Anxiety

The initial suggestion that the CCK system might be involved in anxiety came from experiments of Bradwejn and de Montigny (1984) showing that benzodiazepine receptor agonists could attenuate CCK induced excitation of rat hippocampal neurones. Subsequent clinical studies demonstrated that bolus injections of the CCK2 receptor agonist CCK4 or pentagastrin provoke panic attacks in patients with panic disorders (Bradwejn et al. 1991, 1992). Recent investigations have revealed that the panicogenic effects of CCK2 receptor agonists are not limited to patients with panic disorder, because individuals with social phobia, generalized anxiety disorder, obsessive compulsive disorder, and premenstrual dysphoric disorder also exhibit an augmented behavioural response to these ligands (Le Melledo et al. 1995; De Leeuw et al. 1996; van Vliet et al. 1997). Interestingly, a significant association exists between panic disorder and polymorphism of the CCK2 receptor gene (Kennedy et al. 1999). The neurobiological mechanisms by which CCK2 receptor agonists

Table 14.5 Cholecystokinin receptors

Cholecystokinin receptors

CCK1

cck2

Alternative names

ccka, cck-a

CCKB, CCK-B, CCK-B/gastrin

Structural information (Accession no.)

h 428 aa (P32238) r 444 aa (P30551) m 436 aa (008786)

h 447 aa (P32239) AS r 452 aa (P30553) AS m 453 aa (P56481)

Chromosomal location

4p16.2-15.1

11p15.4

Selective agonists

A71378, A71623, A70874, GW5823, GW7854

BC254, BC197, BC264, CCK-8ns, CCK-4, Gastrin, RB400

Selective antagonists

Devazepide (L364718), FK480, Lorglumide (CR1409), PD140548, IQM95333, SR27897

L365260, YM022, PD134308, LY262691, CI1015, RB211, RP73870

Radioligands

[3H]-devazepide, [3H] or [125I]-CCK8

[3H]-L365,260, [3H]-PD140,376, [125I]-PD142,308, [3H] or [125I]-gastrin, [3H] or [125I-CCK8

G protein coupling

Gq/Gs

Gq/Gi/Go

Expression profile

found in discrete brain regions, nucleus tractus solitarius, area postrema, interpeduncular nucleus, high in the periphery, gall bladder, pancreas, pyloric sphincter and vagal afferent fibres

highly expressed in brain, cerebral cortex, caudate nucleus, limbic system, also expressed in the gastrointestinal tract and pancreatic acinar and parietal cells

Physiological function

mediates action of CCK on cell proliferation, pancreatic enzyme secretion, gallbladder contraction, dopamine related behaviours and release; satiety, nociception

mediates action of CCK on increased neuronal firing rates, nociception, anxiety, attention, memory, respiration, dopamine related behaviours and dopamine release

Knock-out phenotype

learning and memory functions are impaired in OLETF rats which lack the CCK1 receptor (a model of obese, non insulin dependent diabetes)

impaired performance in memory tests, up-regulation of the opioid system, sensitisation of the dopamine system

Disease association

acute pancreatitis, schizophrenia, cognitive decline

panic attacks, depression, cognitive decline

provoke panic and concomitant biological changes (robust increase in heart rate, blood pressure, hypothalamic-pituitary-adrenal axis activity, elevated blood levels of dopamine, epinephrine, norepinephrine, and neuropeptide Y) have been the subject of considerable research activity. Animal studies suggest that anxious behaviour induced by various CCK fragments is associated with selective CCK2 receptor stimulation (Harro and Oreland 1993). However, the anxiogenic effects of CCK peptides in animals have not been observed by all investigators, and the relevant negative findings should not be ignored (Shlik et al. 1997). The effect of CCK compounds could vary considerably because of existing differences in the distribution and binding characteristics of CCK receptor types and/or affinity states among species. Recently, the effects of the selective CCK2 receptor agonist BC264 and BC197 and of the nonselective CCK receptor agonist BDNL were investigated in rats subjected to the elevated plus maze (Fig. 14.1). Surprisingly, BDNL and BC197 did induce anxiogenic like effects although BC264 was devoid of any effect (Derrien etal. 1994c; Fig. 14.2).

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