Behavioral comparison of sucrose and l-2-amino-4-phosphonobutyrate (L-AP4) tastes in rats: does L-AP4 have a sweet taste?

Even though it is generally thought that umami stimuli such as monosodium glutamate (MSG) and sweet stimuli such as sucrose are detected by different taste receptors, these stimuli appear to share taste qualities when amiloride (a sodium channel blocker) is present to reduce the sodium taste. Single fiber recording studies of the facial and glossopharyngeal nerves have shown that encoding of L-2-amino-4-phosphonobutyrate (L-AP4), a potent mGluR4 agonist that elicits a taste quite similar to MSG, may occur in the same fibers that also encode sweet stimuli. This suggests that L-AP4 and sweet substances may activate common receptors or afferent signaling mechanisms. We report results of behavioral experiments that test this hypothesis. In the first study, rats conditioned to avoid sucrose or L-AP4 generalized the aversion to the opposite substance, indicating that both substances elicited similar tastes. However, two taste discrimination experiments showed that rats easily discriminated between sucrose and L-AP4 over a wide range of concentrations, even when the cue function of sodium associated with L-AP4 was reduced by amiloride and neutralized by adding equimolar concentrations of NaCl to sucrose. These data suggest that even though L-AP4 and sucrose elicit similar taste qualities, one or both substances also elicit other taste qualities not shared by the opposite substance. They also suggest that the taste-mGluR4 receptor and the signal pathway activated by L-AP4 are not the same as those activated by sucrose. These data, when combined with fiber recording data, suggest that there is convergence of L-AP4 and sucrose signals at some point early in the gustatory pathway.

Comparison of L-monosodium glutamate and L-amino acid taste in rats.

T1R2/T1R3 heterodimers are selectively responsive to sweet substances whereas T1R1/T1R3 receptors are selective for umami substances, represented by monosodium glutamate (MSG), and for L-amino acids. If a single receptor is responsible for detection of umami and L-amino acids, then it would be predicted that MSG and L-amino acids elicit similar tastes in rats. The present study compared the taste profile of MSG with four amino acids (glycine, L-proline, L-serine and L-arginine) using conditioned taste aversion, detection threshold, and taste discrimination methods. These experiments were designed to either reduce or neutralize the taste of sodium associated with MSG and the other amino acids. Detection threshold studies showed that rats were most sensitive to L-arginine and least sensitive to L-proline. Glycine and L-serine thresholds were similar to those previously reported for MSG. Like MSG, a conditioned taste aversion to each of the four amino acids generalized to sucrose in the presence of amiloride, a sodium channel blocker. Rats showed moderate generalization of aversion between MSG and L-arginine, suggesting that these two amino acids taste only moderately alike. However, the taste aversion experiments indicated that glycine, L-serine, and L-proline elicit taste sensations similar to MSG when amiloride is present. Discrimination experiments further compared the tastes of these three amino acids with MSG. When the sodium taste associated with MSG was reduced or neutralized, glycine and L-proline elicited tastes very similar but not identical to the taste of MSG. Low (but not higher) concentrations of L-serine were also difficult for rats to discriminate from MSG. While there are taste qualities common to all of these amino acids, the perceptual differences found in this study, combined with previous reports, suggest either multiple taste receptors and/or multiple signaling pathways may be involved in umami and amino acid taste perception in rats.

Metabotropic glutamate receptors are involved in the detection of IMP and L-amino acids by mouse taste sensory cells.

