PD 168077 maleate

The novel dopamine D4 receptor agonist (PD 168,077 maleate): doses with different effects on locomotor activity are without effect in classical conditioning.[Pubmed:12691779]

Prog Neuropsychopharmacol Biol Psychiatry. 2003 May;27(3):441-9.

Conditioning is normally selective to the most likely predictors of motivationally significant events and some dopamine (DA) agonists produce dysfunction in this process. Moreover, the DA D(4) receptor is implicated in normal and abnormal functions that have some dopaminergic basis (e.g., in attention deficit hyperactivity disorder and schizophrenia). We therefore used locomotor activity to identify doses of a novel D(4) receptor agonist (PD 168,077) with contrasting behavioral effects (over the range 0.064-1 mg/kg). Doses that either did (0.064 mg/kg) or did not (0.5 mg/kg) significantly increase activity were then tested using aversive and appetitive procedures, in which conditioning was reflected in decreased and increased response rates, respectively. Associating a signal with food or foot shock is normally reduced in trace conditioning, when stimulus events are separated in time. Similarly, animals normally learn relatively little about background stimuli that do not well predict food delivery or the onset of shock. Both doses of PD 168,077 were without effect on conditioning, whether appetitive or aversive, and irrespective of how informative the predictive stimulus was. Thus, we find no evidence that the D(4) receptor has any likely effect on associative learning or its disorder. Furthermore, D(4)-mediated hyperactivity was dissociable from cognitive effects.

Activation of dopamine D4 receptors induces synaptic translocation of Ca2+/calmodulin-dependent protein kinase II in cultured prefrontal cortical neurons.[Pubmed:16365279]

Mol Pharmacol. 2006 Mar;69(3):813-22.

One of the important targets of dopamine D4 receptors in prefrontal cortex (PFC) is the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII). In the present study, we investigated the effect of D4 receptor activation on subcellular localization of CaMKII. We found that activation of D4 receptors, but not D2 receptors, induced a rapid translocation of alpha-CaMKII from cytosol to postsynaptic sites in cultured PFC neurons. Activated CaMKII (Thr286 phospho-CaMKII) was also redistributed to postsynaptic sites after D4 receptor stimulation. The translocation was blocked by inhibiting the phospholipase C/inositol 1,4,5-trisphosphate receptor/Ca2+ signaling. Point mutation of the calmodulin binding site (Ala302), but not the autophosphorylation site (Thr286), of alpha-CaMKII prevented the D4-induced CaMKII translocation. Moreover, D4 receptors failed to induce CaMKII translocation in the presence of an actin stabilizer, and D4 activation reduced the binding of CaMKII to F-actin. Concomitant with the synaptic accumulation of alpha-CaMKII in response to D4 receptor activation, a D4-induced increase in the CaMKII phosphorylation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor glutamate receptor 1 (GluR1) subunits and the amplitude of AMPA receptor-mediated excitatory postsynaptic currents was also observed. Thus, our results show that D4 receptor activation induces the synaptic translocation of CaMKII through a mechanism involving Ca2+/calmodulin and F-actin, which facilitates the regulation of synaptic targets of CaMKII, such as AMPA receptors.

Topographically based search for an "Ethogram" among a series of novel D(4) dopamine receptor agonists and antagonists.[Pubmed:10731629]

Neuropsychopharmacology. 2000 May;22(5):538-44.

The effects of three selective D(4) antagonists [CP-293,019, L-745, 870, and Ro 61-6270] and two putative selective D(4) agonists [CP-226,269 and PD 168077] were compared with those of the generic D(2)-like [D(2L/S),D(3), D(4)] antagonist haloperidol to identify any characteristic "ethogram," in terms of individual topographies of behavior within the natural rodent repertoire, as evaluated using ethologically based approaches. Among the D(4) antagonists, neither L-745,870 (0.0016-1.0 mg/kg) nor Ro 61-6270 (0.2-25.0 mg/kg) influenced any behavior; whereas, CP-293,019 (0.2-25.0 mg/kg) induced episodes of nonstereotyped sniffing, sifting, and vacuous chewing; there were no consistent effects on responsivity to the D(2)-like agonist RU 24213. Among the putative D(4) agonists, CP-226, 269 (0.2-25.0 mg/kg) failed to influence any behavior; whereas, PD 168077 (0.2-25.0 mg/kg) induced nonstereotyped shuffling locomotion with uncoordinated movements, jerking, and yawning, which were insensitive to antagonism by CP-293,019, L-745,870, or haloperidol. These findings fail to indicate any "ethogram" for selective manipulation of D(4) receptor function at the level of the interaction between motoric and psychological processes in sculpting behavioral topography over habituation of exploration through to quiescence and focus attention on social, cognitive, or other levels of examination.