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During early ontogeny infant rats show specific responses to a variety of age-dependent threatening situations. When isolated from nest and dam, they emit ultrasonic vocalizations and show decreased reactivity to noxious stimulation, or analgesia. When exposed to an unfamiliar adult male, they become immobile and analgesic. The midbrain periaqueductal gray (PAG) is an important area within the circuitry that controls responses to threatening stimuli in the adult. Little is known about the functions of the PAG in early life. It was hypothesized that the PAG mediates the responses to the age-specific threats social isolation and male exposure in the infant rat. Rat pups were lesioned electrolytically either in the lateral or the ventrolateral PAG on postnatal day 7, tested in social isolation on day 10, and exposed to a male on day 14. On day 10 during isolation, ultrasonic vocalizations and isolation-induced analgesia were decreased in both lesion groups. On day 14, male-induced immobility and analgesia were decreased in ventrally lesioned animals. In conclusion, the PAG seems to play a developmentally continuous role in age-specific responses to threat such as ultrasonic vocalization, analgesia, and immobility.

The dorsal midbrain including the periaqueductal gray (PAG) is involved in the control of threat-induced vocalizations and other behavioral and autonomic defensive responses in adult animals. Little is known of its function early in life. The present study examined the ability of kainate receptor stimulation in these midbrain areas to trigger behavioral and physiological responses during the first three postnatal weeks in the rat. Kainate (0.03-0.3 nmol) was infused into the dorsal midbrain of postnatal day 7 (P7), P14 and P21 rat pups. At P7, subjects exhibited only a brief period of locomotor activation immediately following infusion of kainate. There were no changes in the heart rate or in any other behavioral measures, including their production of ultrasonic vocalizations. At P14, kainate induced adult-typical escape behaviors consisting of running and jumping, increases in the duration of time spent immobile, and increases in heart rate. At P21, subjects given kainate exhibited escape behavior coupled with elevated heart rate and immobility coupled with decreased heart rate. P14 and P21 subjects produced only small, non-significant increases in their production of ultrasonic vocalizations. These results indicate that kainate receptor stimulation in the dorsal midbrain does not mediate most adult-typical, threat-induced responses until sometime during the second postnatal week in the rat.

The present study was undertaken to assess the functional ontogeny of alpha 2-noradrenergic receptors in the hypothalamic paraventricular nucleus (PVN) that mediate noradrenergic stimulation of feeding in the rat. Rat pups, ranging in age from 2 to 15 days, were removed from their mothers and implanted with a brain cannula directed unilaterally at the PVN or third ventricle. On the following day, each pup was implanted with an intra-oral cannula for oral infusion of milk or water that could be swallowed or rejected. Following a 1-h period of satiation, each pup received an intracerebral injection of saline, or a single dose of norepinephrine (NE, 0.01-100.0 nmol) or the alpha 2-noradrenergic receptor agonist clonidine (0.01-1.0 nmol). Milk or water intake was then assessed following a 1-h period of infusion. Injection of NE into the PVN and third ventricle significantly enhanced milk intake at 2 days of age. NE was 10-fold more potent in the PVN than in the ventricle. While paraventricular injections of NE stimulated milk and water intake equally at 2 days of age, NE produced a greater stimulation of milk than water intake at 15 days of age. Like NE, clonidine significantly enhanced milk intake at 2 days of age following injection into the PVN. Collectively, these findings suggest that alpha 2-noradrenergic receptors, mediating noradrenergic stimulation of feeding, are functionally mature very early in the postnatal development of the rat. Moreover, consistent with evidence in the adult rat, these findings indicate that alpha 2-noradrenergic receptors relevant to feeding are located in the vicinity of the PVN.

When given peripherally, morphine produces a conditioned place preference (CPP) in adult and infant rats. In adults, morphine injected into the ventral tegmental area (VTA) is reinforcing and likely acts by activating mesolimbic dopamine neurons. Little is known of the neurobiological basis of reinforcement in the immature animal. To test whether the neural substrate of drug reinforcement is similar in adults and infants, 4-day-old pups were injected with one of 4 doses (0.05, 0.15, 0.45, 1.35 micrograms) of morphine or the vehicle directly into the VTA and were immediately confined to an odor-cued environment for 30 min. They were then tested for a preference between the cued environment and unadulterated wood shavings. The low dose of morphine (0.05 micrograms) injected into the VTA significantly increased duration of time spent in the conditioned environment, demonstrating conditioned preference for the conditioned area over the unscented area; the most effective injection sites were directly into the VTA. Stimulation of structures just outside the VTA, and higher doses of morphine were ineffective. On the basis of these findings we conclude that the neural substrates of reward in the neonate are similar to those of the adult.

The possibility was investigated that specific opioid receptor types might selectively alter the production of isolation-induced ultrasonic vocalizations. Intracisternal injections of mu, delta and kappa opioid receptor agonists were administered to isolated 10-day-old rat pups. The mu receptor agonist [D-Ala2-NMe-Phe4-Gly-ol]-enkephalin (DAMGO) and delta receptor agonist [D-Pen2, D-Pen5]-enkephalin (DPDPE) both reduced the rate of isolation-induced ultrasonic calling in the absence of sedation. The kappa receptor agonist U50,488 had the opposite effect, significantly raising the rate of vocalization. Fourteen-day-old pups, with a larger delta receptor population, showed a greater sensitivity to DPDPE than was seen in the younger animals.

The prototypic kappa opiate ketocyclazocine produced robust analgesia in 10-day-old rats in the tail-flick nociceptive test. The kappa-opiate behavioral response coincided with the onset of a rapid rise to adult levels in brain kappa receptor site density. In contrast, morphine (prototypic mu opiate) was without marked effect until 14 days of age. The period of rapid mu receptor increase did not take place until days 14-16, which was after kappa receptor levels had already plateaued. Further, there was no or incomplete cross-tolerance between ketocyclazocine and morphine at 14 days of age. The present study, therefore, establishes a role for the kappa binding site in thermal analgesia in the tail flick test and differentiates its ontogenetic pattern from that of the mu receptor.