While learned behaviors allow animals to adapt flexibly to complex and changing environments, some species-specific behaviors are expressed reliably with no requirement for previous exposure or learning (
1). This type of fixed behavior in animals is often elicited by chemical signals in the secretions of conspecifics (pheromones) or chemical cues from predators or prey (kairomones), where a reliably evoked behavioral response is important for survival. In addition, some plant odorants can also elicit characteristic responses in animals. A well-known example of plant-induced behavior in mammals is observed in domestic cats (
Felis silvestris catus) and other felids such as lions (
Panthera leo) and bobcats (
Lynx rufus) (
2–
4). When felids sniff specific plants such as catnip (
Nepeta cataria) and silver vine (
Actinidia polygama), they exhibit a typical behavioral response that comprises licking and chewing the plants, face and head rubbing against the plants, and rolling over on the ground (
2,
4,
5). This catnip and silver vine response usually lasts 5 to 15 min, followed by a period of one or more hours when they are nonresponsive (
6). Because cats demonstrate an intoxicated response that does not have any pathophysiological effects (
7), dried leaves of these plants are used commercially in toys for domestic cats worldwide.
The first reports of the feline behavioral response to silver vine and catnip were described by a Japanese botanist in 1704 (
8) and by a British botanist in 1759 (
9), respectively. The behavioral response to silver vine has been captured in Japanese culture: An Ukiyo-e (a type of traditional painting) drawn in 1859 depicts a folk story concerning a battle between cats and mice, wherein mice use silver vine as a weapon to intoxicate cats (
10). While silver vine is endemic to Japan and China, its potent effects on cat behavior came to global recognition following its import from China to the United States (
11). Bioactive iridoid compounds in catnip (nepetalactone) and silver vine (isoiridomyrmecin, iridomyrmecin, isodihydronepetalactone, and dihydronepetalactone) induce the same characteristic response (
12–
15). Cats perceive these secondary plant metabolites through the main olfactory system (
6), while oral administration of nepetalactone induces no response (
16). The strength of behavioral response increases with cat maturity (
17), but there is no sexual dimorphism in response among adults. However, despite widespread recognition of this characteristic behavioral response to specific plants by feline carnivores, its functional outcome is not yet understood.
This study aimed to uncover the neurophysiological mechanism and biological function of the silver vine response in domestic cats. To establish a reliable and reproducible behavioral assay for precise control of stimulus presentation, we first purified potent bioactive compounds from silver vine leaves and identified nepetalactol, which had been missed in previous studies (
13–
15,
18). Using chemically synthesized nepetalactol, we demonstrated that the silver vine response is regulated via μ-opioid receptors that are involved in rewarding and euphoric effects in humans. The rubbing and rolling response transfers nepetalactol from the plant leaves onto the cat’s face and head where it acts as a mosquito repellent, finally revealing the likely biological significance of this enigmatic feline behavior, first observed more than 300 years ago.
DISCUSSION
This study has found that the iridoid nepetalactol is the major bioactive compound in the leaves of silver vine that induces characteristic rubbing and rolling in cats (
Fig. 6). Further, nepetalactol had similar bioactivity in Amur leopard, jaguar, and Eurasian lynx. As most of the Felidae species so far tested have shown positive responses toward catnip (13 of 21 species tested from a total of 41 living species in this family) (
2–
4), it is likely that this characteristic response to nepetalactol will also be common across many of the Felidae. Using synthesized nepetalactol, we have demonstrated that the μ-opioid system regulating euphoric and rewarding effects in humans (
26) is involved in the expression of the catnip and silver vine response in cats. We have uncovered an adaptive benefit of the behavioral response in cats: Rubbing and rolling on the leaves of silver vine transfers nepetalactol to the heads, faces, and bodies of cats. As a consequence, this reduces the number of
A. albopictus mosquitoes that land on the animal’s head, helping to protect from mosquito bites. These findings provide new insight into this well-known and characteristic plant-induced feline response, for which the biological function was first questioned in popular science culture more than 300 years ago.
We have yet to understand fully how the μ-opioid system is activated by nepetalactol in cats. In previous reports, essential oils from
N. caesarea, of which nepetalactone is a major component, had an analgesic effect involving μ-opioid receptors in rats, but these compounds were injected intraperitoneally (
31). Oral administration of nepetalactone to cats has no marked physiological effects (
16). Further, cats do not require naso-oral contact with nepetalactol-paper for this to stimulate the silver vine response. This suggests that nepetalactol and other bioactive iridoids activate the μ-opioid system via chemical sensing through the olfactory system for the response. The vomeronasal system does not appear to be involved in inducing the response in cats (
6). Previous studies have reported functional connections between the olfactory and opioidergic processes in mammals such as rats (
32–
35), suggesting that cats may have neural circuitry that connects the olfactory neurons that detect bioactive iridoids with the μ-opioid system. While our results indicate that taste is not essential for the silver vine response, cats exhibiting the response commonly lick the stimulus when this is possible. As previous studies have reported that tastes and other orosensory stimulation can activate β-endorphin release in mammals (
36,
37), the possibility cannot be excluded that the taste system also participates in regulating the silver vine response in cats.
