PD 135158

PD-135158, a CCKB receptor antagonist, microinjected into the nucleus accumbens and the expression of conditioned rewarded behavior.[Pubmed:8761988]

Neurosci Lett. 1996 May 10;209(2):85-8.

Cholecystokinin (CCK) has been localized in the nucleus accumbens (NAC) where it may interact with dopamine neurotransmission. NAC dopamine is involved in the control over behavior produced by conditioned rewards. The present experiment examines whether the blockade of CCKB receptors in the NAC with microinjection of PD-135158 (10 micrograms in 0.5 microliter) potentiates bar-pressing for stimuli previously associated with food reward. Intra-NAC microinjections of amphetamine (10 micrograms in 0.5 microliter) increased the number of bar presses for conditioned reward presentation. Furthermore, similar administration of PD-135158 produced no significant effect on responding when administered alone but potentiated the level of amphetamine responding. These findings suggest that endogenous CCKB mechanisms in the NAC may normally inhibit dopamine function in reward-related behaviors.

PD 135158, a CCKB/gastrin receptor antagonist, stimulates rat pancreatic enzyme secretion as a CCKA receptor agonist.[Pubmed:7901038]

Eur J Pharmacol. 1993 Sep 21;242(1):105-8.

The CCKB/gastrin receptor antagonist, PD 135158 (CAM 1028), surprisingly stimulates lipase release from isolated rat pancreatic acini dose dependently in a biphasic manner, with identical efficacy but lower potency compared to cholecystokinin octapeptide (CCK-8). Half-maximal stimulation occurred at 0.6 microM and maximal secretion was induced at 50 microM. Supramaximal concentrations decreased lipase release. Acinar lipase secretion in response to 25 pM CCK-8 or 1 microM CAM-1028 was abolished by 5 microM of the specific CCKA receptor antagonist loxiglumide (CR 1505), half-maximal inhibition was observed at 0.6 microM for CCK-8 and 0.4 microM for PD 135158. These data demonstrate that the CCKB/gastrin receptor antagonist, PD 135158, acts as a full agonist at the rat pancreatic CCKA receptor.

PD-135,158, a cholecystokinin(B) antagonist, enhances latent inhibition in the rat.[Pubmed:10683486]

Pharmacol Biochem Behav. 2000 Mar;65(3):459-63.

The antipsychotic potential of cholecystokinin (CCK)-related compounds stems from CCK's colocalization with dopamine (DA). CCK demonstrates excitatory and inhibitory effects on DA in the mesolimbic pathway. Such diverse actions might be mediated by different receptor subtypes (CCK(A) or CCK(B)). Multiple hypotheses have emerged regarding the clinical application of CCK-based drugs. Administering selective nonpeptide antagonists within animal models relevant to schizophrenia would help delineate CCK receptor involvement. One animal model simulating a cognitive dysfunction of schizophrenia is latent inhibition (LI). An animal repeatedly exposed to a stimulus that is devoid of consequence is subsequently inhibited in making new associations with that stimulus. This reflects a process of learning to ignore irrelevant stimuli. The present study examined the effects of the selective CCK(B) antagonist PD-135,158 (0.001, 0. 01, and 0.1 mg/kg) using a conditioned suppression of drinking procedure in rats. For purposes of comparison the effects of haloperidol (0.1 mg/kg) were also investigated. PD-135,158 (0.1 mg/kg), similar to haloperidol (0.1 mg/kg), elicited a clear LI effect under conditions that did not lead to LI in control rats (low number of preexposures). These findings highlight the antipsychotic potential of CCK(B) antagonists, and further illustrate the LI paradigm's capacity to detect novel, antipsychotic-like, drug activity.

Suppression of conditioned fear by administration of CCKB receptor antagonist PD135158.[Pubmed:10657528]

Neuropeptides. 1999 Dec;33(6):483-6.

In order to examine the involvement of CCK in the formation of anxiety, we have investigated whether CCKB receptor antagonist PD135158 suppressed conditioned fear stress. Rats were individually subjected to 30 min of inescapable electric footshock in a chamber with a grid floor. First, the rats were individually subjected to 30 min of footshock. Twenty-four h after the footshock, the rats were again placed in the chamber and observed for 5 min without shocks. PD135158 was administered 30 min before placing the rats in the chamber again. Secondly, PD135158 was administered 30 min before footshock. Thirdly, PD135158 was administered 5 min after footshock. Administration of PD135158 30 min before conditioned fear stress significantly reduced freezing behavior. Administration of PD135158 30 min before footshock also significantly reduced freezing behavior. But, administration of PD135158 5 min after footshock did not significantly reduce freezing behavior. PD135158 blocked not only the acquisition but also the expression of conditioned fear. These results suggest that the CCKB receptor might play an important role in conditioned fear stress and that it might be related to anxiety.

CholecystokininB receptor antagonist increases food intake in rats.[Pubmed:9811359]

Physiol Behav. 1998 Aug;65(1):11-4.

To investigate the role of cholecystokininB (CCKB) receptors in the brain in the control of food intake, we administered PD-135158, a specific and potent CCKB antagonist, into the lateral ventricle of male, Sprague-Dawley rats 30 min before a 60-min intake test. PD-135158 (0.001-0.5 mg) increased intake significantly; the mean peak increase was 39% more than the intake after vehicle treatment. The increased intake was due to a larger first meal and more intake during the last 30 min of the test. Because intake during the first 3 min, a measure of palatability or orosensory stimulation did not change significantly, we suggest that antagonism of brain CCK at central CCKB receptors decreased the satiating potency of the ingested food during the meal and decreased the potency of the mechanisms that prevent the reinitiation of eating during the postprandial intermeal interval.