Olanzapine, a novel atypical antipsychotic, reverses d-amphetamine-induced inhibition of midbrain dopamine cells.

This study compared the ability of the novel atypical antipsychotic olanzapine with that of clozapine to reverse the d-amphetamine-induced inhibition of substantia nigra (A9) and ventral tegmental area (A10) dopamine (DA) cells. Extracellular single-unit recordings were made from A9 and A10 DA cells in anesthetized rats. When administered alone, neither olanzapine nor clozapine altered the firing rate of A9 or A10 DA cells. Administration of d-amphetamine (0.5, 1.0 and 2.0 mg/kg, IV, decreased the firing rate of A9 and A10 DA cells. Olanzapine completely reversed the inhibitory effects of d-amphetamine on A10 DA cells (ED100 = 0.18 mg/kg, IV) and on A9 DA cells (ED100 = 1.0 mg/mg, IV). Clozapine completely reversed the inhibitory effects of d-amphetamine on A10 DA cells (ED100 = 3.8 mg/kg, IV), but only partially reversed the effects of d-amphetamine on A9 DA cells at the highest dose tested (8.0 mg/kg, IV). Thus, olanzapine, like clozapine, was more potent in reversing the effects of d-amphetamine on A10 than A9 DA cells. In addition, olanzapine was more potent than clozapine in the reversal of d-amphetamine effects on A9 and A10 DA cells. These results indicate that olanzapine and clozapine have similar effects on DA unit activity and predict that olanzapine should have an atypical antipsychotic profile in man.

Electrophysiological effects of olanzapine, a novel atypical antipsychotic, on A9 and A10 dopamine neurons.

This study examined the effects of the novel atypical antipsychotic olanzapine (LY170053) on the activity of substantia nigra pars compacta (A9) and ventral tegmental area (A10) dopamine cells in anesthetized rats. Acute administration of olanzapine (10, 20 mg/kg sc) increased the number of spontaneously active A10, but not A9, dopamine cells. Chronic administration of olanzapine (10, 20 mg/kg/day x 21 days) decreased the number of spontaneously active A10, but not A9, dopamine cells. Administration of the dopamine agonist apomorphine reversed the effects of chronic olanzapine on A10 cells, indicating a possible depolarization-inactivation mechanism. In conclusion, olanzapine has selective effects on A10 versus A9 dopamine cells following acute and chronic administration. These effects of olanzapine on dopamine cells are similar to the effects observed with clozapine and may play an important role in the atypical antipsychotic profile of olanzapine.

Inhibition of A9 and A10 dopamine cells by the cholecystokinin-B antagonist LY262691: mediation through feedback pathways from forebrain sites.

The diphenylpyrazolidinone cholecystokinin-B (CCK-B) antagonist LY262691 has been shown to decrease the number of spontaneously active dopamine (DA) cells in the ventral tegmental area (A10) and substantia nigra (A9) of the anesthetized rat. In the present study, we examined the localization of the receptors mediating these effects of LY262691 on A9 and A10 DA cells. In one group of anesthetized rats, the effects of systemic administration of LY262691 on the number of spontaneously active A9 or A10 DA cells was determined using extracellular, single-unit recordings after radio frequency lesions were placed in the nucleus accumbens, caudate-putamen, or medial prefrontal cortex. Lesions of the caudate-putamen blocked the effects of systemically administered LY262691 on the number of spontaneously active A9, but not A10, DA cells. Conversely, lesions of the n. accumbens blocked the effects of systemically administered LY262691 on A10, but not A9, DA cells. Lesions of the medial prefrontal cortex blocked the effects of systemically administered LY262691 on both A9 and A10 DA cells. In a separate group of anesthetized rats, the number of spontaneously active A9 or A10 DA cells was determined after LY262691 was microinjected into the n. accumbens, caudate-putamen, or medial prefrontal cortex. Microinjection of LY262691 into the caudate-putamen led to a significant decrease in the number of spontaneously active A9, but not A10, DA cells. Conversely, microinjection of LY262691 into the n. accumbens or medial prefrontal cortex led to a significant decrease in the number of spontaneously active A10, but not A9, DA cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiological effects of diphenylpyrazolidinone cholecystokinin-B and cholecystokinin-A antagonists on midbrain dopamine neurons.

The diphenylpyrazolidinone cholecystokinin (CCK)-B antagonist LY262691 has recently been demonstrated to decrease the number of spontaneously active dopamine (DA) cells in the ventral tegmental area (A10) and substantia nigra (A9) of the anesthetized rat. In the present study, three structural analogs of LY262691 with high selectivity for CCK-B receptors, LY262684, LY191009 and LY242040, also decreased the number of spontaneously active A10 DA cells. Neither an inactive analog (LY206890) nor a CCK-A-selective analog (LY219057) affected the number of spontaneously active A10 DA cells. L-365,260, a benzodiazepine CCK-B antagonist, also decreased the number of spontaneously active A10 DA cells. In addition, the more active optical isomer of LY262691 (LY288513) caused twice as large a decrease in the number of spontaneously active A10 DA cells as the less active optical isomer (LY288512). The diphenylpyrazolidinone CCK-B antagonists, but neither the inactive nor the CCK-A selective analog, also decreased the number of spontaneously active A9 DA cells; however, none of these compounds produced catalepsy in awake animals. Single-unit recordings indicated that LY262691 administration inhibited the activity of individual A9 and A10 DA neurons. These results indicate that the firing of A9 and A10 DA neurons is suppressed specifically by antagonism of CCK-B, but not CCK-A receptors. CCK-B antagonists may therefore represent a novel class of antipsychotic drugs. Furthermore, because CCK-B antagonists have no cataleptogenic effects, they may also have a reduced propensity for producing extrapyramidal side effects. In addition, these actions on midbrain DA neurons may contribute to the known anxiolytic activity of CCK-B antagonists.

