Effects of nicotine on target biting and resident-intruder attack

doi:10.1016/S0024-3205(03)00289-3

Life Sciences

Volume 73, Issue 3, 6 June 2003, Pages 311-317

https://doi.org/10.1016/S0024-3205(03)00289-3 Get rights and content

Abstract

The effects of acute administration of nicotine on target biting (defensive) and resident-intruder (offensive) attack of male mice were assessed. In the target biting procedure confined mice received tail shock on a fixed time, 2-min schedule. Under baseline conditions, biting attack directed toward an inanimate target occurred at three distinct rates. A high target biting rate (13.5 ± 3.8 bites/15 sec) followed shock delivery, an intermediate biting rate (9.6 ± 4.1 bites/15 sec) occurred during the inter-shock interval, and a low biting rate (1.0 ± 0.5 bites/15 sec) occurred during a tone stimulus which signalled the impending shock. Nicotine (administered IP, 15 min presession) reduced post-shock and inter-shock interval target biting in a dose-dependent manner (ED50 values estimated at 0.13 and 0.14 mg/kg, respectively) but exerted more variable effects on target biting during the tone. In the resident-intruder paradigm the same mice were exposed to an intruder introduced into its home cage for a 10-min test session. Under baseline conditions, residents directed 20 ± 3.2 biting attacks toward the intruder during the session with an average latency of 89 ± 40 sec to the first attack. Nicotine caused a dose-dependent decrease in this attack behavior (ED50 values estimated to be 0.48 and 0.49 mg/kg, respectively). These observations are interpreted to indicate that nicotine has an increased potency at reducing “defensive” aggression.

Introduction

Nicotine has been shown to reduce aggressive behaviors in a variety of species and experimental paradigms. In rats, nicotine reduced intraspecific fighting, muricide, and the shock-induced attack of conspecifics (Driscoll, 1979, Rodgers, 1979, Silverman, 1971, Waldbillig, 1980, Redolat et al., 2000, 2002). In cats, nicotine administration also reduced muricide and suppressed aggressive biting attack induced by the muscarinic agonist, arecoline (Berntson et al., 1976). In squirrel monkeys, nicotine reduced the shock-induced biting of a rubber hose (Emley and Hutchinson, 1983) and, in humans, the cigarette smoking of nicotine reduced the frequency of aggressive responses directed toward others Cherek, 1984, Cherek et al., 1991, File et al., 2001. These aggression-reducing effects occurred at doses, which did not alter the subject's sensitivity to shock Rodgers, 1979, Waldbillig, 1980 or the consumption of food (Berntson et al., 1976). Consequently, it appears that the anti-aggressive properties of nicotine are not merely the result of non-specific drug effects (Redolat et al., 2000).

While the above studies represent a wide range of species and experimental procedures, there has been a disproportionate representation of “predation” and “defensive” behaviors with fewer studies investigating “offensive” aggression. Furthermore, systematic attempts to compare the potency of nicotine at reducing “defensive” versus “offensive” aggression in the same set of animals are lacking. Accordingly, the objective of the present studies was to compare the aggression-reducing effects of nicotine in the target biting (defensive) and resident-intruder (offensive) paradigms.

Section snippets

Subjects

Ten adult male, Swiss Webster mice (Charles River Breeders, North Wilmington, DE) were housed individually in a colony room with 12/12 hr light/dark cycle. Twelve additional mice were used as intruders and group housed in clear plastic cages. All mice had free access to food and water throughout the study.

Apparatus

The apparatus has been described in detail elsewhere (Wagner et al., 1983). Briefly, mice were confined in an opaque, plastic cylinder (2.8 cm inner diameter; 9.8 cm long). Their tails were

Target biting

Under baseline (saline) conditions, mice exhibited three distinct rates of target biting behavior. There was a high target biting rate (13.5 ± 3.8 bites per 15 sec) immediately after the shock (bin 1), an intermediate rate (9.6 ± 4.1 bites per 15 sec) during the inter-shock interval (bins 2–7), and a low target biting rate (1.0 ± 0.5 bite per 15 sec) during the tone CS (bin 8) (Fig. 1). Nonparametric sign tests indicated that the post-shock (bin 1) target biting rate was significantly greater

Discussion

Target biting at three distinguishable rates was engendered by the presentation of a tail shock (to confined mice) on a fixed-time schedule with a tone CS signalling the impending shock. These observations are in agreement with previously published reports Carelli and Wagner, 1988, Jarvis et al., 1985, Wagner et al., 1983 and have been traditionally interpreted as a measure of “defensive” aggression (see Blanchard and Blanchard, 1984, Hutchinson, 1984 for two perspectives). Nicotine

Conclusion

The presession administration of nicotine caused dose-dependent reductions in shock-induced target biting as well as resident attack of an intruder. Nicotine was 3.8 times more potent at reducing attack behavior in the former as compared to the latter paradigm. These observations may indicate that nicotine is more effective at reducing defensive as compared to offensive aggression.

