Noradrenergic modulation of play in Sprague-Dawley and F344 rats.

RATIONALE: For many mammals, engaging in social play behavior as a juvenile is important for cognitive, social, and emotional health as an adult. A playful phenotype reflects a dynamic interplay between genetic framework and experiences that operate on hard-wired brain systems so the relative lack of play in an otherwise playful species may be useful for identifying neural substrates that modulate play behavior. The inbred F344 rat has been identified as a strain that is consistently less playful than other strains commonly used in behavioral research. Norepinephrine (NE) acting on alpha-2 receptors has an inhibitory effect on play and F344 rats differ from a number of other strains in NE functioning. As such, the F344 rat may be particularly useful for gaining insight into NE involvement in play. OBJECTIVE: The objective of this study was to determine whether the F344 rat is differentially sensitive to compounds that affect NE functioning and that are known to affect play behavior. METHODS: Using pouncing and pinning to quantify play, the effects of the NE reuptake inhibitor atomoxetine, the NE alpha-2 receptor agonist guanfacine, and the NE alpha-2 receptor antagonist RX821002 on play behavior were assessed in juvenile Sprague-Dawley (SD) and F344 rats. RESULTS: Atomoxetine and guanfacine reduced play in both SD and F344 rats. RX821002 increased pinning to a comparable extent in both strains but F344 rats were more sensitive to the play-enhancing effects of RX821002 on pounces. CONCLUSIONS: Strain differences in NE alpha-2 receptor dynamics may contribute to the lower levels of play in F344 rats.

Individual differences in social play behaviour predict alcohol intake and control over alcohol seeking in rats.

RATIONALE: Social play behaviour is a rewarding social activity displayed by young mammals, thought to be important for the development of brain and behaviour. Indeed, disruptions of social play behaviour in rodents have been associated with cognitive deficits and augmented sensitivity to self-administration of substances of abuse, including alcohol, later in life. However, the relation between social development and loss of control over substance use, a key characteristic of substance use disorders including alcohol use disorder (AUD), has not been investigated. Moreover, it remains unknown how inherent differences in playfulness relate to differences in the sensitivity to substance use and AUD. OBJECTIVE: The objective of this study is to determine how individual differences in juvenile social play behaviour predict alcohol intake and loss of control over alcohol seeking. METHODS: Juvenile male Lister hooded rats were characterized for their tendency to engage in social play behaviour. Subsequently, alcohol consumption and conditioned suppression of alcohol seeking were assessed in the tertiles of rats that showed the most and least social play. RESULTS: The rats that engaged most in social play behaviour consumed more alcohol than their less playful counterparts. However, whereas the most playful rats showed intact conditioned suppression of alcohol seeking, the least playful rats showed no such suppression. CONCLUSION: Individual levels of playfulness predict the sensitivity to alcohol-directed behaviour. Highly playful rats are more prone to alcohol intake, yet show greater control over alcohol seeking. These findings increase our understanding of the relationship between social development and vulnerability to AUD.

How strain differences could help decipher the neurobiology of mammalian playfulness: What the less playful Fischer 344 rat can tell us about play.

Play is common among the young of many mammalian species. How that play is exhibited results from a dynamic interplay between genetic framework and experiential influences that, in turn, operate on hard-wired brain systems. One approach towards understanding how genes and environment interact with brain substrates to yield a particular playful phenotype is to take advantage of inbred strains of rats that come with a known genetic identity and assess the effects of varying early social experiences and targeted neurobiological interventions on rats of these strains. This paper primarily summarizes research utilizing the F344 inbred strain, a rat that consistently plays less than most other strains.

Basal ganglia involvement in the playfulness of juvenile rats.

Play is an important part of normal childhood development and can be readily studied in the laboratory rat in the form of rough-and-tumble play. Given the robust nature of rough-and-tumble play, it has often been assumed that the basal ganglia would have a prominent role in modulating this behavior. Recent work using c-fos expression as a metabolic marker for neural activity combined with temporary inactivation of relevant corticostriatal regions and pharmacological manipulations of opioid, cannabinoid, and dopamine systems has led to a better understanding of how basal ganglia circuitry may be involved in modulating social play in the juvenile rat. Studies using selective play deprivation have also provided insight into the consequences of playful experiences on basal ganglia function. Data reviewed in this paper support a role for the basal ganglia in social play and also suggest that corticostriatal functioning also benefits from playful activities.

