/3 cc). (The following abstract of the original article appeared in record 1993-24959-001.) The nature of flavor–drug associations produced by a range of doses of the reinforcing agents cocaine (5, 10, 15, 20, or 40 mg/kg, sc), phencyclidine (0.5, 2, 10, or 20 mg/kg, sc), and methamphetamine (2, 5, or 10 mg/kg, ip) were assessed by the taste reactivity (TR) test and the conditioned taste avoidance (CTA) test. Even at the highest doses tested, none of the agents produced aversive TR responding. At doses that produced equivalent-strength CTA, lithium did establish aversive TR responding. Results provide evidence that drugs that serve as reinforcers in other paradigms produce conditioned flavor avoidance that is not motivated by a conditioned dislike for the flavor. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Taste reactivity as a dependent measure of the rapid formation of conditioned taste aversion: A tool for the neural analysis of taste-visceral associations.

Investigated the ability of animals to form taste aversions following neural manipulations. In Exp 1, 10 rats received intraoral infusions of sucrose every 5 min starting immediately after the injection of LiCl. 12 controls were injected with NaCl. Oromotor and somatic taste reactivity behaviors were videotaped and analyzed. Lithium-injected Ss decreased their ingestive taste reactivity over time; aversive behavior increased. Controls maintained high levels of ingestive responding and demonstrated virtually no aversive behavior following sodium injection. Ss were tested several days later for a conditioned taste aversion (CTA). Rats previously injected with lithium demonstrated significantly more aversive behavior than controls. Exp 3 revealed that when similarly treated rats were tested for a CTA while in a lithium-induced state, difference in the ingestive behavior was observed. In Exp 2, naive rats were injected with NaCl or LiCl but did not receive their 1st sucrose infusion for 20 min. Ss also received infusions at 25 and 30 min postinjection. There were no differences in the task reactivity behavior displayed. Rats dramatically changed their oromotor responses to sucrose during the period following LiCl administration, provided the infusions started immediately after injection, a change attributable to associative processes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Column-switching high-performance liquid chromatographic assay for determination of apigenin and acacetin in human urine with ultraviolet absorbance detection

Postweaning social isolation can influence the sensitivity of rats to several effects of drugs of abuse. The present study investigated the influence of postweaning housing conditions on the sensitivity of rats to the aversive effects of a number of psychoactive agents using a conditioned taste aversion (CTA) test procedure. Development of a CTA was assessed by pairing administration of the drug with the consumption of a 0.05% (weight/volume) saccharin solution in water-deprived (18 h) rats in a 20 min drinking period. Saccharin consumption was then measured in 20 min test sessions over the next 4 consecutive days. Consumption of saccharin solution was significantly reduced in both isolated and enriched rats following administration of d-amphetamine (2 mg/kg), cocaine (30 mg/kg), morphine (10 mg/kg), nicotine (1.0 mg/kg), caffeine (20 mg/kg), alcohol (1.5 g/kg), and LiCl (0.15 M, 4 ml/kg). There was no significant effect of housing conditions on the CTA induced by cocaine, nicotine, alcohol, or LiCl; however, isolation-reared rats were found to be less sensitive to the aversive effects of d-amphetamine, morphine, and caffeine in this paradigm. These results suggest that rearing rats in social isolation induces an attenuation in sensitivity to the aversive effects of some psychoactive agents.     

Taste reactivity to alcohol and basic tastes in outbred mice

The taste reactivity test was used to determine the response of outbred mice to orally infused taste solutions. For the initial measures, mice (n = 10) were tested with 3%, 6%, 9%, and 12% (v/v) alcohol and four taste solutions: sucrose, sodium chloride, hydrochloric acid, and quinine hydrochloride (a single concentration of each). A second group of naive mice (n = 16) was tested with 5%, 10%, 20%, 30%, and 40% alcohol. The final set of measures with naive mice (n = 26) was taken with a range of sucrose concentrations: 0.01 M, 0.05 M, 0.1 M, 0.5 M, and 1.0 M. In general, mice made similar reactivity responses to all solutions tested. A predominant component of the mouse response to all infused fluids was forelimb flailing; gaping was also a common response to all solutions. Despite the large number of aversive-type responses, mice rejected very little fluid via passive drip or fluid expulsion. The single, significant difference in responding to the four taste stimuli was that mice made fewer aversive responses to sucrose. Differential responding to the 5 to 40% alcohol concentrations and sucrose concentrations was observed. Mice increased ingestive responding as the concentration of alcohol and sucrose increased. Aversive responding decreased reliably only with increases in the sucrose concentration. Data provide the first reported taste reactivity responses of mice to orally infused taste solutions. These results can be compared with the extant data available in rats and can also be used as a basis for exploring taste factors in genetically defined mouse populations.     

