Intake of and preference for sweet solutions are attenuated in morphine-withdrawn rats.

The hypothesis that intake of sweet solutions is partially controlled by endogenous opioid peptides was tested in 2 experiments that examined the effects of repetitive morphine administration and withdrawal on subsequent intake of and preference for saccharin solutions in rats. Experiment 1 established that 17 hr after morphine withdrawal, rats consumed less saccharin, but not less water, than did controls. The groups did not differ 8 days later. In Experiment 2, using a 2-bottle saccharin-preference test, rats exhibited a reduced preference to saccharin solutions (1, 3, 9, 30, or 60 mM) for 6 days after morphine withdrawal. The difference between the groups was most pronounced at the most preferred concentrations (9 and 30 mM). The results suggest that cross-tolerance occurs between morphine and the opioid-mediated hedonic effects of sweet solutions.

Stimulus novelty and significance as determinants of electrodermal responsivity: the serial position effect.

Three experiments examined the effects of stimulus novelty and significance on the skin conductance component of the orienting response. The test stimuli used in the different experiments involved either a neutral change in stimulation (i.e., adding or deleting components to the standard stimuli), or an introduction of a significant element to the standard stimulus. The serial position of the test stimulus was manipulated in all three experiments. In Experiment 1, nonsignificant test stimuli were introduced at the second, fourth, sixth, or eighth trial of the complex sequence of eight stimuli (i.e., a sequence comprised of varying standard stimuli). None of the test stimuli produced enhanced skin conductance responses under these conditions. Experiment 2 utilized the same design with only one difference: the test stimuli were presented following a simple stimulus sequence (i.e., repetition of a fixed standard stimulus). In this design enhanced skin conductance responses to the test stimuli were observed in almost all experimental conditions, with an advantage of a late over an early presentation of the test stimulus. Experiment 3 was designed to compare serial position effects of significant and neutral test stimuli. A serial position effect was obtained only for the neutral test stimuli, showing once again an advantage for late presentations. It was suggested that different mechanisms might underlie skin conductance responses to significant stimuli and to novel neutral stimuli.

Reduced saccharin preference in CXBK (opioid receptor-deficient) mice.

The preference for sweet solutions in opioid receptor-deficient (CXBK) and control (C57BL/6By) mice was compared. CXBK and C57BL/6By (C57) mice were presented for 2 h/day with 2 tubes, one always containing water and the other containing either water or various concentrations of saccharin solution. Fifteen minutes before the drinking session, half of the mice in each strain were injected with naltrexone (0.2 mg/kg) and the other half with saline. Compared to C57 mice, CXBK mice had significantly lower saccharin preference. Naltrexone reduced the saccharin preference in both strains, almost completely abolishing preference in CXBK mice. The results support the hypothesis that brain opioid receptors are involved in mediating sweet palatability and suggest that genetic differences in opioid receptor density contribute to differences in the palatability of sweet solutions.

Naltrexone reverses a long term depressive effect of a toxic lithium injection on saccharin preference.

In 2 experiments, using female rats, we demonstrated that an injection of 2% body weight 150 mM lithium chloride (LiCl) reduced saccharin preference, measured 48 hr later. Furthermore, Experiment 1 showed that this effect of lithium was reversed by 10 mg/kg naltrexone injected immediately before lithium administration. Experiment 2 demonstrated that one injection of 10 mg/kg morphine also depressed saccharin preference 48 hr post-injection. Paradoxically, morphine given before lithium reversed the effects of lithium on saccharin preference. The experiments suggest the involvement of endogenous opioid peptides in the long term toxic effects of lithium on saccharin preference.

Opiate reinforcement and naloxone aversion, as revealed by place preference paradigm, in two strains of rats.

Two strains of rats--LC2-Hi and LC2-Lo--selected for high and low self-stimulation rates, respectively, were tested for responses to opiates and to naloxone using conditioned place preference paradigm. In the two experiments which used opiates as UCS, conditioning was carried out in the non-preferred compartment while in the experiment which used naloxone, conditioning was performed in the preferred compartment. The preference changes were determined on the basis of times spent in the compartments before and after conditioning with drugs. LC2-Hi rats showed positive changes in the preference to the initially non-preferred side when morphine or heroin (5 mg/kg and 1 mg/kg, respectively) were used; no such effect was observed with LC2-Lo rats. Both lines exhibited aversive reactions to naloxone by diminishing the time spent in the environment paired with this drug, but again the response of LC2-Hi animals was significantly larger than the response of LC2-Lo rats. Chronic intake of a sweet solution (3 mM saccharin for 4 weeks) tended to amplify the aversive reaction to naloxone in both lines. It may be inferred from the present findings that there exists a common genetic factor, as revealed by the conditioned place preference paradigm, underlying positive reinforcing properties of opiates and aversive effects of naloxone.