G-protein-coupled receptors are thought to be involved in the detection of umami and L-amino acid taste. These include the heterodimer taste receptor type 1 member 1 (T1r1)+taste receptor type 1 member 3 (T1r3), taste and brain variants of mGluR4 and mGluR1, and calcium sensors. While several studies suggest T1r1+T1r3 is a broadly tuned lLamino acid receptor, little is known about the function of metabotropic glutamate receptors (mGluRs) in L-amino acid taste transduction. Calcium imaging of isolated taste sensory cells (TSCs) of T1r3-GFP and T1r3 knock-out (T1r3 KO) mice was performed using the ratiometric dye Fura 2 AM to investigate the role of different mGluRs in detecting various L-amino acids and inosine 5' monophosphate (IMP). Using agonists selective for various mGluRs such as (RS)-3,5-dihydroxyphenylglycine (DHPG) (an mGluR1 agonist) and L-(+)-2-amino-4-phosphonobutyric acid (l-AP4) (an mGluR4 agonist), we evaluated TSCs to determine if they might respond to these agonists, IMP, and three L-amino acids (monopotassium L-glutamate, L-serine and L-arginine). Additionally, we used selective antagonists against different mGluRs such as (RS)-L-aminoindan-1,5-dicarboxylic acid (AIDA) (an mGluR1 antagonist), and (RS)-α-methylserine-O-phosphate (MSOP) (an mGluR4 antagonist) to determine if they can block responses elicited by these L-amino acids and IMP. We found that L-amino acid- and IMP-responsive cells also responded to each agonist. Antagonists for mGluR4 and mGluR1 significantly blocked the responses elicited by IMP and each of the L-amino acids. Collectively, these data provide evidence for the involvement of taste and brain variants of mGluR1 and mGluR4 in L-amino acid and IMP taste responses in mice, and support the concept that multiple receptors contribute to IMP and L-amino acid taste.

Facilitative effects of cross-modality training on recovery of a conditioned avoidance response following striate cortex ablations in the rat.

Two experiments with visual decorticate rats examined the effects of cross-modality transfer on the recovery of a preoperatively learned avoidance task using high intensity light cues. In both experiments, brief postoperative cross-modality training with high intensity noise cues produced significantly better recovery of the visual avoidance response than either reversed intensity noise training or retraining with the original task. Training with a reversed intensity visual cue produced relearning deficits. In the second experiment, control conditions eliminated re-exposure to the test environment, the shock-response relationship, and compound conditioning as possible explanations for these findings. These results indicated that rats are capable of cross-modality transfer after posterior cortical lesions and that this transfer effect can facilitate recovery of behavioral function. The clinical implications of these findings are also discussed.

Age-related differences in the effects of d-amphetamine and illumination on fixed-interval responding of rats.

The effects of d-amphetamine (0.0, 0.4, and 0.8 mg/kg) on fixed-interval responding in light and dark sensory conditions were examined in rats that were 25, 100, and 200-days-old at the beginning of the experiment. In the youngest and oldest groups, the drug increased responding in light more than in dark. The drug increased responding of the middle age group in the light, but decreased operant rates in the dark. These data appear to support the notion that d-amphetamine reduces the effects of ambient light on behavior in rats.

Reduction of lesion-induced deficits in visual reversal learning following cross-modal training.

Two experiments examined the effects of postoperative auditory intensity training on serial brightness reversal learning of visual decorticate rats. In Experiment 1 rats learned an avoidance response cued by a high intensity light prior to visual decortication. Six days later the rats were given either avoidance training with an auditory intensity cue, additional training with the preoperative visual cue, or no training. The next day all rats began a series of 8 brightness discrimination reversals. The no-training lesion group failed the early reversals but reached criterion in later reversals. Lesion rats retrained with visual cues failed early reversals with the low intensity light cue but not reversals with the high intensity cue. In contrast, lesion rats given auditory training easily reached criterion in all reversals. Experiment 2 followed a similar training sequence except auditory training was given after the second reversal. All rats showed rapid acquisition of all visual reversals subsequent to auditory training. These data suggest that generalization of a learning set by cross-modal transfer training with an intact modality can reduce reversal learning deficits following brain damage more efficiently than comparable training with the damaged system.

Recovery of a temporally based visual discrimination after visual cortex lesion in the rat.

In Expt. 1, rats were conditioned to emit a shock avoidance response when the pulse rate of a light was increased. Then, after bilateral visual cortex lesions, the rats were given 10, 20, or 40 days recovery before relearning the discrimination. While all rats were able to relearn the discrimination response, lesion rats had a performance deficit after all recovery periods. Expt. 2 compared the effects of postoperative visual pulse rate training to those of auditory pulse rate training on relearning of the photic pulse-rate discrimination 10 days after visual decortication. Recovery of discrimination responding was better after auditory pulse rate training than after visual training. These data suggest that visual cortex lesions in the rat disrupt perceptual or associational functions involving the temporal features of a visual stimulus. In addition, generalization of relational properties during cross-modal training through multimodal CNS structures appears to enhance recovery of behavior after brain insult.

Comparison of compound and cross-modal training on postoperative visual relearning of visual decorticate rats.

