Colin A. Hendrie

Exploration and predation models of anxiety: Evidence from laboratory and wild species

The current article addresses several issues within the context of issues within the context of modeling human anxiety disorders in the laboratory. First, evidence is presented to support the suggestion that behavior in exploration models of anxiety may be motivated by apprehension relating to intraspecific encounters rather than interspecific, predator/prey interactions, which has consequences for the interpretation of findings generated using these tests. Second, data are reviewed concerning the use of stimuli indicating the presence of a predator in the context of anxiety modeling, and it is suggested that tests involving the reactions of animals following exposure to such stimuli may be more closely related to pathologic anxiety mechanisms than tests employing observations during contact with these stimuli. Third, comparative studies, using wild-caught rodents, are outlined that show that, although there are similarities in the defensive strategies adopted by these animals in response to the call of an owl, there are also important differences. Finally, the suggestion is made that the distance-dependent-defense-hierarchy may be of important heuristic value in the interpretation of these data and that, perhaps more significantly, it may also provide a mechanism that allows animal defensive strategies and human anxiety disorders to be placed within the same conceptual framework.

The effects of CCKA and CCKB antagonists on activity in the black/white exploration model of anxiety in mice

In view of evidence suggesting that cholecystokinin (CCK) may have a role in the mediation of human panic disorders, it was predicted that CCK receptor antagonists may have anxiolytic-like activity in an animal model of anxiety, the black/white exploration test. Data revealed that, in mice, the CCKA receptor antagonist, devazepide (formerly L-364,718, MK-329), produced a clear anxiolytic-like profile with an inverted U-shaped dose-response curve centered around 5 micrograms/kg. Similarly, L-365,031, a specific, but less potent, CCKA antagonist, also produced a profile consistent with weak anxiolysis but only at 5 micrograms/kg. By direct contrast, the potent and specific CCKB antagonist L-365,260 had no robust anxiolytic-like effects in this test. Therefore, these data suggest that devazepide has the greatest effects in this model, that L-365,031 is only marginally active, and that L-365,260 is without influence. These results suggest that CCKA receptor mechanisms are involved in the mediation of anxiolytic-like effects in the black/white model of exploration in mice.

The calls of murine predators activate endogenous analgesia mechanisms in laboratory mice

In view of the suggested role of endogenous analgesia mechanisms as an antipredator defense mechanism, the effects on nociception of exposure to the calls of various murine predatory and nonpredatory species were assessed. Data revealed that the calls of the Tawny Owl, Barn Owl and Common Gull all induced significant analgesia following exposure to 2 min of birdsong. Time course analysis revealed the analgesia induced by the Tawny Owl call to have a duration in excess of 40 min while the Barn Owl and Gull call-induced analgesias were much shorter lasting (approximately 10 min or less). Five mg/kg naloxone was found to attenuate the analgesia induced by the Tawny and Barn Owls but not the Common Gull. Together, these data suggest that brief exposure to the calls of night-hunting, aerial predators activate endogenous opioid-mediated analgesia mechanisms in mice.

Effects of Diazepam and Buspirone on the Behaviour of Wild Voles (Microtus socialis) in Two Models of Anxiety

Exploration models of anxiety rely almost universally on the use of laboratory species. Furthermore, the spontaneous patterns of locomotion displayed are often interpreted as being an expression of antipredator defense. However, there is no direct link between the experience of these animals and the proposed motivation for their behaviour. To address this problem, the behaviour of wild trapped voles (Microtus socialis), a small-rodent species that is heavily predated upon, was examined in the elevated plus-maze and the black/white exploration model. It was hypothesised that the patterns of locomotion in these exploration models of anxiety should be similar to those reported for laboratory animals if the reactions of the laboratory animals are related to antipredator defense. Data revealed that voles show a similar preference for the protected areas in these models (closed arms or dark section) and that this preference can be modified by buspirone and diazepam. Interestingly, although the effective doses of each drug was the same within each model, it differed between models, with the minimum effective doses of these compounds being lower in the black/white exploration model (1 mg/kg) than in the elevated plus-maze (4 mg/kg). These data provide valuable information concerning the actions of anxiolytic compounds in wild trapped animals as assessed by formal laboratory models and provide useful verification that findings in these models may be generalised to species other than laboratory rodents.