Acknowledgments

Supported in part by ES-05022, ES-11256, NS-43981, and grants from Johnson and Johnson and the Charles and Johanna Bush Memorial Fund.

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Nicotine's effects on defensive aggression have also been explored in other animal models. Nicotine dose-dependently reduced target biting in mice immediately after shock (ED50 = 0.13 mg/kg) and in an intermediate post-shock period (ED50 = 0.14 mg/kg), without a systematic effect on target biting during a tone conditioned stimulus (Johnson et al., 2003). Similarly, acute nicotine administration suppressed aggressive biting in response to tail shock in squirrel monkeys, despite enhanced unconditioned lever pressing (Emley and Hutchinson, 1983).
Neuropsychiatric disorders are frequently complicated by aggressive behaviors. For some individuals, existing behavioral and psychopharmacological treatments are ineffective or confer significant side effects, necessitating development of new ways to treat patients with severe aggression. Nicotinic acetylcholine receptors (nAChRs) are a large and diverse family of ligand-gated ion channels expressed throughout the brain that influence behaviors highly relevant for neuropsychiatric disorders, including attention, mood, and impulsivity. Nicotine and other drugs targeting nAChRs can reduce aggression in animal models of offensive, defensive, and predatory aggression, as well as in human laboratory studies. Human genetic studies have suggested a relationship between the CHRNA7 gene encoding the alpha-7 nAChR and aggressive behavior, although these effects are heterogeneous and strongly influenced by genetic background and environment. Here we review animal, human genetic, and clinical studies supporting a consistent role of nicotine and nAChR signaling in modulation of aggressive behaviors. We integrate findings from recent studies of aggression neuroscience, discuss the circuitry that may be involved in these effects of nAChRs, and identify multiple key questions that must be answered prior to safe and effective translation for human patients.
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Increased alcohol consumption and heightened aggression have been linked to social isolation. Furthermore, animals treated with alcohol following social separation showed higher aggression together with lower serotonin transmission. Although reduced serotonin transmission in the brain may be related to alcohol-induced heightened aggression and fluoxetine has been used to reduce alcohol intake and aggression, it remains unclear whether there are specific brain regions where changes in serotonin transmission are critical for animal aggression following the alcohol treatment. In the present study, we isolated mice for 4–6 weeks and injected them with alcohol, fluoxetine and alcohol with fluoxetine. We studied their aggression by using two types of behavioral paradigms: isolation-induced attack behavior towards a naïve mouse in a neutral cage, or shock-induced target biting aggression. We observed that alcohol administered at 500 mg/kg significantly increased animal attack behaviors towards naïve mice 30 min after injections. This dose of alcohol co-administered with a low dose of fluoxetine (2 mg/kg) further increased the attack behaviors, but with higher doses of fluoxetine, the attack behaviors were decreased. Alcohol administered at a dose of 1,000 mg/kg significantly decreased the shock-induced target biting rates 24 h after injections. Interestingly, 24 h after injections, we observed a significant increase in target biting rates when alcohol was co-administered with fluoxetine at a dose of 16 mg/kg. We also observed the same heightened target biting rates when animals were injected with fluoxetine alone. This heightened biting attack engendered by the fluoxetine (alone or in combination with the alcohol) occurred at a time when brain serotonin activity was reduced by these drugs in the frontal cortex and hypothalamus. These observations, in concordance with previous findings reported by others, indicate that heightened biting attack behavior may be associated with reduced serotonergic activity in brain regions regulating aggression.
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Aggression is frequently comorbid with neuropsychiatric conditions and is a predictor of worse outcomes, yet current pharmacotherapies are insufficient and have debilitating side effects, precluding broad use. Multiple models of aggression across species suggest that the nicotinic acetylcholine receptor (nAChR) agonist nicotine has anti-aggressive (serenic) properties. Here we demonstrate dose-dependent serenic effects of acute nicotine administration in three distinct mouse strains: C57BL/6, BALB/c, and CD1. While acute nicotine administration (0.25 mg/kg) modestly reduced solitary homecage locomotion, this could not account for nicotine’s serenic effects since social encounters eliminated the hypolocomotor effect, and nicotine did not alter social interaction times. Pretreatment with the homomeric (α7 subunit) nAChR antagonist methyllycaconitine (5 mg/kg), but not the heteromeric (β2 or β4 subunit-containing) nAChR antagonist dihydro-β-erythroidine (DHβE, 3 mg/kg), blocked the serenic effects of nicotine. By contrast, pretreatment with DHβE blocked the effect of acute nicotine administration on locomotion, uncoupling nicotine’s serenic and hypolocomotor effects. Finally, the α7 nAChR partial agonist GTS-21 reduced aggression in C57BL/6 mice. These results support the idea that acute nicotine administration has serenic effects and provide evidence for specificity of this effect distinct from effects on locomotion. Furthermore, pharmacological studies suggest that activation of α7 nAChRs underlies the serenic effects of nicotine. Further studies of nAChRs could enhance understanding of the neurobiology of aggression and may lead to the development of novel, more specific treatments for pathological aggression.