Effects of neonatal handling on play and anxiety in F344 and Lewis rats.

Play is an important part of normal childhood development and seen in many mammals, including rats. To better understand the interplay between genotype and postnatal experiences, the effects of neonatal handling on play were assessed in Lewis (LEW) and Fischer 344 (F344) rats. Handled litters experienced brief periods of separation during the first two postnatal weeks. F344 rats were less likely to direct nape contacts toward an untreated Sprague-Dawley (SD) partner and less likely to rotate to a supine position in response to a nape contact. When compared to rats from control litters, handled LEW, and F344 rats were more likely to respond to nape contacts with complete rotations, suggesting that handling increased playful responsiveness to a comparable extent in both strains. SD rats paired with handled inbred rats had more nape contacts than those paired with non-handled rats. While handled LEW rats also tended to direct more nape contacts to the SD partner than non-handled LEW rats there was no difference between handled and non-handled F344 rats. These results could not be readily explained by handling-induced changes in either maternal care or anxiety. These data suggest that the behavioral consequences of neonatal handling may not depend to a great extent on the genetic platform that these manipulations are acting on. These data also suggest that the ability to maintain the ebb and flow between playful solicitation and playful responsiveness may be compromised in F344 rats and may contribute to the lower levels of play in this strain.

Effects of cross-fostering on play and anxiety in juvenile Fischer 344 and Lewis rats.

A cross-fostering design was used to assess the relative involvement of genetic variability and early postnatal experiences on differential levels of playfulness in juvenile Fischer 344 (F344) and Lewis (LEW) rats and the extent to which strain differences in anxiety may influence play in these two strains. F344 dams were found to lick and groom their pups less than LEW dams and this was not dependent upon the strain of the pups in the litter. As expected, F344 rats were less playful than LEW rats as demonstrated by fewer playful contacts directed to the nape of a Sprague-Dawley (SD) partner and a decreased likelihood of rotating completely to a supine position when their nape was contacted by the SD partner. These differences could not be readily explained by parallel strain differences in anxiety. The pattern of effects on play as a function of cross-fostering depended on both the genetic background of the pup and the motivational state of the pup prior to testing. Whereas in-fostered LEW pups solicited more play as isolation prior to testing increased from 4 to 24h, cross-fostered pups of both strains as well as in-fostered F344 pups were relatively insensitive to the motivational modulation of play solicitation. Responsiveness to play solicitations in pups of both strains reared by F344 dams was insensitive to prior isolation whereas pups reared by LEW dams were less likely to respond with a complete rotation to a supine position when solicited as isolation increased from 4 to 24h prior to testing. These data suggest that the overall level of playfulness in a particular strain of rat is fairly resistant to cross-fostering and may be particularly sensitive to genetic variation whereas how this urge is titrated and modified by motivational factors may be influenced more by epigenetic factors.

A Brain Motivated to Play: Insights into the Neurobiology of Playfulness.

Play is an important part of normal childhood development and is seen in varied forms among many mammals. While not indispensable to normal development, playful social experiences as juveniles may provide an opportunity to develop flexible behavioral strategies when novel and uncertain situations arise as an adult. To understand the neurobiological mechanisms responsible for play and how the functions of play may relate to these neural substrates, the rat has become the model of choice. Play in the rat is easily quantified, tightly regulated, and can be modulated by genetic factors and postnatal experiences. Brain areas most likely to be involved in the modulation of play include regions within the prefrontal cortex, dorsal and ventral striatum, some regions of the amygdala, and habenula. This paper discusses what we currently know about the neurobiological substrates of play and how this can help illuminate functional questions about the putative benefits of play.

Rough-and-tumble play as a window on animal communication.

Rough-and-tumble play (RT) is a widespread phenomenon in mammals. Since it involves competition, whereby one animal attempts to gain advantage over another, RT runs the risk of escalation to serious fighting. Competition is typically curtailed by some degree of cooperation and different signals help negotiate potential mishaps during RT. This review provides a framework for such signals, showing that they range along two dimensions: one from signals borrowed from other functional contexts to those that are unique to play, and the other from purely emotional expressions to highly cognitive (intentional) constructions. Some animal taxa have exaggerated the emotional and cognitive interplay aspects of play signals, yielding admixtures of communication that have led to complex forms of RT. This complexity has been further exaggerated in some lineages by the development of specific novel gestures that can be used to negotiate playful mood and entice reluctant partners. Play-derived gestures may provide new mechanisms by which more sophisticated communication forms can evolve. Therefore, RT and playful communication provide a window into the study of social cognition, emotional regulation and the evolution of communication systems.