The failure of the antidepressant drug discovery process is systemic

Current antidepressants are crude compared with the ideal and patents on most have expired. There are therefore strong clinical and commercial pressures for new drugs to replace them. The prospects for this are, however, now markedly reduced as several major pharmaceutical companies have abandoned work in this area whilst many others have sharply decreased their research investment. These changes and the lack of progress over such a long period are indicative of a catastrophic systems failure which, it is argued, has been caused in large part by a logical flaw at the animal modelling stage. This tautology has served to lock the current antidepressant drug discovery process into an iterative loop capable only of producing further variations of that which has gone before. Drugs produced by this approach have proved to be only poorly effective in the context of the clinically depressed population as a whole. Hence, the inevitable failure of the current antidepressant drug discovery process has left little behind that can be salvaged. Therefore, it is suggested that this be urgently reformulated on more rational grounds using more appropriate species in new animal models based upon a thorough understanding of the behavioural expressions of depression in the clinic.

Pair-Bond Disruption in Mongolian Gerbils: Effects on Subsequent Social Behaviour

Gerbils are social rodents which form stable male-female pairs. These pair bonds appear to be based on prolonged association rather than an exclusive mating relationship. However, both sexes contribute to territorial defense and pup rearing. Therefore, pair-bond disruption may be expected to have consequences for subsequent behaviour. This hypothesis was examined in a series of laboratory studies. Behavioural consequences of pair-bond disruption were seen in both sexes and the optimum housing parameters were found to be to pair males and females for 5 weeks and to examine their behaviour 1 week after pair-bond disruption. Two further studies using these parameters were conducted to examine the combined influence of pair-bond disruption and the sex of the animal being interacted with. Results across all studies revealed a consistent pattern. Females showed increased immobility in contact, that is, freezing upon another animals approach, and altered cage-orientated behaviour, regardless of the sex of the animal they were interacting with. In contrast, males showed decreased social investigation and offense and initiated fewer social interactions. However, these effects were only seen in interactions with other males. No changes in social behaviour were evident in interactions between pair-bond-disrupted males and females. The behavioural strategies of pair-bond-disrupted males and females in a social situation therefore differ. From these studies, it may be concluded that pair-bond disruption has consistent and reproducible effects on subsequent social behaviour in gerbils and that there are important sex differences in the behavioural expression of this.

Evidence to suggest that nightclubs function as human sexual display grounds

Summary Young, sexually mature humans Homo sapiens sapiens of both sexes commonly congregate into particular but arbitrary physical locations and dance. These may be areas of traditional use, such as nightclubs, discotheques or dance-halls or areas that are temporarily commissioned for the same purpose such as at house parties or rock festivals etc. This type of behaviour is seen in a variety of animals although there are no apparent attempts to monopolize particular areas within these locations as is often seen in species that lek. The present studies were conducted in order to investigate this phenomenon in a commercial nightclub environment. Data revealed that more than 80% of people entering the nightclub did so without a partner and so were potentially sexually available. There was also an approx. 50% increase in the number of couples leaving the nightclub as compared to those entering it seen on each occasion this was measured, indicating that these congregations are for sexual purposes. Within the nightclub itself more than 80% of bouts of mixed sex dancing were initiated by a male approaching a female, demonstrating that males are stimulated to approach females rather than vice versa. In consequence, females are placed in competition with each other to attract these approaches. Various female display tactics were measured and these showed that whilst only 20% of females wore tight fitting clothing that revealed more than 40% of their flesh/50% of their breast area and danced in a sexually suggestive manner, these attracted close to half (49%) of all male approaches seen. These data reveal the effectiveness of clothing and dance displays in attracting male attention and strongly indicate that nightclubs are human display grounds, organised around females competing for the attention of males. Females with the most successful displays gain the advantage of being able to choose from amongst a range of males showing interest in them.

Disruption of Pairs Produces Pair-Bond Disruption in Male But Not Female Mongolian Gerbils

Previous studies have shown that separating gerbils from established male/female pairs has consequences for subsequent social behaviour. In males, this is characterized by decreased initiation of social contact, social investigation, and either decreased aggressive behaviour or increased defense. In females, there is an increase in immobile-in-contact, which serves to terminate social encounters initiated by another animal. Although these data show the effects of disrupting established pairs, they do not, per se, demonstrate the existence of male/female pair-bonds. Three studies were performed to address this issue in more detail. In the first study, separating females from single-sex groups was found to produce similar effects to those seen following separation from male/female pairs. Generally, opposite effects were seen in males. In the second study, the effects of separating females from male/female pairs were not seen when the original cagemate was replaced with a different animal. These effects persisted in males. The third study revealed that the presence of a female until immediately prior to testing was crucial in producing high levels of social investigation and aggression in males and that the observation of decreases in these behaviours following separation from male/female pairs was dependent on this. Together, these data show that, in males, individual housing is not a critical variable, that effects seen following the breaking of male/female pairs are not attenuated by the presence of a new female, and that these effects are not seen following separation from male/male pairs. It is concluded, therefore, that the behavioural consequences of removing males from established male/female pairs are due to separation from a specific female and that this is highly indicative of the existence of a bonding mechanism in male but not female, gerbils.