The effects of postoperative bimodal compound conditioning and cross-modal transfer of learning on behavior were compared by training rats prior to visual decortication to avoid shock with visual intensity cues. On Postop Day 6, rats were given avoidance training in one of three cue conditions: auditory intensity cues (cross-modal), paired auditory and visual cues (compound conditioning), or no cues (no-training control). On Postop Day 7 rats in the no-training control and the cross-modal transfer conditions were retrained with the visual discrimination while rats in the compound conditioning group were either retrained with the visual intensity cue or trained with the auditory intensity cue. Postoperative cross-modal transfer training enhanced visual relearning whereas bimodal compound conditioning interfered with relearning. However, compound conditioning facilitated subsequent auditory discrimination learning. These results support the notion of an injury-induced neurological bias that is increased after bimodal compound conditioning and reduced after cross-modal training. Potential implications for neurological rehabilitation are also discussed.

Endogenous cannabinoids as an aversive or counter-rewarding system in the rat.

Human use of marijuana (Cannabis sativa) is widely assumed to have rewarding properties, a notion supported by its widespread recreational use. However, no study has clearly demonstrated such effects in animal models. The purpose of this study was to test for the presumed rewarding effect of cannabinoids using a conditioned place preference paradigm. The results showed that animals failed to develop place conditioning at a low dose (1.5 mg/kg) and developed a place aversion at a high dose (15 mg/kg) of the active principle in marijuana, delta 9-tetrahydrocannabinol (delta 9-THC), a finding consistent with most previous studies. Moreover, the administration of the cannabinoid antagonist SR141716A induced a conditioned place preference at both a low (0.5 mg/kg) and a high (5 mg/kg) dose. In summary, cannabinoid antagonism produced place preference while cannabinoid agonism induced place aversion. These results suggest that endogenous cannabinoids serve normally to suppress reward or to induce aversion.

Cross-modal transfer effects on visual discrimination depends on lesion location in the rat visual system.

The effects of postoperative visual and auditory training on a brightness discrimination task were examined after lesions of various structures in the visual system. In Experiment 1, rats were trained to avoid shock with visual intensity cues. Twenty-four hours later, each rat received bilateral lesions in one of the following areas of the visual system: (1) sham, (2) visual cortex (VC), (3) pretectal (PT) area, (4) combined PT/VC, (5) superior colliculus (SC), or (6) combined SC/VC. Six days later, each rat received either training with visual or auditory intensity cues, or no training. The next day all rats were retrained on the preoperative visual avoidance task. All lesions except those in the SC condition produced relearning deficits. Auditory training reduced these deficits significantly more than visual training, except in rats with combined SC/VC lesions. In Experiment 2, sham and combined PT/VC lesion rats were given either direct or reversal intensity training using visual or auditory cues before relearning the visual discrimination. Rats given auditory direct training relearned the task faster than rats given reversal training or visual direct training. Postinjury training with an intact sensory system can enhance functional recovery more effectively than training with the damaged system. The differential effects of direct and reversal training suggest that cross-modal training involves both specific and nonspecific transfer that may be mediated through the VC or the SC.

Crossmodal training reduces behavioral deficits in rats after either auditory or visual cortex lesions.

Rats were trained with either visual or auditory intensity cues until they emitted nine avoidance responses in 10 trials (9/10) prior to bilateral ablation of the corresponding sensory neocortex. Six days after surgery, rats were trained to 5/10 criterion in one of the following conditions: within-modality direct, within-modality reversal, crossmodality direct, crossmodality reversal, or no training control. The next day all rats were retrained to 9/10 on their preoperative tasks. For visual decorticate rats, the no training and the visual within-modality direct groups relearned the discrimination at the same rate as preoperative learning. Auditory crossmodal direct training enhanced relearning more than other forms of training and visual within-modality reversal training hindered retraining. For auditory decorticate rats, similar postoperative auditory within-modality and visual crossmodality training effects were seen during retraining of the auditory discrimination. These findings suggest crossmodality training facilitates functional recovery through relational information and learning sets transferred from experimental training to the relearning task.

Age changes in electrophysiological measures of the superior colliculus and occipital cortex.

Locomotor activity and electrophysiological recordings of the superior colliculus and the occipital cortex were measured for two age groups of rats (100-105 and 230-235 days old) tested in ambient light and dark sensory conditions. Age differences in response to ambient illumination were observed in both behavioral and electrophysiological data. While no age differences were found for the superior colliculus data, cortical activity of the older rats differed from that found in the younger rats. These results are interpreted in terms of potential cortical development and arousal functions.