Effects of amphetamine on striatal dopamine release, open-field activity, and play in Fischer 344 and Sprague-Dawley rats.

Previous work from our laboratories has shown that juvenile Fischer 344 (F344) rats are less playful than other strains and also appear to be compromised in dopamine (DA) functioning. To determine whether the dysfunctional play in this strain is associated with deficits in the handling and delivery of vesicular DA, the following experiments assessed the extent to which F344 rats are differentially sensitive to the effects of amphetamine. When exposed to amphetamine, striatal slices obtained from F344 rats showed a small increase in unstimulated DA release when compared with slices from Sprague-Dawley rats; they also showed a more rapid high K+-mediated release of DA. These data provide tentative support for the hypothesis that F344 rats have a higher concentration of cytoplasmic DA than Sprague-Dawley rats. When rats were tested for activity in an open field, F344 rats presented a pattern of results that was consistent with either an enhanced response to amphetamine (3 mg/kg) or a more rapid release of DA (10 mg/kg). Although there was some indication that amphetamine had a dose-dependent differential effect on play in the two strains, play in F344 rats was not enhanced to any degree by amphetamine. Although these results are not consistent with our working hypothesis that F344 rats are less playful because of a deficit in vesicular release of DA, they still suggest that this strain may be a useful model for better understanding the role of DA in social behavior during the juvenile period.

Amphetamine and cocaine suppress social play behavior in rats through distinct mechanisms.

RATIONALE: Social play behavior is a characteristic form of social behavior displayed by juvenile and adolescent mammals. This social play behavior is highly rewarding and of major importance for social and cognitive development. Social play is known to be modulated by neurotransmitter systems involved in reward and motivation. Interestingly, psychostimulant drugs, such as amphetamine and cocaine, profoundly suppress social play, but the neural mechanisms underlying these effects remain to be elucidated. OBJECTIVE: In this study, we investigated the pharmacological underpinnings of amphetamine- and cocaine-induced suppression of social play behavior in rats. RESULTS: The play-suppressant effects of amphetamine were antagonized by the alpha-2 adrenoreceptor antagonist RX821002 but not by the dopamine receptor antagonist alpha-flupenthixol. Remarkably, the effects of cocaine on social play were not antagonized by alpha-2 noradrenergic, dopaminergic, or serotonergic receptor antagonists, administered either alone or in combination. The effects of a subeffective dose of cocaine were enhanced by a combination of subeffective doses of the serotonin reuptake inhibitor fluoxetine, the dopamine reuptake inhibitor GBR12909, and the noradrenaline reuptake inhibitor atomoxetine. CONCLUSIONS: Amphetamine, like methylphenidate, exerts its play-suppressant effect through alpha-2 noradrenergic receptors. On the other hand, cocaine reduces social play by simultaneous increases in dopamine, noradrenaline, and serotonin neurotransmission. In conclusion, psychostimulant drugs with different pharmacological profiles suppress social play behavior through distinct mechanisms. These data contribute to our understanding of the neural mechanisms of social behavior during an important developmental period, and of the deleterious effects of psychostimulant exposure thereon.

In search of the neurobiological substrates for social playfulness in mammalian brains.

Play behavior is a fundamental and intrinsic neurobehavioral process in the mammalian brain. Using rough-and-tumble play in the juvenile rat as a model system to study mammalian playfulness, some of the relevant neurobiological substrates for this behavior have been identified, and in this review this progress. A primary-process executive circuit for play in the rat that includes thalamic intralaminar nuclei, frontal cortex and striatum can be gleaned from these data. Other neural areas that may interact with this putative circuit include amygdala, ventral hypothalamus, periaqueductal gray (PAG), and deep tectum, as well as ascending dopamine systems which participate in all types of seeking urges. At the neurochemical level, considerable evidence points to specific cholinergic and dopaminergic controls, but also endogenous opioids and cannabinoids as having a positive modulatory influence over playfulness, with all neuropeptides known to have aversive effects to reduce play. Monoamines such as norepinephrine and serotonin certainly modulate play, but they influence all psychobehavioral systems, suggesting non-specific effects. We proceed to discuss how increased insights into the neurobiological mechanisms of play can inform our understanding of normal and abnormal childhood development.

Dysfunctional play and dopamine physiology in the Fischer 344 rat.