The funding crisis in psychopharmacology: an historical perspective.

Clare Stanford’s recent editorial (Stanford, 2008) concerning the current lack of funding for pre-clinical psychopharmacology is the story of a crisis that has its roots in the demise of the ‘dual-support’ system and is the result of the individual and collective failure of government, research funders and Industry to heed warnings they were given more than a decade ago about the disastrous consequences of this inaction. Prior to the mid 90s, universities were required to spend a significant percentage of their government block grant on research activities, which most of them did. This arrangement made small-scale blue-sky research relatively easy to do, but when ideas required more resources to be developed, research council grants were applied for or support from Industry sought (hence, ‘dual-support’). By the mid 90s, however the dual support system was on the point of collapse, the result of a pen stroke in someone’s accounts department somewhere that determined that henceforth the block grant would be used only to pay for an academics’ time to do research but not the actual research itself. In consequence, there were concerns about the growing number of university-based preclinical laboratories that were reporting significant problems in obtaining the funding to remain research active. I was elected to the BAP Council in 1997 on the basis of a mandate that committed me to trying to convince the Association to investigate the causes of these funding difficulties and then to take a lead in bringing about some sort of remedial action. Over the next couple of years, three main studies were conducted under the auspices of the British Association for Psychopharmacology (BAP) to determine the distribution of research funding for preclinical psychopharmacology within the UK. The first involved a questionnaire to the entire BAP membership asking questions about funding held, staff employed, students being trained etc. Respondents were also asked for their views on the current state of British psychopharmacology and their expectations for the future. The second involved getting the MRC and Wellcome to interrogate their funding databases to confirm or otherwise the funding profile indicated by the first study. The final study was directed at the major industrial recruiters to determine whether they were experiencing skill shortages. Data showed that in the period 1997-2001 the MRC had, by its own report, made a major investment in preclinical psychopharmacology to the tune of £5 million. This was however very narrowly distributed, divided into only nine grants and concentrated into just a couple of laboratories. During this same period, the Wellcome Trust had made just one grant to preclinical psychopharmacology (of less than £350K). In the absence of the dual-support system, these grants represented the only significant funds available to the discipline at the time, apart from industrial contracts, which by their very nature are not usually intended to fund basic research. Indeed, Industry itself was experiencing severe skill shortages throughout the in-vivo area and in psychopharmacology in particular. One senior figure in Industry commented on their returned questionnaire that ‘I do not anticipate that recruitment will get any easier in the near future as funding for training posts in universities continues to be derisory’. In the late 90s, the Government lauded the Pharmaceutical Industry as one of the great jewels in the United Kingdom’s Industrial crown. However, by the mid 2000s, major players such as Eli Lilly & Co and Merck, Sharp & Dohme had closed or significantly downsized their UK research presence, and even at the time of writing, GSK are in the advanced stages of relocating many key areas of their operation to China. This has been a dramatic turn round in fortunes by anybody’s standards, and it cannot be coincidence that the rapid contraction of the industrial psychopharmacology base has closely followed the precipitous decline in the strength of the academic discipline. A strong university sector helped keep these pharmaceutical giants embedded within the United Kingdom. The reality of the situation now is that 75% of employers in this skill-based industry cannot find appropriately trained people to fill their existing vacancies (Stanford, 2008), and Letter to the Editors

Kissing as an evolutionary adaptation to protect against Human Cytomegalovirus-like teratogenesis

Mouth to mouth sexual kissing is seen in more than 90% of human cultures. Various theories have been put forward to account for this but none offer a full explanation within an evolutionary framework. As mouth to mouth sexual kissing exposes each participant to the diseases of the other, it must confer significant benefit. Human Cytomegalovirus (HCMV) is a ubiquitous infection that carries a severe teratogenic risk if primary infection is acquired during certain critical periods. As HCMV is present in salivary gland epithelial cells and sheds from periodontitis induced lesions, female inoculation with a specific males HCMV is most efficiently achieved through mouth to mouth contact and saliva exchange, particularly where the flow of saliva is from the male to the typically shorter female. The current hypothesis proposes that mouth to mouth sexual kissing enables females to control when they become infected with a particular males HCMV and so protect their offspring from the threat of teratogenesis from primary infection during vulnerable times in their development. Females only gain this benefit if they also avoid becoming infected by other males. Hence HCMV induced teratogenesis is a strong viral pressure towards the development of monogamy as well as kissing as a behavioural strategy to protect against it.