Neonatal thermotaxis improves reversal of a thermally reinforced operant response

One-, 5-, and 11-day-old rats in a cool environment (25 degrees C) acquired an operant response when rewarded with a 20-s-long warming of the platform (from 25 to 36 degrees C) on which they lay. In Experiment 1, the head-turning response was learned by pups at all ages. When the contingency was reversed so that pups were reinforced for turning to the side opposite that correct during training, the original response extinguished for 1-day-olds, but not for 5- or 11-day-olds. In Experiment 2, the rewarded side was randomly selected for each trial. One-day-olds perseverated in turning to the side correct on that trial while the reinforcer remained on, but 5- and 11-day-old rat pups did not. We conclude that 1-day-old pups were more responsive to the change in experimental contingency in Experiment 1 due to this thermotaxic behavior.     

Effects of SCH 23390 and sulpiride on the reinforced responding of the young rat.

Reinforced responding of 17-day-old rat pups was assessed after blockade of dopamine D1 and D2 receptor systems. Rat pups were trained to traverse a straight alley for nipple attachment reward and then injected with various doses of either sulpiride (D2 antagonist), SCH 23390 (D1 antagonist), or a combination of sulpiride and SCH 23390. The approach performance of drug-treated pups was then compared with vehicle-treated pups on both reinforcement and extinction trials. SCH 23390, but not sulpiride, depressed the appetitive approach responding of the pups. During extinction testing, SCH 23390-treated pups had longer response latencies than pups given vehicle. "Best score" data suggested that SCH 23390 primarily affected reward processes and not motor capability. Most important, the effects of SCH 23390 on reinforced responding were potentiated by sulpiride, suggesting that both the D1 and D2 receptor systems are involved in reward processes.     

Indirect dopamine agonists augment the locomotor activating effects of the kappa-opioid receptor agonist U-50,488 in preweanling rats

kappa-Opioid receptor agonists (e.g., enadoline or U-50,488) increase the locomotor activity of preweanling rats, while the same drugs depress the locomotor activity of adults. Curiously, direct stimulation of dopamine (DA) D2-like receptors fully attenuates the U-50,488-induced locomotor activity of preweanling rats. The purpose of the present study was to determine whether indirect DA agonists (i.e., cocaine, methylphenidate, and amphetamine) would also attenuate U-50,488's behavioral effects. In two experiments, 17-day-old rats were injected with saline or U-50,488 (5 mg/kg, sc) and locomotor activity and stereotyped sniffing were assessed. After 20 min, the saline- and U-50,488-pretreated rats were injected with saline, cocaine (5, 10, or 20 mg/kg, i.p.), methylphenidate (10 or 20 mg/kg, i.p.), amphetamine (2.5 or 5 mg/kg, i.p.), or the direct D2-like receptor agonist NPA (1 mg/kg, i.p.). As expected, U-50,488 dramatically enhanced the locomotor activity of 17-day-old rats, while attenuating the stereotyped sniffing caused by indirect and direct DA agonists. All three indirect DA agonists augmented U-50,488's locomotor activating effects across the initial 10 min of testing and then activity declined to U-50,488 control values. Direct stimulation of DA receptors produced nearly opposite effects because NPA attenuated U-50,488-induced locomotor activity across the entire testing session. It is uncertain why direct and indirect DA agonists affected U-50,488-induced locomotor activity differently, but the relative amount of DA D1-like receptor activation is probably not responsible.     

Effects of chronic and acute methylphenidate hydrochloride (Ritalin) administration on locomotor activity, ultrasonic vocalizations, and neuromotor development in 3- to 11-day-old CD-1 mouse pups.

The present study examined the effects of chronic and acute treatment with methylphenidate hydrochloride (Ritalin) on isolation-induced ultrasonic vocalizations, spontaneous locomotor activity, and neuromotor coordination in 3- to 11-day-old CD-1 mouse pups. In Experiment 1, 3- to 11-day-old pups received daily injections of saline, 5 mg/kg or 20 mg/kg of methylphenidate hydrochloride, or no injection and were tested on postnatal Days 3, 5, 7, 9, and 11. Both doses of methylphenidate resulted in significant increases in locomotor activity at all ages, but had no significant effect on body weight, neuromotor development, or emission of ultrasonic vocalizations. In Experiment 2, pups were given a single dose of methylphenidate (5 or 20 mg/kg), saline, or no injection on one of postnatal Days 5, 7, 9, or 11. This acute methylphenidate treatment increased locomotor activity, but had no significant effects on ultrasonic vocalizations or neuromotor coordination. These results indicate that short-term, chronic methylphenidate treatment elevates locomotor responses, but has no immediate effects on anxietylike responses or on the development of neuromotor behavior of CD-1 mice in the first 11 days of life.     

