J.M. van Ree

The neurobiology of social play behavior in rats

Social play behavior is one of the earliest forms of non-mother-directed social behavior appearing in ontogeny in mammalian species. During the last century, there has been a lot of debate on the significance of social play behavior, but behavioral studies have indicated that social play behavior is a separate and relevant category of behavior. The present review provides a comprehensive survey of studies on the neurobiology of social play behavior. Evidence is presented that opioid and dopamine systems play a role in the reward aspect of social play behavior. The role of cholinergic, noradrenergic and opioid systems in attentional processes underlying the generation of social play behavior and the involvement of androgens in the sexual differentiation of social play behavior in rats is summarized. It is concluded that there is not only behavioral, but also neurobiological evidence to suggest that social play behavior represents a separate category of behavior, instead of a precursor for adult social, sexual or aggressive behavior.

Play is indispensable for an adequate development of coping with social challenges in the rat

In this study, young rats were deprived of early social interactions during weeks 4 and 5 of life. Different behavioral tests were conducted in adulthood to study the behavioral responses of rats lacking early social experiences. Juvenile deprivation resulted in decreased social activity and an altered sexual pattern, but did not affect locomotor activity or the performance in the elevated plus maze. Furthermore, behavioral and neuroendocrine responses of juvenile isolated rats were dramatically altered when they were confronted with territorial aggression. Juvenile deprived rats did not readily display a submissive posture in response to the resident and showed no immobility behavior after being returned to the residents territory, while their plasma corticosterone and adrenaline concentrations were significantly increased compared to nonisolated controls. In contrast, behavioral responses in the shock prod test were not affected by previous isolation. The results suggest that early social experiences are vital for interactions with conspecifics later in life, i.e., aggression, sexual, and social interactions.

Effect of naltrexone on alcohol consumption during chronic alcohol drinking and after a period of imposed abstinence in free-choice drinking rhesus monkeys

Relapse into problematic alcohol drinking is a serious problem in the treatment of alcoholism. Free-choice drinking rhesus monkeys show relapse-like behaviour after imposed abstinence of alcohol, by immediately reinitiating ethanol intake at an increased level. The relapse-like behaviour of the monkeys seems not induced by physical withdrawal, but rather argues for a resistance to extinction of ethanol-reinforced behaviour. It has been suggested that endogenous opioids play a role in the positive reinforcing effect of ethanol. In this study, the effect of the opiate antagonist naltrexone was investigated in eight adult male rhesus monkeys(Macaca mulatta) who had about 1 year experience with alcohol drinking, under two conditions: 1) (expt 1) during continuous and concurrent supply of drinking water and two ethanol/water solutions (16% and 32% (v/v)), and 2) (expt 2) after 2 days of alcohol abstinence. In both experiments, each monkey received six doses of naltrexone (0.02, 0.06, 0.17, 0.5, 1.0, 1.5 mg · kg−1); each dose was paired with a placebo injection (im) in a cross-over design. Consumption was measured from 16.00 hours in the afternoon (30 min after injection) to 9.00 hours the next morning. In experiment 1 naltrexone reduced total net ethanol intake in a graded dose-dependent manner. The effect of naltrexone was apparent shortly after injection, and lasted until the following day. Consumption of drinking water was reduced only shortly after injection. In expt 2, reduction of net ethanol intake was largely restricted to the first few hours of reinitiation of alcohol drinking, i.e. the period in which the abstinence-induced increase was manifest. Consumption of drinking water was not affected by naltrexone. Naltrexone hardly influenced consumption of the non-preferred ethanol solution of 32%. It is postulated that the opioid modulation specifically interacted with positively reinforced behaviour. In expt 2 naltrexone reduced ethanol intake at a lower dose (0.17 mg · kg−1) compared to expt 1 (0.50 mg · kg−1), but net ethanol intakes however remained higher. It might be that alcohol abstinence resulted in altered opioid activity, leading to increased ethanol-seeking behaviour. The renewed presentation of ethanol solutions (also) might have stimulated reinitiation of alcohol drinking, representing conditioned incentive stimuli. The reported monkey model of relapse in alcohol drinking could be a useful tool to evaluate new hypotheses and experimental treatments with respect to human alcoholism.

