Neurochemical actions of CCK underlying the therapeutic potential of CCK-B antagonists

CCK-B antagonists such as CI 988 (PD 134308) have potent and selective pharmacological effects including anxiolysis (1) and facilitation of morphine analgesia (2). These effects may be important pointers to the functional role of some central CCK neuronal systems. CCK itself coexists with a number of other putative neurotransmitters including dopamine (3) and gamma-aminobutyric acid (GABA) (4). In the mesolimbic dopaminergic projection it is thought that CCK acting through CCK-A receptors may reinforce dopaminergic activity (5,6) but the role of CCK-B receptors is uncertain in this system. Although activation of CCK receptors may facilitate GABA release (7) the role of CCK co-stored in GABA neurones is unknown. Co-storage or co-transmission may be important in interpreting the actions of CCK-receptor antagonists however, In this review we shall try to summarise our current knowledge in respect of the neurochemical events initiated by CCK-B receptor activation and relate this to the apparent involvement of CCK in anxiogenic mechanisms. We also wish to draw attention to the potential relationship between anxiety and substance abuse since this may have relevance to the possible use of CCK-B antagonists to treat drug abuse. CCK containing neurones and both CCK-A and CCK-B receptors are known to be located in those brain areas associated with alerting and rewarding mechanisms. Such brain areas include the basal ganglia, amygdala and hypothalamic nuclei amongst others. We are a long way from understanding or even recognising all the neurochemical sequelae of CCK induced activity but in general it appears that CCK is excitatory in its actions at both CCK-A and CCK-B receptor sites. This is supported by both electrophysiological (8,9) and neurochemical evidence as discussed in the following sections.