Juvenile Fischer 344 rats are known to be less playful than other inbred strains, although the neurobiological substrate(s) responsible for this phenotype is uncertain. In the present study, Fischer 344 rats were compared to the commonly used outbred Sprague-Dawley strain on several behavioral and physiological parameters in order to ascertain whether the lack of play may be related to compromised activity of brain dopamine (DA) systems. As expected, Fischer 344 rats were far less playful than Sprague-Dawley rats, with Fischer 344 rats less likely to initiate playful contacts with a playful partner and less likely to respond playfully to these contacts. We also found that Fischer 344 rats showed less of a startle response and greater pre-pulse inhibition (PPI), especially at higher pre-pulse intensities. The increase in PPI seen in the Fischer 344 rat could be due to reduced DA modulation of sensorimotor gating and neurochemical measures were consistent with Fischer 344 rats releasing less DA than Sprague-Dawley rats. Fast scan cyclic voltammetry (FSCV) revealed Fischer 344 rats had less evoked DA release in dorsal and ventral striatal brain slices and high-performance liquid chromatography revealed Fischer 344 rats to have less DA turnover in the striatum and prefrontal cortex. We also found DA-dependent forms of cortical plasticity were deficient in the striatum and prefrontal cortex of the Fischer 344 rat. Taken together, these data indicate that deficits in play and enhanced PPI of Fischer 344 rats may be due to reduced DA modulation of corticostriatal and mesolimbic/mesocortical circuits critical to the execution of these behaviors.

Serotonin, motivation, and playfulness in the juvenile rat.

The effects of the selective 5HT(1A) agonist 8-OH-DPAT were assessed on the play behavior of juvenile rats. When both rats of the test pair were comparably motivated to play, the only significant effect of 8-OH-DPAT was for play to be reduced at higher doses. When there was a baseline asymmetry in playful solicitation due to a differential motivation to play and only one rat of the pair was treated, low doses of 8-OH-DPAT resulted in a collapse of asymmetry in playful solicitations. It did not matter whether the rat that was treated initially accounted for more nape contacts or fewer nape contacts, the net effect of 8-OH-DPAT in this model was for low doses of 8-OH-DPAT to decrease a pre-established asymmetry in play solicitation. It is concluded that selective stimulation of 5HT(1A) receptors changes the dynamic of a playful interaction between two participants that are differentially motivated to play. These results are discussed within a broader framework of serotonergic involvement in mammalian playfulness.

Effects of chlordiazepoxide on predator odor-induced reductions of playfulness in juvenile rats.

The extent to which a non-sedative dose of chlordiazepoxide (CDP) is able to modify the behavioral responses toward a predator odor was assessed in juvenile rats. Play behavior was suppressed and defensive behaviors were enhanced in the presence of a collar previously worn by a cat, when tested 24 h later in the same context as that where the exposure occurred, and when tested in a context different than that in which the exposure occurred for up to 3 h after exposure. CDP had no effect on the ability of cat odor to suppress play when rats were tested in the presence of the odor or when tested 24 h later in the same context where that exposure occurred. When rats were exposed to a worn cat collar in their home cage and tested in a different context CDP attenuated the ability of cat odor to reduce one measure of play (nape contacts) but not another measure (pins). Rats had an opportunity to hide during testing and CDP either decreased hiding or increased risk assessment from within the hide box in all of the testing scenarios. These data suggest that CDP can alter the defensive strategy used by juvenile rats that are confronted with a predatory threat and can also lead to an earlier return to pre-threat levels of playfulness when that threat becomes less immediate.

Effects of pre-pubertal social experiences on the responsiveness of juvenile rats to predator odors.

The extent to which social variables may modulate the fear associated with a predator cue was assessed in juvenile rats. Cat odor reduced play to a comparable extent in both socially housed and isolate-housed rats, although socially housed rats exhibited more risk assessment during extinction. Rats that had played previously in the context used for assessing fear hid slightly less when exposed to cat odor than those rats that had not played previously in the testing context. However, no other differences were found between these two groups suggesting that prior social experience with the testing context has minimal effects on fear. In a direct test of a 'social buffering' hypothesis, rats that were tested for contextual fear conditioning in the presence of an unfamiliar partner were less fearful than those rats tested alone. These data are consistent with a social buffering hypothesis and suggest that positive social cues may help animals cope with the threat of predation.