Isolation during the play period in infancy decreases adult social interactions in rats

The effects of 1 or 2 weeks of social isolation immediately after weaning on social activity in adulthood were investigated in rats. In addition, it was studied whether these effects were influenced by social experiences of the cagemate when rehoused after the isolation period. Isolation during weeks 4 and 5 of age caused a reduction of social activity as compared to non-isolated controls. Previous social experiences of the cagemate (isolated or non-isolated) did not affect this decreased social activity. Isolation during week 4 of age resulted in similar effects, but the reduced social activity was not present when the rats were rehoused with non-isolated rats. Isolation during week 5 of age did not influence social activity patterns in adulthood. These findings support the idea of a sensitive period in infancy for subsequent social behavior in rats. It is suggested that especially deprivation of acquiring play behavior underlies the social disturbances in adulthood.

Prolyl-leucyl-glycinamide (PLG) facilitates morphine dependence.

Abstract The development of physical dependence to morphine is facilitated in rats treated with [desglycinamide (9), arginine (8)] -vasopressin (DG-AVP) or with oxytocin. Oxytocin appeared to be more potent than DG-AVP. The essential elements of vasopressin and oxytocin required for facilitating morphine tolerance and physical dependence, are located in the C-terminal part of these hormones. It was found that the C-terminal tripeptide of oxytocin, prolylleucyl-glycinamide, was the most potent oligopeptide in this respect.

The effects of a sub-anaesthetic dose of ketamine on human selective attention

A growing number of studies demonstrate that antagonists of the N-methyl-D-aspartate (NMDA) receptors can induce a broad range of psychophysiological anomalies in healthy subjects similar to those observed in schizophrenia. In this study, the effect of a sub-anaesthetic dose of the non-competitive NMDA antagonist, ketamine, on human selective attention was explored. It was hypothesized that ketamine would induce in healthy subjects psychophysiological anomalies that are commonly observed in schizophrenic patients, such as reduced P300 amplitude and a reduction of both mismatch negativity (MMN) and processing negativity (PN). In a double-blind randomized placebo-controlled design, healthy male volunteers (n = 18) were challenged with a sub-anaesthetic dose of ketamine (0.3 mg/kg iv) after which they were tested in a selective attention task. In this task, two types of stimuli were evenly presented to the left or right ear: standard tones (80%) and deviant tones (20%) of either 1000 or 1100 Hz. The duration of a stimulus (95 dB) was 50 ms, the interstimulus intervals were randomized between 1750 and 2150 ms. The volunteer was instructed to push a button as quickly as possible after hearing the deviant tone in a specified ear. Ketamine did not alter performance of the subjects: in both the placebo and drug condition their reaction times for and percentages of hits and false alarms did not differ. Ketamine did, however, reduce PN and the P300 amplitude (both in general and to deviant stimuli in particular). However, no drug effect on MMN was found. In addition, ketamine enhanced the N100 amplitude to deviant stimuli. In conclusion, ketamine induces some of the attentional deficits in healthy controls that are observed in schizophrenic patients. Consequently, reduced glutamatergic activity in the brain may be involved in some of the symptoms of schizophrenia.

The effects of low dose ketamine on sensory gating, neuroendocrine secretion and behavior in healthy human subjects