Once is too much: Conditioned changes in accumbens dopamine following a single saccharin-morphine pairing.

The present study tested whether presentation of a taste cue would support conditioned suppression of dopamine in the nucleus accumbens (NAcc) following a single taste-drug pairing. Nondeprived male Sprague-Dawley rats were given 20-min access to a 0.15% saccharin conditioned stimulus (CS). Immediately thereafter, experimental rats were injected with morphine (15 mg/kg ip); standard controls were injected with saline; and explicitly unpaired controls were injected with morphine, but approximately 24 hr later. All rats were then given one 20-min CS-only test. Microdialysis samples from the NAcc were measured over 20-min intervals before, during, and after CS access on the conditioning and test trial. The results showed that a single saccharin-morphine pairing led to a marked reduction in CS intake, and the reduction in intake was accompanied by a conditioned blunting of the accumbens dopamine response to the saccharin reward cue. In turn, a single exposure to the saccharin cue also blunted the unconditioned dopamine response to morphine. Reward comparison effects, then, are cross-modal, bidirectional, and immediate, resulting in both unconditioned and conditioned changes in brain and behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chronic morphine treatment exaggerates the suppressive effects of sucrose and cocaine, but not lithium chloride, on saccharin intake in Sprague-Dawley rats.

Three experiments examined the effect of chronic morphine treatment on cocaine-, sucrose-, and lithium chloride (LiCl)-induced suppression of saccharin intake in Sprague-Dawley rats. All rats were either water- or food-deprived and then implanted subcutaneously with 1 morphine (75 mg) or vehicle pellet for 5 days. They were then given brief access to 0.15% saccharin and soon thereafter injected with either cocaine (10 mg/kg sc) LiCl (0.009 M, 1.33 ml/100 g body weight ip), or saline, or in Exp 2, given a 2nd access period to either a preferred 1.0 M sucrose solution ot the same 0.15% saccharin solution. There was 1 taste–drug or taste–taste paring per day for a number of days. The results showed that a history of chronic morphine treatment exaggerated the suppressive effects of a rewarding sucrose solution and cocaine but not those of the aversive agent, LiCl. These data provide further support for the reward compairison hypothesis. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Morphine- and naltrexone-induced modification of palatability: Analysis by the taste reactivity test.

Used the taste reactivity (TR) test, a direct measure of the hedonic properties of a tastant, to assess in Sprague-Dawley rats the ability of morphine (an opiate agonist) and naltrexone (an opiate antagonist) to modify the palatability of a bitter quinine solution and a sweet sucrose solution. Morphine reduced the aversive hedonic properties of both novel and familiar quinine solution (0.05% and 0.1%) but did not modify the palatability of 20% sucrose solution. Naltrexone reduced the positive hedonic properties of sucrose solution (2% and 20%) but did not modify the palatability of 0.05% quinine solution. The pattern of results suggests that the modification of feeding produced by opiate agonists and antagonists may be mediated by a hedonic shift in the palatability of the tastant. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Morphine-conditioned changes in locomotor activity: Role of the conditioned stimulus.

When a multisensory environment was reliably paired with morphine (2 mg/kg) in rats, that environment, in a drug-free test, evoked a hyperactive conditioned response (CR). When an olfactory cue (banana odor) was the only stimulus element reliably paired with morphine, it also elicited a hyperactive CR. However, a gustatory cue (saccharin solution) evoked a hypoactive CR. This taste-elicited decrease in activity was dose dependent; morphine at 2 and 4 mg/kg conditioned hypoactivity, whereas a higher dose (8 mg/kg) did not. A robust conditioned saccharin aversion occurred only at the highest dose of morphine, suggesting disassociation between the hypoactive CR and taste aversion. A taste cue present during context conditioning also prevented either acquisition or expression of the hyperactive CR to the context. The modality of the conditioned stimulus is a critical determinant of the form of the CR in a morphine locomotor conditioning paradigm. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of caerulein and CCK antagonists on tolerance induced to morphine antinociception in mice