Opposing effects of dopamine D2 receptor stimulation on the spontaneous and the electrically evoked release of [3H]GABA on rat prefrontal cortex slices.

The spontaneous and the electrically evoked release of [3H]GABA were studied in vitro on slices of rat medial prefrontal cortex. The slices were preincubated with [3H]GABA and then superfused with a Krebs' solution. The superfusion with a Ca(2+)-free medium progressively increased the spontaneous [3H]GABA release and strongly decreased the electrically evoked release of [3H]GABA (-65%). The effects of three dopaminergic D2 receptor agonists (RU24926, lisuride and LY171555) were studied on both the spontaneous and the electrically evoked [3H]GABA release. The spontaneous release of [3H]GABA was increased by exposure to each of these three D2 agonists. RU24926 produced a dose-dependent increase from 10(-9) to 3 x 10(-8) M and the maximal effect was totally abolished by the dopaminergic D2 receptor antagonist sulpiride (10(-5) M). With lisuride a progressive increase of [3H]GABA release was observed and a plateau value was reached with concentrations between 10(-7) and 10(-6) M. These effects were totally reversed by 10(-5) M sulpiride. The dose-response relation for LY171555 was bell-shaped, with a maximal effect being obtained with 10(-9) M) LY171555. This effect decreased with a higher concentration (10(-8) M) and finally was no longer observed for 10(-7) M LY171555. The maximal increase induced by LY171555 was totally abolished by 10(-5) M sulpiride. In contrast, the electrically evoked release of [3H]GABA was inhibited by these three D2 agonists. The IC50 value of the inhibition was 4.1 x 10(-8) M for RU24926 and 2 x 10(-7) M for lisuride. Sulpiride (10(-5) M) totally abolished the effect of 10(-7) M RU24926. In the concentration range of lisuride examined, a 50% reduction of the lisuride inhibition was obtained in the presence of sulpiride (10(-5) M). The dose-response curve obtained with LY171555 had a U-shape, with a maximal inhibition reached with 10(-8) M, whereas no effect was observed with 10(-6) M. The inhibition induced by 10(-8) M LY171555 was completely antagonized by 10(-5) M sulpiride. The D2 agonist-induced inhibition of the electrically evoked release of [3H]GABA was mimicked by dopamine endogenously released by 10(-5) M amphetamine. This effect was reversed by 10(-5) M sulpiride. Our data provide further evidence for a dopaminergic control of GABA interneurons in the prefrontal cortex. This regulation implies the activation of D2 dopaminergic receptors. The possible mechanisms underlying the opposite effects of D2 agonists on the spontaneous and the electrically evoked release of [3H]GABA are discussed.     

The effects of 8-OH-DPAT and (+/-)-pindolol on isolation-induced ultrasonic vocalizations in 3-, 10-, and 14-day-old rats

It has been established that administration of 5-HT1A agonists attenuates the rate of isolation-induced ultrasonic vocalizations (USV) in 10-day-old rat pups. In this study we extended these findings by examining the effects of administration of the serotonergic 1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), and mixed 5-HT1A antagonist/beta adrenergic antagonist, (+/-)-pindolol, in 3-, 10-, and 14-day-old rat pups in order to assess the effect of these drugs from a developmental perspective. At all three ages, 8-OH-DPAT significantly reduced the rate of isolation-induced USV. While only the highest dose (1.0 mg/kg) of 8-OH-DPAT administered to the 10- and 14-day-olds significantly reduced the rate of vocalization, both the 0.1- and 1.0-mg/kg doses significantly attenuated the vocalization rate in the 3-day-olds. Pindolol administration did not alter the rate of USV at any age nor did it block the quieting effect that generally occurs when an anesthetized littermate is placed with the isolated pup. We conclude that 8-OH-DPAT is effective as early as 3 days of age in the quieting of isolation-induced USV and that the regional age-dependent development of 5-HT1A receptors and projections are important factors in the observed differential sensitivity to 8-OH-DPAT administration during development.     