Abstract Recently, much interest has been given to the role of glutamatergic N-methyl-D-aspartate receptors (NMDA) in sensory gating, such as prepulse inhibition (PPI) and reduction of the P50 evoked response potential (ERP). Currently, mainly animal data are available describing the role of NMDA receptors in these stimulus evaluation processes. Human data are virtually lacking and are potentially important, for instance for the understanding of sensory gating deficits observed in schizophrenia. Therefore, the effects of the NMDA antagonist ketamine, in a dose of 0.3 mg/kg IV, on concurrent assessment of PPI and P50 reduction was studied in 18 healthy male volunteers. Ketamine was administered in a pseudo-steady state model with a subacute loading dose. In addition, the effects of ketamine on behavior, vital signs, homovanillic acid (HVA) plasma levels and secretion of cortisol and luteinizing hormone (LH) were also determined. Ketamine did not significantly alter PPI or the reduction of the P50 ERP. A small but significant increase in Brief Psychiatric Rating Scale (BPRS) total scores and BPRS composite scores “thinking disorder” and “withdrawal/retardation” was observed. Several subjects experienced visual perceptional alterations, but complex hallucinations did not occur. Ketamine induced mild analgesia and coordination problems. In addition, ketamine induced a marked rise in cortisol secretion, while LH secretion was not affected. Finally, systolic and diastolic, blood pressure and heart rate increased during ketamine infusion. Although in humans NMDA receptors may not be involved in the regulation of PPI and P50 reduction, the most likely explanation for the lack of effect of ketamine on these sensory gating paradigms is the dose used in this experiment. However, using a higher dose is hampered by the aspecificity of racemic ketamine. Future studies should use the enantiomer S-ketamine, which is more specific to NMDA receptors, to evaluate the involvement of NMDA receptors in these neurophysiological processes further.

Neuroleptic-like activity of peptides related to [DES-TYR1] γ-endorphin: Structure activity studies

The potency of various fragments of γ-endorphin (β-LPH61–77) was compared on their ability to facilitate extinction of pole-jumping avoidance behavior and their effects in two “grip tests” used as measures of neuroleptic-like activity. It appeared that β-LPH66–77 is the shortest sequence which shows potencies in the three tests comparable to that of DTγE (β-LPH62–77). The activity of β-LPH67–77 was less. It is proposed that β-LPH66–77 rather than DTγE represents an endogenous neuroleptic-like neuropeptide which may play a key role in psychopathology.

Influence of environmental factors on social play behavior of juvenile rats

The effects of light level and familiarity to the testing environment on social behaviors related and unrelated to play were investigated in juvenile rats accustomed to dim light conditions. Pinning, a measure characteristic for social play in rats, was completely suppressed under intense light conditions. Following/chasing and boxing/wrestling, social behaviors related to play, were also decreased under intense light. Of the measures of social behavior not related to play, contact behavior was decreased under intense light whereas social exploration was hardly affected. Levels of social exploration and following/chasing gradually declined during the 15-min test period. Frequency of contact behavior decreased, whereas duration increased with time. Under dim light conditions, unfamiliarity to the test cage suppressed pinning and boxing/wrestling but not the other social behaviors in the first part of the test period. These findings show that social behavior in juvenile rats, as in adult rats, can be influenced by light level and familiarity to the test cage. Social behaviors related and unrelated to play seem to be differentially influenced by environmental stimuli.

Effects of morphine on different aspects of social play in juvenile rats

To clarify the influence of opioids on social play, the effects of morphine on playful and non-playful social behavior in juvenile rats was investigated under different conditions. Environmental variables employed were different (dim and intense) levels of illumination during testing, familiarity to the test cage, and different periods of social isolation prior to testing. Under dim light conditions, morphine markedly increased playful social behavior, such as pinning, boxing/wrestling and following/chasing, whereas non-playful social behavior such as social exploration and contact behavior was hardly affected. This effect of morphine was independent of duration of previous isolation and dose-dependent, with a maximal effect at 1.0 mg/kg. The mechanism of this effect is interpreted as an action on the rewarding aspects of play. A dose of 0.1 mg/kg of morphine abolished the initial suppression of play induced by unfamiliarity to the test cage, without influencing total levels of play. This may be an effect of morphine on the integration of sensory stimuli. Under intense light conditions, where playful behavior was completely suppressed, morphine itself hardly affected such behavior, but decreased some aspects of non-playful social behavior. These results suggest that in juvenile rats playful and non-playful forms of social behavior are differentially regulated. In addition, opioid systems may be involved at different levels in the regulation of social play.