Biological Psychiatry - Vol. 2

By Hugo D'Haenen; J.A. Den Boer et al. | Go to book overview

Peptidergic Transmitter System and Anxiety Disorders

Michel Bourin, Martine Hascoët, Denis David and Bríd Áine Nic Dhonnchadha


Since their introduction in the beginning of the 1960s benzodiazepines (BZD) have been mainly used in treating anxiety disorders. With the exception of general anxiety disorder (GAD) the identity of the specific anxiety disorder for which each drug is most effective has been hindered by early clinical trials and psychiatric classification. Few proficient drugs have been launched since, the exception being buspirone a 5-HT1A partial agonist. The recent utilization of 5-HT reuptake inhibitors is mainly in the field of panic disorder, social phobia, post-traumatic stress disorder and possibly GAD. Nevertheless, the treatment of anxiety disorders remains a very active field of research and there are some promising results in animal research with neuroactive peptides in the modulation of anxiety behaviours. This section reviews the literature on the potential effects of cholecystokinin (CCK), corticotrophin-releasing factor (CRF), neuropeptide Y (NPY), substance P (SP) and neurokinin (NK) and natriuretic peptides (NP) in anxiety disorders in various animal and human models.


Cholecystokinin (CCK) is synthesized de novo in the brain (Goltermann, Rehfeld and Roigaard-Petersen, 1980). CCK has been shown to induce excitation of central neurons. However, inhibitory postsynaptic effects have been also recorded (Dodd and Kelly, 1981; Mac Vicar, Kerrin and Davison, 1987). CCK receptors have now been classified as CCK1 and CCK2 independent of their localization replacing CCK-A and CCK-B. CCK receptors are widely distributed throughout the CNS, with high densities in the striatum and nucleus accumbens (Hill et al., 1987).

Animal Models

Evidence suggests that CCK is implicated in the regulation of anxiety. The peripheral administration of CCK agonists induces anxiety in various animal species, including mouse, rat, cat and monkey (Bourin et al., 1996; Shlik, Vasar and Bradwejn, 1997). This effect is apparently mediated via CCK–2 receptors (previously named CCK-B) since the selective CCK–2 receptor agonists (CCK4 and pentagastrin) are effective. Moreover, the anxiogenic action of CCK agonists is reversed by preferential CCK–2 receptor antagonists (L–365, 260, Cl–988). It should be noted that CCK is active in ethological, but not in conditioned, models of anxiety. However, several studies were unable to reveal the anxiogenic action of CCK agonists in ethological models either. The anxiolytic action of CCK–2 receptor antagonists is even more doubtful since recent studies did not establish any significant action when CCK–2 receptor antagonists were given as single treatments (Dawson et al., 1995).

Some evidence exists that CCK-induced anxiety may be dependent on the level of pre-experimental stress in animals (Koks et al., in press). Therefore, an attempt was made to reveal the significance of pre-experimental stress on CCK-induced anxiety in the elevated plus-maze. Male Wistar rats were divided into four different groups. Two groups of rats were handled in the experimental room for three consecutive days before the experiment. The other two groups of animals were brought to the experimental room immediately before the beginning of the experiment. The handled and non-handled rats were divided into two groups after the injection of caerulein (5 µgkg–1), a CCK receptor agonist. Half of the animals were isolated after the injection, whereas the other half were returned to their home cage. The anxiogenic action of caerulein was strongest in the rats brought to the experimental room immediately before the plus-maze exposure and kept isolated after the injection of CCK agonist. By contrast, caerulein did not cause any anxiety in the handling habituated and non-isolated rats. Accordingly, the anxiogenic action of caerulein was dependent on the level of pre-experimental stress in rats. The anxiogenic action of caerulein in the stressed rats was dose-dependently reversed by L–365, 260 (l–100mgkg–1), a CCK-B receptor antagonist.

In another study the behavioural and neurochemical effects of long-term treatment with L–365, 260, a CCK-B receptor antagonist, were investigated. L–365, 260 (lOOmgkg–1) was administered twice daily for 14 days. The repeated treatment with L–365, 260 did not change locomotor activity, but it did reduce the exploratory behaviour of rats in the elevated plus-maze test (Koks et al., in press). The neurochemical studies performed demonstrated that L–365, 260 induced a sufficient blockade of CCK-B receptors in the brain. Namely, the density of CCK receptors was increased in the frontal cortex and the serum levels of thyrotrophin were reduced due to the repeated administration of L–365, 260. Collectively, it is unlikely that CCK is directly involved in the neural networks mediating anxiety. The anxiogenic effect of CCK is rather mediated via other neurotransmitter systems like CRF, GABA, 5-hydroxytryptamine, noradrenaline and nitric oxide.

Human Studies

The starting point for human studies was in 1984 with the electrophysiological experiment of Bradwejn and de Montigny (1984), which demonstrated that benzodiazepine receptor agonists selectively and specifically antagonized sulphated CCK–8-induced excitation of hippocampal pyramidal neurons in rats. These studies provided evidence that anxiolytic benzodiazepines could antagonize the central action of a neuropeptide and it was proposed that benzodiazepine-mediated antagonism of CCK-induced excitation might be an important mechanism by which benzodiazepines exert


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