Different groups of mice received one daily dose (50 mg/kg) of morphine subcutaneously (SC) for 3, 4 or 5 days to develop tolerance to the opioid. The antinociceptive response of morphine (9 mg/kg) was tested in the hot-plate test 24 h after the last dose of the drug. Tolerance to morphine was obtained in all groups. The group of mice that received morphine for 4 days was employed for the rest of the experiments. Pretreatment of animals with a single dose of caerulein (0.025, 0.05, and 0.1 mg/kg, SC) 30 min prior to receiving morphine (50 mg/kg; during the development of tolerance to the opioid) on day 1, 2, 3, 4 or 5 of morphine administration potentiate antinociception induced by morphine (test dose of 9 mg/kg). The dose of 0.05 mg/kg of caerulein, used 30 min before morphine administration on day 3, was also used to evaluate the effects of antagonists on caerulein-induced decrease in tolerance. The selective cholecystokinin (CCK) receptor antagonists, MK-329 [1-methyl-3-(2 indoloyl)amino-5-phenyl-3H-1,4-benzodiazepin-2-one; 0.25 and 0.5 mg/kg] or L-365,260 [3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H- 1,4-benzodiazepin-3-yl)-N-(3-methyl-phenyl)urea: 0.25 and 0.5 mg/kg] decreased potentiation of morphine response induced by caerulein. MK-329 or L-365,260, when were injected 35 min before morphine injection during the development of tolerance and on day 3, decreased the tolerance to morphine. A single administration of MK-329 or L-365,260 (in the absence of caerulein) 35 min and 48 h before the test dose of morphine (9 mg/kg) potentiated the antinociception of morphine in nontolerant animals. In conclusion, CCK mechanism(s) may interact with morphine tolerance.     

Taste reactivity responses elicited by cocaine-, phencyclidine-, and methamphetamine-paired sucrose solutions.

[Correction Notice: An erratum for this article was reported in Vol 107(2) of Behavioral Neuroscience (see record 2008-10474-001). Table 1, on page 119, contains two errors. In the first section, the dose/route for the agent nicotine should read as follows: 1.2-2.0 mg/kg sc. In the second section, the dose/route for the agent morphine should read as follows: 2-80 mg/kg ip. Also, on page 121, paragraph 3, line 14, the parenthetical information after 40 mg/kg cocaine should read (40C; 2 × 20 mg/kg/3 cc).] The nature of flavor–drug associations produced by a range of doses of the reinforcing agents cocaine (5, 10, 15, 20, or 40 mg/kg, sc), phencyclidine (0.5, 2, 10, or 20 mg/kg, sc), and methamphetamine (2, 5, or 10 mg/kg, ip) were assessed by the taste reactivity (TR) test and the conditioned taste avoidance (CTA) test. Even at the highest doses tested, none of the agents produced aversive TR responding. At doses that produced equivalent-strength CTA, lithium did establish aversive TR responding. Results provide evidence that drugs that serve as reinforcers in other paradigms produce conditioned flavor avoidance that is not motivated by a conditioned dislike for the flavor. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Amphetamine and morphine produce a conditioned taste and place preference in the house musk shrew (Suncus murinus).

Rats have been shown to avoid consuming a flavor, but prefer a location, previously paired with amphetamine or morphine. A series of 4 experiments evaluated the hedonic properties of amphetamine and morphine in the house musk shrew (Suncus murinus), an insectivore that (unlike rats) is capable of vomiting when exposed to toxins. Unlike rats, amphetamine (20 mg/kg) and morphine (20 mg/kg) produced both a conditioned sucrose (0.3 M) and saccharin (0.1%) preference in shrews (administered intraperitoneally), when measured by both a 1-and a 2-bottle test. At the same dose, both drugs also produced a place preference in shrews. These results suggest that the potential of rewarding drugs to produce taste avoidance may vary on the basis of the ability of the species to vomit. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sodium depletion enhances salt palatability in rats.

Stereotyped fixed action patterns (FAPs) elicited in rats by oral infusions of taste solutions can be classified as either ingestive or aversive. They reflect the palatability of the taste and can be modified by learning and by the physiological state of the animal. The present 2 experiments, with 5 male Sprague-Dawley rats, demonstrated that when the physiological state of the S was altered by sodium depletion, the pattern of FAPs elicited by oral infusions of 0.5 M NaCl shifted from a mixture of ingestive and aversive components (while sodium replete) to exclusively ingestive ones (while sodium deplete). This shift in taste reactivity occurred the 1st time the Ss were made sodium deplete. A similar shift did not accompany infusions of 0.01 M HCl, a taste solution that also elicited mixed ingestive and aversive FAPs. This result suggests that the shift in response to NaCl was not due to a general change in ingestive bias or to a general taste deficit. On the basis of the change in FAPs, it is concluded that the palatability of highly concentrated salt solutions increases in sodium-deplete rats. Such a shift in salt palatability may be instrumental in directing the appetitive behavior of the animal. (33 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Associative and nonassociative tolerance: the effects of dose and interdose interval