Ontogenetic adaptation and learning: a developmental constraint in learning for a thermal reinforcer

Hoffman, Flory, and Alberts (1999) demonstrated that 1-, 5-, and 11-day-old rats in a cool environment (25 degrees C) acquired an operant head-turning response when rewarded with a 20-s warming of the platform on which they lay. In the current experiment 5- and 11-day-old rats in a hot environment (40 degrees C) acquired the head-turning response when rewarded with a 20-s cooling of the platform on which they lay, but 1-day-olds did not. The concept of ontogenetic adaptation helps us interpret these results: Neonatal thermotaxis constrains the 1-day-olds from learning a novel operant response for a cool reinforcer in a hot environment. Because the thermotaxis wanes from birth, it is not as strong in 5- and 11-day-old pups that are thus able to learn the operant for a cool reinforcer.     

Effect of dopamine-depleting brain lesions in rat pups: role of striatal serotonergic neurons in behavior

Previous results from our laboratory have demonstrated that 3-day-old rats given dopamine (DA)-depleting brain lesions are spared the severe behavioral dysfunctions seen after comparable brain damage in adults. This behavioral sparing is accompanied by a sprouting of serotonin (5-HT)-containing neurons in the striatum. The present results extend these observations by demonstrating that rats given the brain lesions as 15- or 27-day-olds continue to suckle, wean, and grow into adulthood without exhibiting any obvious behavioral dysfunctions, yet striatal 5-HT levels do not increase. Moreover, combined destruction of DA- and 5-HT-containing neurons in 3-day-old rat pups also produced no obvious behavioral dysfunctions. These and other results indicate that increases in striatal 5-HT are not necessary for the behavioral sparing observed after DA-depleting brain lesions in neonatal rats.     

Studies on the origin of rat hippocampal dihydroxyphenylacetic acid using microdialysis.

With a dialysis probe implanted in the rat ventral hippocampus we have monitored effects on noradrenaline (NA) and dihydroxyphenylacetic acid (DOPAC) of the infusion through the dialysis probe of drugs acting at dopaminergic and noradrenergic presynaptic autoreceptors; clonidine and idazoxan produced changes in the extracellular concentration of both NA and DOPAC, whereas LY171555 and sulpiride had no effect on NA but produced changes in the concentration of DOPAC. The combined effect of clonidine and LY171555 on DOPAC was additive. Hippocampal DOPAC is therefore derived from both the noradrenergic and the dopaminergic projection to the hippocampus.     

Early-life malnutrition impairs the performance of both young and adult rats on visual discrimination learning tasks

Previously malnourished young (20-40-day-old) and mature (70-77-day-old) rats were compared on position, brightness, and pattern discrimination problems using an aquatic version of the Lashley jump stand. Malnutrition did not affect performance on the position discrimination. In contrast, previously malnourished 24-34-day-olds failed to solve the brightness discrimination, 40-day-olds were impaired on the brightness problem, and 40-77-day olds were impaired on the pattern problem. The impaired performance of the 40-day-olds on the brightness problem was eliminated by prior training on the pattern discriminations, and the impaired performance of the 70-day-olds on the pattern discrimination could be eliminated if they were first trained on the brightness problem. These impairments were attributed to the effects of early-life malnutrition on the maturation of attention processes that enable the rat to suppress responding to irrelevant cues. The relevance of a contextual-organismic perspective for understanding the effects of early-life malnutrition was discussed.     