Effects of neonatal handling on play behavior and fear towards a predator odor in juvenile rats (Rattus norvegicus).

The effects of brief daily separation, also known as "handling," during the first 2 weeks of life on play behavior and fearfulness toward a predatory odor were assessed in juvenile rats. Handled rats were more playful than nonhandled control rats, and while handling had no effect on the direct response of these rats toward a predatory odor, handled rats did not exhibit a conditioned suppression of play when tested later in the same context where they had been exposed to the predatory odor. Handled rats were still wary of the environment in that they continued to show a heightened level of risk assessment behavior. These data suggest that early postnatal experiences may play a significant role in determining how an animal deals with predatory threats later in life.

Fear, risk assessment, and playfulness in the juvenile rat.

The effects of predatory odors on play were assessed in juvenile rats. When rats were exposed directly to a collar previously worn by a cat, play was abolished and remained suppressed for up to 6 days. Providing rats with an opportunity to hide did not alter cat odor's ability to reduce their play. Rat play was also suppressed shortly after they were exposed to cat odor in their home cage, and a substantial amount of risk assessment behavior was present up to 24 hr later. Trimethylthiazoline, a component found in fox feces, only reduced play during exposure. These data suggest that predatory odor-induced reductions in play may provide a useful model for gaining insight into the consequences of fear and anxiety in young animals.

The relative playfulness of juvenile Lewis and Fischer-344 rats.

The relative playfulness of inbred Lewis and Fischer-344 rats was characterized. Fischer rats were consistently less playful than Lewis rats, with rats of this strain less likely to initiate playful interactions with either responsive or unresponsive partners and also less likely to respond playfully when playful solicitations were directed to them. While less playful, Fischer rats were more socially inquisitive than Lewis rats when tested with an unresponsive partner, suggesting that Fischer rats are less likely to escalate a social encounter into a playful one. Strain differences in playful responsiveness were present with or without prior social isolation, suggesting that this aspect of play represents a relatively stable trait difference. Unlike play responsiveness, strain differences in play solicitation were only apparent after a period of social isolation. Low levels of play were still present in Fischer rats that had been reared by Lewis dams, suggesting a genetic source for the altered play in rats of this strain. Further studies of play behavior in Lewis and Fischer rats could illuminate relevant neural involvement in rough-and-tumble play and also help understand the genetic bases for this complex social behavior.

Effects of neonatal handling and maternal separation on rough-and-tumble play in the rat.

The extent to which brief daily handling and longer periods of separation from the mother during the first 2 weeks of life can affect play behavior in juvenile rats was assessed. Rat pups were separated from the mother for either 15 min daily (handling) or for 3 hr daily (maternal separation), and play was observed as juveniles. Overall levels of playfulness were not affected by either manipulation, although certain aspects of playful responsiveness were affected in males, but not females. In particular, the pattern of responsiveness to playful contacts was feminized in both handled and separated male rats. Activity in a novel open field at 15 days of age was increased in both males and females from the separated group, but not in the handled animals, as were the number of rears exhibited during the play bouts. These data suggest that early rearing experiences can have subtle gender-dependent effects on some aspects of play in juvenile rats and that the underlying mechanism(s) responsible for these effects may differ from those associated with other effects reported for handling and maternal separation.

Behavioral sensitization to amphetamine follows chronic administration of the CB1 agonist WIN 55,212-2 in Lewis rats.

The extent to which acute and repeated administration of the CB(1) agonist WIN 55,212-2 would affect the stimulatory properties of amphetamine was assessed in Lewis rats. In the first experiment, Lewis rats were treated with either 1 mg/kg of WIN 55,212-2 or vehicle and subsequently treated with 2 mg/kg amphetamine. Acute treatment with WIN 55,212-2 initially increased locomotor activity and then attenuated the stimulating effect of amphetamine on locomotion and exploration (as measured by rears). In a separate experiment, Lewis rats were given daily injections of either WIN 55,212-2 (1 mg/kg) or vehicle for 10 days and the effects of amphetamine were assessed at 1 and 3 days following the last chronic cannabinoid treatment. Those rats, which had been treated with WIN 55,212-2, had an enhanced response to amphetamine with rearing but not with ambulatory movements, suggesting the occurrence of behavioral cross-sensitization to the ability of amphetamine to increase rearing. These data add to the growing evidence that there is at least some overlap between those neural systems acted upon by cannabinoids and those that are believed to be involved in incentive properties associated with other drugs of abuse.