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The κ-opioid receptor plays a central role in mediating the response to stressful life events. Inhibiting κ-opioid receptor signaling is proposed as a mechanism for treating stress-related conditions such as depression and anxiety. Preclinical testing consistently confirms that disruption of κ-opioid signaling is efficacious in animal models of mood disorders. However, concerns about the feasibility of developing antagonists into drugs stem from an unusual pharmacodynamic property of prototypic κ-opioid receptor-selective antagonists; they inhibit receptor signaling for weeks to months after a single dose. Several fundamental questions include - is it possible to identify short-acting antagonists; is long-lasting inhibition necessary for efficacy; and is it safe to develop long-acting antagonists in the clinic. Here, we test representative compounds (AZ-ECPC, AZ-MTAB, and LY-DMPF) from three new chemical series of κ-opioid receptor ligands for long-lasting inhibition. Each compound dose-dependently reversed κ-opioid agonist-induced diuresis. However, unlike the prototypic antagonist, nBNI, which fully inhibited evoked diuresis for at least four weeks, the new compounds showed no inhibition after one week. The two compounds with greater potency and selectivity were tested in prenatally-stressed rats on the elevated plus maze, an exploration-based model of anxiety. Spontaneous exploration of open arms in the elevated plus maze was suppressed by prenatal stress and restored with both compounds. These findings indicate that persistent inhibition is not an inherent property of κ-opioid-selective antagonists and that post-stress dosing with transient inhibitors can be effective in a mood disorder model. This further supports κ-opioid receptor as a promising target for developing novel psychiatric medications.

The effects of acute intracerebroventricular administration of the tridecapeptide, neurotensin, and a pseudopeptide analog of neurotensin-(8-13) were compared to the effects of haloperidol and clozapine on the spontaneous activity of dopamine cells in both the ventral tegmental area (A10) and the substantia nigra compacta (A9). Unlike the typical antipsychotic haloperidol, which causes a non-selective increase in both A9 and A10 cell activity, both neurotensin and a neurotensin analog, H-Lys (CH2NH)Lys-Pro-Tyr-lle-Leu-OH, in like manner to clozapine, at low doses selectively increase the number of spontaneously active A10 dopamine cells. These data provide the first in vivo evidence that acute administration of neurotensin can produce changes in spontaneous activity of midbrain dopamine cells similar to the atypical antipsychotic, clozapine.

Extracellular single unit recording techniques were employed to compare the effects of seroquel with the reference antipsychotic (AP) agents clozapine and haloperidol in electrophysiological tests that may predict AP activity. Seroquel and clozapine were differentially more active in reversing the inhibitory actions of d-amphetamine on mesolimbic (A10) than nigrostriatal (A9) dopamine (DA)-containing neurons, whereas haloperidol exhibited the opposite selectivity. In cell population studies, acute treatment with seroquel and clozapine selectively increased the number of spontaneously active A10 DA cells, which was found to correlate with the ability of both these drugs to cause depolarization inactivation (DI) of A10 DA cells following repeated (28 day) administration. This profile of activity was unlike that of haloperidol, which acutely caused a nonselective increase in the number of active A9 and A10 DA cells, associated with the ability of this agent to cause DI of both A9 and A10 DA cells after repeated treatment. Since DI of A10 DA cells may be correlated with AP efficacy whereas DI of A9 DA cells may predict the ability of an AP to cause extrapyramidal side effects (EPS) and tardive dyskinesia (TD), seroquel, like clozapine, may be an atypical AP with a reduced likelihood for producing EPS/TD.

The effects of NBQX and DNQX on synaptic transmission in rat hippocampal slice were investigated. Both agents produced dose-dependent blockade of field potentials evoked by low frequency stimulation of Schaffer collateral-commissural fibers recorded in medium containing 4 mM Mg2+ (non-NMDA mediated transmission), with half-maximal effects at about 0.15 microM for NBQX and 1.0 microM for DNQX. When the studies were conducted in Mg(2+)-free medium (predominantly NMDA mediated transmission), 100 microM NBQX failed to block transmission; however, the response could be completely blocked by the addition of 10 microM of the competitive NMDA antagonist CPP. In contrast, 47 microM DNQX completely blocked secondary field potentials recorded in Mg(2+)-free medium and this effect could be reversed by the addition of 200 microM of the glycine agonist D-serine. Thus, NBQX exhibited selective blockade of non-NMDA mediated synaptic transmission whereas DNQX had effects at both non-NMDA and NMDA receptor sites, the latter effect via an interaction with the glycine site on the NMDA receptor complex.

The effects of SCH 23390 on d-amphetamine-induced suppression of A9 and A10 DA neuronal firing were determined. SCH 23390 potently reversed d-amphetamine on both A9 and A10 DA neurons. Compared to haloperidol, SCH 23390 was 5 times more potent on A9 DA neurons and 20 times more potent on A10 DA neurons. However, the magnitude of the reversal effect was greater with haloperidol than SCH 23390. In addition, haloperidol produced a further increase in firing of both A9 and A10 DA neurons after SCH 23390 maximally increased firing. It was concluded that SCH 23390 has D-2 DA antagonist-like properties, possibly mediated via an interaction at D-1 DA receptors, which may be functionally linked with D-2 DA receptors. The marked potency of SCH 23390 in reversing d-amphetamine could be due to its combined antagonist effects at 5HT2 and D-1 DA receptor sites.

The effects of acute and chronic treatment with the selective dopamine (DA) D-1 antagonist SCH 23390 on the population response of midbrain DA cells were determined. One hour pretreatment with SCH 23390 (0.0125, 0.025, 0.05 mg/kg s.c.) caused a dose-related increase in the number of spontaneously firing DA neurons in both the A9 and A10 cell regions. Chronic (28 day) administration of SCH 23390 (0.05 mg/kg s.c.) caused depolarization inactivation of only A10 DA cells. These data suggest that SCH 23390 may have antipsychotic properties with a reduced likelihood of producing extrapyramidal side effects.