Anxiogenic effect of cholecystokinin in the dorsal periaqueductal gray.

Systemic administration of cholecystokinin (CCK) fragments produces anxiogenic effects. The dorsal periaqueductal gray (dPAG) has been related to anxiety and panic reactions. The objective of this study was to investigate a possible anxiogenic effect of CCK-8 microinjected into the dPAG. At 10 min after the last microinjection (0.5 microl) into the dPAG male Wistar rats (N=7-17) were tested in the elevated plus-maze, an animal model of anxiety. The following treatments were tested alone or in combination: sulfated CCK-8 (CCK-8s, 0.5-1 microg), PD 135158 (N-methyl-D-glucamine, 0.1 microg), a CCK-2 receptor antagonist, lorglumide (0.1-0.3 microg), a CCK-1 receptor antagonist. In addition, Fos immunohistochemistry was performed in rats (n=3-4) treated with CCK-8s (1 microg) alone or in combination with PD 135158 (0.1 microg). CCK-8s produced anxiogenic-like effect, decreasing the percentage of time spent in open arm (saline=30.3+/-6.6, CCK 0.5 microg=15.2+/-1.8; CCK 1 microg=14.6+/-2.1). This effect was prevented by pretreatment with PD 135158, but not by lorglumide. CCK-8s injected into the dPAG induced Fos immunoreactivity in several brain areas related to defensive behavior, including the PAG, median, and dorsal raphe nuclei, superior colliculus, lateral septal nuclei, medial hypothalamus, and medial amygdala. This effect was also prevented by pretreatment with PD 135,158. These results suggest that CCK-8s, acting on CCK-2 receptors, may modulate anxiety reactions in the dPAG.

Puerperal blockade of cholecystokinin (CCK1) receptors disrupts maternal behavior in lactating rats.

Blockade of cholecystokinin (CCK) receptors potentiates the morphine-induced disruption of maternal behavior. The present study was undertaken to determine whether treatment with lorglumide, a CCK1 antagonist during late pregnancy and early lactation can influence the maternal behavior during lactation. A possible influence of this treatment on general activity was also assessed. Twenty-seven female Wistar rats were pretreated with lorglumide (1.0mg/kg/day; sc) or saline for seven days, starting on the 17th d of pregnancy. After the withdrawal of this treatment, animals were acutely challenged with saline on day 5 and with morphine sulfate (3.0mg/kg; sc) on days 6,10, and 17 of lactation. Groups were pretreated with saline and challenged with saline (group SS) and morphine (group SM), pretreated with lorglumide and challenged with saline (group LS) and morphine (group LM). Animals were also tested for general activity on days 25 and 33 postpartum after an acute challenge with saline and morphine, respectively. Maternal behavior testing began 30 min after the acute injections at which time pups were placed throughout each mother's cage. Latencies for pup retrieval, grouping, crouching and for full maternal behavior responses were scored. Lorglumide pretreatment inhibited maternal behavior of LS vs SS group and potentiated the morphine-induced disruption of this behavior in all days of test (LM vs SM group). No significant differences were found in general activity on days 25 and 33 postpartum. These data suggest that blockade of CCK1 receptors during puerperal period has long-term implications for maternal behavior.

Differential role of cholecystokinin receptor subtypes in opioid modulation of ongoing maternal behavior.

Cholecystokinin (CCK) can have effects opposite those of opioids. The present study was undertaken to determine whether peripheral injections of antagonists of the CCK1 receptor (lorglumide) and the CCK2 receptor (L-365,260) can influence the effects of morphine on maternal behavior during lactation. A total of 110 female Wistar rats were tested on days 5 and 6 postpartum. Groups were randomly assigned to morphine vehicle (MV-SC) + saline (S-IP), MV + lorglumide (LOR: 1.0 or 10.0 mg/kg), MV + L-365,260 (10 mg/kg), morphine chlorhydrate (MC: 7.0 mg/kg) + S, MC + LOR (1.0 or 10.0 mg/kg), and MC + L-365,260 (1.0 or 10 mg/kg). Maternal behavior testing was started 30 min after the injections, at which time pups were placed in the home cage of their mother. Latencies for retrieval, grouping, and crouching responses were scored. The results show that both lorglumide and L-365,260 potentiated the MC-induced inhibition of maternal behavior. In addition L-365,260 treatment alone inhibited maternal behavior. Blockade of both the CCK1 and CCK2 receptors potentiated the morphine-induced disruption of maternal behavior, while CCK2 antagonism alone also inhibited this behavior. The results suggest that CCK antagonism of opioid-induced disruption of maternal behavior occurs due to the action of CCK on both CCK1 and CCK2 receptor subtypes.