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The co-morbidity between smoking and mood disorders is striking. Preclinical and clinical studies of nicotinic effects on mood, anxiety, aggression, and related behaviors, such as irritability and agitation, suggest that smokers may use the nicotine in tobacco products as an attempt to self-medicate symptoms of affective disorders. The role of nicotinic acetylcholine receptors (nAChRs) in circuits regulating mood and anxiety is beginning to be elucidated in animal models, but the mechanisms underlying the effects of nicotine on aggression-related behavioral states (ARBS) are still not understood. Clinical trials of nicotine or nicotinic medications for neurological and psychiatric disorders have often found effects of nicotinic medications on ARBS, but few trials have studied these outcomes systematically. Similarly, the increase in ARBS resulting from smoking cessation can be resolved by nicotinic agents, but the effects of nicotinic medications on these types of mental states and behaviors in non-smokers are less well understood. Here we review the literature on the role of nAChRs in regulating mood and anxiety, and subsequently on the closely related construct of ARBS. We suggest avenues for future study to identify how nAChRs and nicotinic agents may play a role in these clinically important areas.
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This type of aggression may elicit submissive posture or, if the threat persists, attacks directed toward the nearest offending body parts, which are usually the head and snout [8]. The target biting test has been used to measure this type of aggressive behavior in rodents [9,10]. Different brain regions and signaling molecules are linked to aggression including the hypothalamus, medial amygdala (MEA), lateral septum (LAS), periaqueductal gray (PAG) and the bed nucleus of the stria terminalis (BNST) [1,2,4].
The Eph family of receptor tyrosine kinases play key roles in both the patterning of the developing nervous system and neural plasticity in the mature brain. To determine functions of ephrin-A5, a GPI-linked ligand to the Eph receptors, in animal behavior regulations, we examined effects of its inactivation on male mouse aggression. When tested in the resident-intruder paradigm for offensive aggression, ephrin-A5-mutant animals (ephrin-A5^−/−) exhibited severe reduction in conspecific aggression compared to wild-type controls. On the contrary, defensive aggression in the form of target biting was higher in ephrin-A5^−/− mice, indicating that the mutant mice are capable of attacking behavior. In addition, given the critical role of olfaction in aggressive behavior, we examined the ability of the ephrin-A5^−/− mice to smell and found no differences between the mutant and control animals. Testosterone levels in the mutant mice were also found to be within the normal range. Taken together, our data reveal a new role of ephrin-A5 in the regulation of aggressive behavior in mice.
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Although the epidemiological literature reported associations between maternal smoking and aggression in children, the animal literature has not explored this relationship in detail. In adult animals, acute nicotine administration was found to decrease aggressive behavior in a variety of paradigms (Driscoll and Baettig, 1981; Silverman, 1971), including the resident–intruder task (Johnson et al., 2003), which is supported by a study in humans (Cherek, 1984). The data reported here appear to be the first in the published literature reporting that prenatal exposure of an animal to CS results in increased aggression in the offspring, as evidenced by an increased number of attacks by CS-exposed offspring.
Smoking during pregnancy is associated with a variety of untoward effects on the offspring. However, recent epidemiological studies have brought into question whether the association between neurobehavioral deficits and maternal smoking is causal. We utilized an animal model of maternal smoking to determine the effects of prenatal cigarette smoke (CS) exposure on neurobehavioral development. Pregnant mice were exposed to either filtered air or mainstream CS from gestation day (GD) 4 to parturition for 4 h/d and 5 d/wk, with each exposure producing maternal plasma concentration of cotinine equivalent to smoking < 1 pack of cigarettes per day (25 ng/ml plasma cotinine level). Pups were weaned at postnatal day (PND) 21 and behavior was assessed at 4 weeks of age and again at 4–6 months of age. Male, but not female, offspring of CS-exposed dams demonstrated a significant increase in locomotor activity during adolescence and adulthood that was ameliorated by methylphenidate treatment. Additionally, male offspring exhibited increased aggression, as evidenced by decreased latency to attack and number of attacks in a resident–intruder task. These behavioral abnormalities were accompanied by a significant decrease in striatal and cortical dopamine and serotonin and a significant reduction in brain-derived neurotrophic factor (BDNF) mRNA and protein. Taken in concert, these data demonstrate that prenatal exposure to CS produces behavioral alterations in mice that are similar to those observed in epidemiological studies linking maternal smoking to neurodevelopmental disorders. Further, these data also suggest a role for monaminergic and BDNF alterations in these effects.

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Effects of nicotine on target biting and resident-intruder attack

Abstract

Introduction

Section snippets

Subjects

Apparatus

Target biting

Discussion

Conclusion

Acknowledgments

Pharmacology Biochemistry and Behavior

Pharmacology Biochemistry and Behavior

Animal Behavior

Pharmacology Biochemistry and Behavior

Inadequacy of pain-aggression hypothesis revealed in naturalistic settings

Aggressive Behavior

The effects of repeated administration of fluprazine on target biting and intruder-evoked attacks

Psychopharmacology

Effects of cigarette smoking on human aggressive behavior