Amphetamine-induced stereotypic responses in Roman high- and Roman low-avoidance rats.

The effects of 0, 1, 3 and 5 mg/kg d, 1-amphetamine (AMPH) on male RHA/Verh and RLA/Verh rats were measured, at 25 and 55 min post-injection, using an observational method in which six categories of behavior were scored. RHA/Verh rats displayed a more rapid increase of AMPH-induced stereotyped behavior, mostly due to drug-related differences in scanning (head-bobbing), whereas the differences in rearing seen (RHA/Verh greater than RLA/Verh) were attributable to purely genetic effects. These results were compared with those of previous experiments which measured apomorphine-induced stereotyped behavior in these, and other, Roman lines. It was concluded that the RHA/Verh rats probably showed a stronger response to AMPH due to their higher, and more drug-responsive, striatal dopamine turnover rate.

Influence of intake of sweet solutions on the analgesic effect of a low dose of morphine in randomly bred rats.

The time course for the development of morphine tolerance, following prolonged sweet intake, was examined in randomly bred Sabra rats. Exposure to 3% glucose in 6 mM saccharin solution increased drinking by about three times as compared to rats supplied only with water. Suppression of the analgesic effect of morphine was already detectable after 24 h of intake and became progressively more marked within the next 5 weeks. These results support an active interaction between sweet consumption and endogenous opioids in randomly bred rats.

Effects of chronically elevated intake of sweet solutions on sexual behavior of male rats.

Three experiments were conducted on the sexual behavior of gonadally intact and castrated male Sabra rats. Half of the animals drank water during the course of the experiment and half were offered sweet solutions, the assumption being that sweet gustatory stimulation elevates the level of central endogenous opioid peptides in rats. The effects on sexual behavior of the following drugs were explored: the opiate receptor blocker naloxone (5 mg/kg, sc), the serotonin precursor 5-hydroxytryptophan (5-HTP) (20 mg/kg, sc), the serotonin antagonist methysergide (1 mg/kg, sc), and naloxone in combination with methysergide. Naloxone, whether administered alone or in combination with methysergide, impaired sexual performance in castrated male rats, and in gonadally intact rats maintained on sweet solutions. Methysergide elevated sexual behavior in all groups, whereas 5-HTP tended to suppress such behavior. The results support the hypothesis that endogenous opiates play a role in the expression of male sexual behavior in rats. While subtle in intact animals this role may become crucial following the disruption of sex hormone supply. Serotonergic influence on male sexual behavior is inhibitory.

Inhibition of mating by naloxone or morphine in recently castrated, but not intact male rats.

Administration of naloxone (SC 5 mg/kg) significantly reduced ejaculation and mounting in male rats in the weeks following castration. A similar effect was obtained by injecting morphine (SC 1 or 5 mg/kg). In contrast, the same dosages of naloxone or morphine did not affect the sexual performance of gonadally intact males. Opioid peptides may contribute to the temporary persistence of sexual behavior in testosterone-deficient male mammals, in which incentive qualities of the female partner are an important determinant of sexual arousal.

Ventral tegmental self-stimulation, sensory reactivity and pain reduction in rats selected for high and low rates of lateral hypothalamic self-stimulation.

Ventral tegmental self-stimulation (VTSS) was studied in 56 male rats of four genetic lines (LC1-Lo, LC1-Hi, LC2-Lo, LC2-Hi), which differed in their inherent tendencies to self-stimulate the lateral hypothalamus. It was found that LC2-Hi rats engage more in VTSS than do rats of the LC2-Lo line. No differences were observed between the LC1-Hi and -Lo lines. In a second experiment, the LC2-Hi and -Lo lines were compared as to peripheral pain thresholds (36 animals) and VT-induced-analgesia (21 animals). Genetically low self-stimulators of the LC2 selection program were found to be more sensitive to acute peripheral pain and to VT analgesic influences than are their high counterparts. Theoretical implications are discussed.

Effects of chronically elevated intake of different concentrations of saccharin on morphine tolerance in genetically selected rats.