Two experiments examined the effects of dose and interdose interval (IDI) on associative and nonassociative tolerance to morphine analgesia in rats. Associative contingencies were manipulated by administering low (5 mg/kg) or high (20 mg/kg) doses of morphine explicitly paired or unpaired with a distinctive context. Nonassociative processes were manipulated by administering morphine at a short (6-h) or long (96-h) IDI. Tolerance was assessed as shifts in morphine dose-response curves on the tail-flick test. Animals in the long IDI conditions showed considerable context-specific tolerance. Tolerance in the short IDI conditions was not influenced by contextual contingencies at the immediate test (Experiment 1) and showed no retention over a 30-day interval (Experiment 2), suggesting this tolerance was nonassociative. The impact of massed exposure to morphine and context on the disruption of learning at the short IDI is discussed.     

Effects of stress on morphine-elicited locomotor activity in hamsters.

Two experiments were conducted to investigate the effects of stress on morphine-elicited locomotor activity in hamsters. In Experiment 1, half of the animals were habituated to handling and injection procedures (low-stress condition) and half were not (high-stress condition) prior to 6 days of testing with a low dose (2.5 mg/kg) of morphine. On the first test day, morphine elicited hyperactivity among habituated animals, whereas among nonhabituated animals morphine elicited hypoactivity. The effects of handling diminished across test days, so that on the last test day, morphine elicited hyperactivity in both habituated and nonhabituated animals. In Experiment 2, the effect of a noise stressor on activity elicited by three doses of morphine (2.5, 5.0, and 15 mg/kg) was investigated. Half of the animals were tested under conditions of low noise stress (70 dB), and half were tested under conditions of high noise stress (90 dB). Results indicated that the effects of each dose of morphine were potentiated in the high-stress relative to the low-stress condition. Both experiments demonstrated that environmental stressors can potentiate the response to exogenous opiate administration in hamsters. Moreover, the results are consistent with the hypothesis that stress induces the release of endogenous opioids which summate with exogenous opiates to determine the final effective dose. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Area postrema mediates the formation of rapid, conditioned palatability shifts in lithium-treated rats.

The rapid acquisition and subsequent retention of lithium-induced conditioned changes in taste reactivity responses to sucrose were examined in rats with the area postrema (AP) either ablated or intact. On 2 conditioning days, a series of brief intraoral sucrose infusions was paired with the effects of LiCl or NaCl injections. Repeated associations of the sucrose taste with the effects of lithium significantly reduced ingestive responses and increased aversive responses only in the AP-intact group. AP-ablated rats treated with LiCl and rats injected with NaCl displayed an ingestive pattern of responses. Only the AP-intact rats, previously injected with LiCl, subsequently displayed evidence of a conditioned taste aversion. We conclude that toxin activation of the AP is required to produce the conditioned shift in taste reactivity responses and subsequent expression of a taste aversion in rats treated with lithium. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

LSD produces place preference and flavor avoidance but does not produce flavor aversion in rats.

The hedonic properties of lysergic acid diethylamide (LSD) were assessed using the place conditioning, taste reactivity, and taste avoidance tests. LSD produced a conditioned place preference, but only at the highest dose tested (0.2 mg/kg). A single preexposure to the conditioning chamber (latent inhibition) prevented the establishment of a place preference. When paired with sucrose, doses of 0.05 to 0.2 mg/kg of LSD produced taste avoidance, but no dose of LSD produced an aversion to the taste as assessed by the taste reactivity test. These results suggest that LSD, like other rewarding drugs, produces taste avoidance by a mechanism other than that produced by emetic drugs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of ibogaine on the development of tolerance to the analgesic effect of morphine.

The results of 3 experiments demonstrated that (a) 20 mg/kg ibogaine (but not 10 mg/kg), administered 30 min before morphine, attenuates the development of tolerance to the analgesic effect of morphine in rats; (b) this 20 mg/kg dose of ibogaine, if administered 5 hr before morphine, has no effect on tolerance development; and (c) a high dose of ibogaine (40 mg/kg), administered 24 hr before morphine, does not affect analgesic tolerance (despite reports that this dose of ibogaine, administered 1 day before morphine, modulates the neurochemical and reinforcing effect of the opiate, see P. Popik, R. T. Layer, & P. Skolnick, 1995). The findings are discussed in the context of suggestions that ibogaine be evaluated as a treatment for opiate dependence, and recent research indicating that ibogaine is an N-methyl-{D}-aspartate antagonist. (PsycINFO Database Record (c) 2010 APA, all rights reserved)