The feline response to specific chemicals in plant materials is nonaddictive (
38). This may be because the μ-opioid system is stimulated by an increase in endogenous β-endorphin secretion when olfactory neurons are activated by these iridoids. This contrasts with the development of addiction to exogenous opiates such as morphine in mammals including cats (
39), when μ-opioid receptors are directly activated by opiates via the bloodstream (
40,
41).
Although we only tested for a repellent effect on
A. albopictus in this study, we might also expect nepetalactol to be repellent to other mosquito species including
A. aegypti, which is a common vector of yellow fever, dengue, and Zika viruses (
42), consistent with the broad repellence of nepetalactone across a range of mosquito and other biting arthropods (
27–
29). Our findings suggest that nepetalactol may be a new natural candidate repellent to help reduce mosquito problems in human society.
We propose that silver vine and catnip response provides repellency against A. albopictus by transferring nepetalactol or nepetalactone from plants onto a cat’s fur. Face rubbing against plant sources of the repellent will help to protect the face and head of the animal, as the mouth, eyelids, ears, and nose of felines have relatively little fur and are therefore easy targets for mosquitoes. Although the rolling response following face rubbing, which exposes the belly, may look like a defenseless behavior, it enables cats to pick up repellent iridoids on other areas of their bodies. Notably, cats did not roll on the ground when stimuli were placed such that rolling would not bring the cat into contact with the stimulus. Therefore, rolling is a functional behavior rather than an indicator of euphoria or extreme pleasure.
The silver vine and catnip response is an important example of how animals use plant metabolites for protection against insect pests. There are other examples that nonhuman animals may exploit some chemicals emitted from other species for protection against insect pests: boat-tailed grackles (
Quiscalus major) and white-nosed coatis (
Nasua narica) rub fruits of
Citrus spp. against themselves (
43), chimpanzees (
Pan troglodytes schweinfurthii) use sleeping platforms created from specific trees as a source of repellents (
44), house sparrows (
Passer domesticus) and house finches (
Carpodacus mexicanus) living in urban habitats bring cigarette butts to the nest (
45), and capuchin monkeys (
Cebus olivaceus) anoint themselves with millipedes (
Orthoporus dorsovittatus) (
46). Each species may select plants and other materials as insect repellents during evolution. The examples so far uncovered of animals self-anointing or using prophylactic self-medication (
47) with secondary plant metabolites to protect against pests and diseases typically occur in individual species, although the same pests and diseases may affect many species. However, self-anointing with plant iridoids is common in Felidae, although not in the Carnivora more generally, suggesting that the behavior first evolved in a common felid ancestor and has been retained. As many felids rely on stealth to stalk and ambush their prey, requiring them to remain cryptic and often unmoving, a repellent that reduces their susceptibility to both the irritation of biting mosquitoes and the diseases that these insect vectors carry is likely to provide a strong selective advantage. Stimulation of the μ-opioid system might further help by providing analgesia to reduce irritation where biting arthropods have not been repelled. While this can explain why this characteristic behavior has been retained in many Felidae species, it does not explain why the behavior has evolved only in felids. A specific ability to detect these iridoid chemicals in a common felid ancestor may have been a crucial preadaptation that provided the opportunity for this self-anointing behavior to evolve, allowing animals from multiple species within this family to acquire mosquito repellence.
The catnip response is inherited as an autosomal dominant trait in domestic cats (
5), strongly suggesting the presence of one or few genes responsible for the silver vine and catnip response in felids. The felids that were positive responders in this study focused close attention toward nepetalactol and other iridoid stimuli presented, responding even to the low level of nepetalactol recovered by wiping donors that had rubbed this into their fur during the silver vine response. By contrast, dogs, mice, and negative responder cats failed to even stop and sniff nepetalactol stimuli. These findings suggest that domestic cats and the nondomestic felids that also respond might have acquired specific olfactory receptor(s) that detect nepetalactol and other iridoids emitted from some plants with high sensitivity. A genome-wide association study among positive and negative responder cats to identify the olfactory receptor genes and specific neuronal pathways involved in this response could provide invaluable clues for understanding how and why this characteristic response to silver vine and catnip has evolved specifically in felids.