Sixty-four LC2-Hi and LC2-Lo female rats were chronically supplied with either water or a solution of 1, 3 or 30 mM of sodium-saccharin. Pain sensitivity, as well as its reduction by a 2.5 mg/kg morphine injection, were measured in a hot-plate test. High saccharin consuming LC2-Hi rats did not exhibit significant morphine-induced analgesia (MIA) compared to baseline, after 38 days of drinking of saccharin, irrespective of concentration. MIA of those rats were maintained on water was significant. In contrast, the low consuming LC2-Lo animals maintained either on water or on 1 and 30 mM saccharin showed significant MIA compared to baseline, following the same exposure period. The findings demonstrate that chronically elevated saccharin intake, activates an endogenous opiate system leading ultimately to cross-tolerance to the analgetic effects of morphine.

Ventral tegmental analgesia in two strains of rats: effects of amphetamine, naloxone and parachlorophenylalanine.

Pain sensitivity and analgesia induced by the stimulation of the ventral tegmentum (VT) were studied in 72 male rats of two lines, LC2-Hi and LC2-Lo, genetically selected for high and low rates of lateral hypothalamic self-stimulation, respectively. LC2-Lo rats were more sensitive to acute peripheral pain and developed a stronger analgesia than their LC2-Hi counterparts. In order to assess the pharmacological substrate of ventral tegmental stimulation-induced analgesia (VT-SIA), the effects of amphetamine (AMP, 21 animals), naloxone (NX, 24 animals) and parachlorophenylalanine (PCPA, 27 animals) injections were studied. VT-SIA was found to be clearly decreased by PCPA, slightly decreased by AMP and not significantly affected by NX. Ventral tegmental self-stimulation ( VTSS ) was increased by PCPA treatment. The comparison of VTSS and VT-SIA did not reveal any correlation between both phenomena. These data suggest that VT-SIA may be mediated by serotonin while catecholamines may have a modulatory role in this analgesia and that VTSS and VT-SIA seem to be governed by different neuronal systems.

Biphasic effects of chronic saccharin intake on pain responses of healthy and diabetic rats of two genetically selected strains.

Rats of the LC-2-HI strain, selected for high rates of self-stimulation, were supplied with a 3 mM saccharin solution. Within 1 week they developed markedly prolonged latencies to painful stimuli on a hot-plate. In contrast, a similar effect became manifest in LC-2-LO rats only after 3 weeks. Both strains of rats were made diabetic by injection of streptozotocin. LO rats showed more polydipsia and hyperglycemia than HI rats and, when drinking saccharin solution, developed cross-tolerance to morphine within about 2 weeks. It is assumed that saccharin consumption stimulates the release of endogenous opioid peptides, probably via stimulation of gustatory sweet receptors. The opioid peptides exert a biphasic effect: initially they raise the pain threshold, but at a later stage they cause chronic cross-tolerance to morphine.

Morphine tolerance in genetically selected rats induced by chronically elevated saccharin intake.

Rats of line LC2-Hi that drank about 50 milliliters of a highly palatable saccharin solution daily for 28 consecutive days did not show morphine analgesia or an opioid form of stress-induced analgesia and were not responsive to naloxone. These findings support the idea that chronically elevated saccharin intake may cause increased release and utilization of endogenous opiates.

Genetic relation between the performance in a two-way avoidance task and increased emotionality following septal lesions.

Large radio frequency septal lesions were performed on male Roman low (RLA/Verh) and high (RHA/Verh) avoidance rats. It was found that the genetic low-avoiders displayed higher acute postoperative irritability than the genetic high-avoiders. This result had been predicted a-priori from an independent set of data, relating the ability to master active avoidance inversely to general emotionality and readiness to engage in intracranial self-stimulation (ICSS), and from research demonstrating a genetic correlation between the severity of the septsal syndrome, and the readiness to engage in ICSS. On the sixth postoperative day, all animals were tested for their performance in a standard shuttle box avoidance task. It was found that septal lesions did not affect the performance of either the low or high genetic avoiders, which behaved as expected from their respective genotypes.

Saccharin preferences in prepubertal male and female rats: relationship to self-stimulation.

Saccharin preferences were studied in 48 male and female prepubertal rats (22-23 days old at the beginning of the experiment) of four genetic lines (LC1-low, LC1-high, LC2-low, and LC2-high) which differed in their inherent tendencies to self-stimulate. Sodium saccharin solutions of 0.1, 0.3, 0.5, 1, 3, 10, and 30 mM concentrations were used against water in two-bottle tests. It was found that (a) prepubertal rats prefer saccharin solutions to water, with the range of favored concentrations similar to that of adults; (b) male and female prepubertal rats do not differ as to saccharin preferences; (c) within the LC2 population, animals of the genetically high self-stimulating line prefer saccharin more than do their LC2-low counterparts; no such differentiation of the LC1 high and low lines was observed.