Dopamine antagonists produce an age-dependent increase in the responding of the young chick

In three experiments the effects of dopamine receptor antagonists on response-contingent punishment and autoshape learning of 1- and 4-day-old chicks were determined. In the first two experiments, 1- or 4-day-old chicks (N = 120) were trained to key-peck for heat reward and then injected intraperitoneally (ip) with either haloperidol (1.5, 2.5, or 5.0 mg/kg) or saline (Experiment 1) and with either haloperidol (2.0 mg/kg), sulpiride (50 mg/kg) or saline (Experiment 2) 30 min before a 96-trial response-contingent punishment session. In Experiment 3, 1- and 4-day-old chicks (N = 48) were injected ip with saline or haloperidol (2.0 mg/kg) 30 min prior to a 30-trial autoshape learning session. In both the punishment and appetitive tasks 1-day-old chicks pretreated with either haloperidol (1.5 to 2.5 mg/kg) or sulpiride showed a significant increase in key-peck responding compared with their saline injected controls. In contrast, 4-day-old chicks given either haloperidol (2.0 mg/kg) or sulpiride did not differ significantly from saline treated chicks on the punishment task, and on the autoshape task haloperidol-treated 4-day-old chicks responded on fewer trials than did their saline controls. These results indicate that dopaminergic synaptic transmission in the young chick as measured by dopamine D2 receptor blockers is functionally different at 1 compared with 4 days of age.     

Effect of D1 receptor stimulation in normal and MPTP monkeys

The effect of a selective agonist of the dopamine D1 receptor (SKF 38393) and of the D2 receptor (LY-171555) was tested acutely in normal and in monkeys with a parkinsonian syndrome induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The D2 agonist induced a strong locomotor response and lingual dyskinesia in both normal and parkinsonian monkeys. The D1 agonist however had no locomotor effect by itself but induced tongue protrusions in normal monkeys only. It appeared to potentiate the dyskinetic effect of LY 171555 in MPTP monkeys but it antagonized the locomotor action of the D2 agonist in both normal and MPTP monkeys. The selective D1 and D2 antagonists SCH 23390 and sulpiride were also tested. Both compounds were able to suppress the dyskinetic action of the combined agonists in normal animals but only the D2 antagonist was effective in the same conditions in MPTP monkeys. These findings emphasize the importance of the D2 receptor in mediating the locomotor response as well as dyskinesia in monkeys.     

Behavioral changes in rat following perinatal exposure to ethanol

Behavioral changes following pre- and postnatal ethanol administration were examined in rat pups of various ages. A significant increase in locomotor activity occurred at all ages (16, 22 and 30 days) examined. Nose poking activity in 22-day-old pups and standing activity in 30-day-old pups were also significantly higher following perinatal ethanol exposure. No significant change in grooming behavior was observed. The overactivity in rat pups following perinatal ethanol exposure is consistent with the frequently observed hyperactivity in fetal alcohol syndrome children.     

The D1 agonist SKF 38393 inhibits the antiparkinsonian activity of the D2 agonist LY 171555 in the MPTP-treated marmoset

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to common marmosets induced persistent motor deficits. Administration of the D1 agonist SKF 38393 (2.5-20 mg/kg, i.p.) caused a dose-dependent increase of this akinesia. Administration of the D2 agonist LY 171555 (0.3 mg/kg, i.p.) reversed the motor deficits induced by MPTP treatment. Pretreatment of animals with SKF 38393 (2.5-20 mg/kg, i.p.) caused dose-dependent inhibition of the anti-parkinsonian action of LY 171555 (0.3 mg/kg i.p.). In primates SKF 38393 does not reverse motor deficits induced by MPTP and inhibits the actions of a D2-agonist.     

Apomorphine and pergolide induce hypothermia by stimulation of dopamine D-2 receptors

Studies in the male rat have shown that the dopamine D-2 receptor antagonists sulpiride and eticlopride, produce a dose-dependent prevention of the hypothermia induced by the D-1/D-2 receptor agonist apomorphine and the relatively selective D-2 agonist pergolide in the rat. In contrast, the D-1 antagonist SCH 23390 (given by the s.c. and i.p. route of administration) failed to prevent the hypothermic effect induced by both DA agonists, but tended to enhance the hypothermia caused by the two DA agonists. Thus, D-2 dopamine receptors appear to play a decisive role in the mediation of the hypothermic response of apomorphine and pergolide. There may also exist an interaction between D-1 and D-2 receptors in the expression of DA-agonist-induced hypothermia.     

Ultrasonic vocalizations by rat pups: the primary importance of ambient temperature and the thermal significance of contact comfort.