Sucrose threshold variation during the menstrual cycle.

Sucrose thresholds were measured at three points during the menstrual cycle for 14 women who were not taking oral contraceptives. Thirteen men also were tested at similar intervals. Sucrose thresholds of the men remained constant throughout the experiment. During menstruation and postovulation, the thresholds of the women were similar to the thresholds of the men, whereas during preovulation the thresholds of the women are significantly lower. The stable sucrose thresholds of the men suggest that ovarian hormones may be involved in the variation in sucrose sucrose thresholds of the women. The increase in sensitivity of the women during preovulation may have been related to the high level of estrogen, whereas the decrease in sensitivity during postovulation may be due to some type of interaction between estrogen and progesterone.

Effects of d-amphetamine and methylphenidate upon auditory threshold in the squirrel monkey.

The effects of d-amphetamine sulfate and methylphenidate hydrochloride on auditory thresholds in ten squirrel monkeys were examined using a 4.2 kHz stimulus in a free field. The results indicated that d-amphetamine raised auditory thresholds but methylphenidate did not alter the thresholds. The elevation of sensory thresholds by d-amphetamine was in agreement with previous studies suggesting that the drug acts as a behavioral depressant in diurnal animals.

Effects of drugs, age and illumination on response speed of squirrel monkeys.

Four young (2 1/2 years) and four older (over 10 years) squirrel monkeys were used to study age differences in the effects of d-amphetamine, methylphenidate and illumination on response speed. Although young monkeys were faster than the old monkeys, only the older monkeys showed an illumination effect. Both d-amphetamine and methylphenidate slowed response speed but only in the older monkeys showed an illumination illumination was present. These results suggest that older, mature squirrel monkeys are more sensitive to the effects of d-amphetamine, methylphenidate and illumination than young squirrel monkeys.

Seashore Rhythm test: comparison of Signal Detection Theory and standard scoring procedures.

The effects of age and instructional set on Seashore Rhythm test performance were examined with standard scoring and Signal Detection Theory (SDT) procedures. Neurologically intact young (17-28 years) and old (65-92 years) subjects were given standard test instructions with sentences added which stated that specific proportions of the test stimuli would be identical or different. Age differences in d' scores were highly correlated with standard Rhythm scores. While standard scores were unaffected by instructional set, all three SDT measures of response criteria detected effects of instructional set, or an age by instructional set interaction. SDT scoring of the Rhythm test yields a measure of auditory sensitivity comparable to standard methods and detects response bias on the lest that standard procedures cannot.

Interactive effects of noise with illumination and age on activity of rats.

Locomotor activity of male, albino rats (25, 90, and 200 days old at the start of the experiment) was measured in conditions of light and dark. Continuous and pulsed noises of 50, 60, 70, 80 and 90 dB were presented under each illumination condition. While noise intensity altered activity of all age groups, it interacted with illumination and age, resulting in different sensory-dependent patterns of activity in each age group. The results are interpreted in terms of arousal theory and potential functional development of CNS structures regulating the effects of ambient sensory input on behavior.

Time estimation in humans: effects of ambient illumination and sex.

7 male and 7 female college students made estimations of 15-sec. intervals in conditions of dark, low and high ambient illumination. Analysis of variance showed significant effects of illumination and illumination by sex. Increased light levels shortened time estimation except for males under high light intensity. Results are discussed in terms of arousal theory and the relevance of these factors in research on time estimation.

Effects of ambient illumination over days on human vigilance performance.

Detection rates of 36 college students were measured for three days in an auditory vigilance task under one of three conditions of ambient illumination: dark (less than .33 lx), low (86 lx), and high (170 lx) intensity levels. Within-session performance decrements were seen in all conditions. Increasing the intensity of ambient illumination improved vigilance performance, an effect which became more potent over days. These results are discussed in terms of arousal theory and habituation.

Effects of ambient noise on time estimation by humans.

10 male and 10 female undergraduates were asked to estimate 5-, 10-, 15-, and 30-sec. intervals under five intensities of ambient noise (50, 60, 70, 80, and 90 dB). Interval estimates became shorter as the intensity of noise increased from 50 to 80 dB but became longer at 90 dB. The effects of intensity of noise were most prominant in the two longest intervals. These results are interpreted in terms of CNS arousal theory.