Cholecystokinin (CCK) and schizophrenia: the selective CCKB antagonist LY262691 decreases midbrain dopamine unit activity.

Chronic administration of antipsychotic drugs has previously been shown to decrease the number of spontaneously active midbrain dopamine cells. In an effort to evaluate CCK antagonists as potential antipsychotic drugs, we have examined the effects of a selective CCK-B antagonist, LY262691, on the number of spontaneously active midbrain dopamine neurons using extracellular, single-unit recordings in anesthetized rats. Acute and chronic administration of LY262691 decreased the number of spontaneously active A9 and A10 dopamine cells. Administration of apomorphine did not reverse the effect of LY262691 on A9 and A10 dopamine neurons. These results suggest that LY262691 may have an antipsychotic effect without delayed onset, and that its effects on dopamine cells may not be mediated through depolarization inactivation.

The 5-HT3 receptor antagonist zatosetron decreases the number of spontaneously active A10 dopamine neurons.

Acute and chronic administration of low doses (e.g. 0.1, 0.3 mg/kg i.p.) of the selective 5-HT3 antagonist zatosetron decreased the number of spontaneously active A 10 dopamine cells but did not change the number of spontaneously active A9 dopamine cells; higher doses (1.0, 10 mg/kg) were less effective. The decrease in the number of spontaneously active A 10 dopamine cells following zatosetron administration was not reversed by the administration of apomorphine. These data indicate that zatosetron's effects on spontaneously active dopamine neurons: (1) differs from other 5-HT3 antagonists; (2) may not be mediated by depolarization inactivation; and, (3) may be predictive of an atypical antipsychotic action without delayed onset.

NMDA receptor antagonists suppress behaviors but not norepinephrine turnover or locus coeruleus unit activity induced by opiate withdrawal.

Pretreatment with the non-competitive NMDA (N-methyl-D-aspartate) antagonist MK801 (0.5, 1.0 mg/kg, s.c.) suppressed the behavioral signs of withdrawal in morphine-dependent rats. However, the same doses of MK801 that suppressed morphine withdrawal also simultaneously produced phencyclidine (PCP)-like behaviors. Pretreatment with the competitive NMDA antagonist LY274614 (25, 50, 100 mg/kg i.p.) also suppressed the behavioral signs of withdrawal in morphine-dependent rats but did not produce PCP-like behavioral effects. Single unit recordings were made from noradrenergic neurons in the locus coeruleus (LC) and, at doses that suppressed morphine withdrawal behaviors, neither MK801 nor LY274614 blocked the withdrawal-induced activation of LC neurons. Biochemical analysis indicated that, at the same behaviorally relevant doses, neither MK801 nor LY274614 blocked the withdrawal-induced increase in norepinephrine turnover in the hippocampus, cerebral cortex, or hypothalamus. These results indicate that NMDA antagonists attenuate the behavioral signs of morphine withdrawal without blocking the withdrawal-induced increase in norepinephrine turnover or the withdrawal-induced increase in LC unit activity. In addition, non-competitive NMDA antagonists, like MK801, may not be useful to alleviate opiate withdrawal symptoms in man because of their PCP-like side effects. However, competitive NMDA antagonists, like LY274614, could be of great benefit for alleviating opiate withdrawal symptoms in man.

Calcium activation of mougeotia potassium channels.

Phytochrome mediates chloroplast movement in the alga Mougeotia, possibly via changes in cytosolic calcium. It is known to regulate a calcium-activated potassium channel in the algal plasma membrane. As part of a characterization of the potassium channel, we examined the properties of calcium activation. The calcium ionophore A23187 activates the channel at external [Ca(2+)] as low as 20 micromolar. However, external [Ca(2+)] is not required for activation of the channel by photoactivated phytochrome. Furthermore, when an inhibitor of calcium release from internal stores, 8-(diethylamino)-octyl-3,4,5-trimethoxybenzoate, hydrochloride (TMB-8), is present, red light no longer stimulates channel activity. We conclude that phytochrome activates the plasma membrane potassium channel by releasing calcium from intracellular calcium vesicles; the elevated cytosolic calcium then stimulates channel activity by an unknown mechanism. In the presence of TMB-8, red light does induce chloroplast rotation; thus, potassium channel activation may not be coupled to chloroplast rotation.

Red light regulates calcium-activated potassium channels in mougeotia plasma membrane.

The alga Mougeotia has a large central chloroplast whose positioning is regulated by photoactivation of phytochrome, possibly via modulation of cytosolic calcium (Serlin B, Roux SJ [1984] Proc Natl Acad Sci USA 81: 6368-6372). We used the patch clamp technique to examine the effects of red and far-red light on ion channel activity in the plasma membrane of Mougeotia protoplasts to determine if ion channels play a role in chloroplast movement. Patch clamping in the cell-attached mode reveals two channels of about 2 and 4 picoamperes amplitude at 0 millivolt (inside pipette) and estimated conductances of 30 and 65 picosiemens. They are activated by red light irradiation after a lag period of about 2 to 5 minutes. Far-red light, when applied immediately after red light irradiation, reverses this activation; otherwise it has no effect. This result implicates phytochrome. The addition of the calcium ionophore, A23187, also activates ion channel activity after a lag of a few minutes. The channels are not specific for calcium since they are present when calcium is removed from the external and pipette media. They are inhibited by quaternary ammonium ions. Thus, we believe they are calcium-activated potassium channels. Their possible role in chloroplast positioning is discussed.