We investigated the effects of isolation, huddling, and air temperature on ultrasound production by rat pups. Experiment 1 showed that ultrasound production by 8- to 9-day-olds was minimal at thermoneutrality and increased in response to small deviations of air temperature on either side of the thermoneutral zone. Experiments 2 and 3 showed that suppression of ultrasound production by contact with littermates is consistent with the thermal consequences of huddling. Experiment 4 showed that, contrary to previous conclusions, ultrasound production is not independent of ambient temperature in pups older than 10 days of age. Taken as a whole, these experiments emphasize (1) the importance of ambient temperature for the elicitation of ultrasound by rat pups of all ages studied, (2) the importance of thermal factors in the suppression of ultrasound by littermate contact, and (3) the manner in which different methods can change interpretations of the behavior and physiology of infant rats.     

Development of the circadian rhythm of neuronal activity in suprachiasmatic nucleus of rat hypothalamic slices

Development of the circadian rhythm of neuronal activity in the suprachiasmatic nucleus (SCN) was studied in rat hypothalamic slices. The firing rate of SCN neurons of 7- and 11-day-old rat pups was low during all of the day, whereas that of 14- and 21-day-old pups was high during daytime and low during nighttime. The present results suggest that the circadian rhythm of SCN neuronal activity is established between 11 and 14 days of age, corresponding closely to the time of onset of the other various hormonal and behavioral circadian rhythms.     

多巴胺自身受体调控大鼠纹状体酪氨酸羟化酶活性的机制

应用ＨＰＬＣ－ＥＣＤ法测定大鼠纹状体突触体ＴＨ的活性，研究ＤＡ自身受体介导的ＤＡ生物合成负反馈调控的机理。发现腺苷环化酶（ＡＣ）激活剂ＦＳＫ和ＰＫＡ激活剂ｄｂｃＡＭＰ均以浓度依赖的方式激活大鼠纹体突触体ＴＨ的活性，增加１－ｄｏｐａ的生成。ＤＡ自身受体激动剂ＬＹ１７１５５５能抑制ＦＳＫ对ＴＨ的激活效应，但不影响ｄｂｃＡＭＰ对ＴＨ的激活。结果表明，ＤＡ自身受体介质的负反馈调控的机理是通过抑制依赖ｃＡＭ     

Role of the Brain Dopaminergic and Opioid System in the Regulation of “Child’s” (Maternal Bonding) Behavior of Newborn Albino Rats

Administration of D₂ receptor antagonist clebopride in a dose not affecting locomotor activity was followed by a decrease in maternal bonding behavior of 10-day-old and 15-day-old albino rat pups. D₁ receptor antagonist SCH23390 had a stimulatory effect only on the behavior of 10-day-old newborns. Opioid peptide β-casomorphin-7 abolished the effect of clebopride in rat pups of the older age group.     

Effects of N-methyl-d-aspartate (dizocilpine) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (LY215490) receptor antagonists on the voiding reflex induced by perineal stimulation in the neonatal rat

The present study was undertaken to examine the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate and N-methyl-D-aspartate glutamate receptors in the regulation of voiding reflexes induced by perineal stimulation in the neonatal rat. Four-, six- and 10-day-old awake rats were used in the experiments and perineal stimulation was applied using the tip of a 1-ml syringe to evoke voiding. Voided volume and residual volume were measured. In 10-day-old rats, LY215490 (3-10 mg/kg, i.p.), a competitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor antagonist, significantly inhibited reflex voiding, increasing the residual volume 34-53-fold. A 3 mg/kg dose decreased the urine release by 55%, whereas 10 mg/kg totally suppressed the voiding reflex induced by the perineal stimulation. LY215490 (10 mg/kg, i.p.) produced similar effects in four- and six-day-old rats. Dizocilpine (1-3 mg/kg, i.p.), a non-competitive N-methyl-D-aspartate receptor antagonist, also significantly decreased the urine release (62-82%) and increased residual volume (180-230-fold). Combined administration of LY215490 (1 mg/kg, i.p.) and dizocilpine (0.3 mg/kg, i.p.) to 10-day-old rats, in doses that individually had no effect on perineal stimulation-evoked voiding, depressed voided volume by 65%. These results indicate that, in neonatal rats, glutamatergic transmission in the spinal cord has an essential role in reflex micturition induced by perineal stimulation, and that facilitatory interactions between alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate and N-methyl-D-aspartate glutamatergic mechanisms are important for voiding, as noted previously in adult rats.