Neonatal exposure to oestradiol increases dopaminergic transmission in nucleus accumbens and morphine-induced conditioned place preference in adult female rats.

Steroid sex hormones produce physiological effects in reproductive tissues and also in nonreproductive tissues, such as the brain, particularly in cortical, limbic and midbrain areas. Dopamine (DA) neurones involved in processes such as prolactin secretion (tuberoinfundibular system), motor circuit regulation (nigrostriatal system) and driving of motivated behaviour (mesocorticolimbic system) are specially regulated by sex hormones. Indeed, sex hormones promote neurochemical and behavioural effects induced by drugs of abuse by tuning midbrain DA neurones in adult animals. However, the long-term effects induced by neonatal exposure to sex hormones on dopaminergic neurotransmission have not been fully studied. The present study aimed to determine whether a single neonatal exposure with oestradiol valerate (EV) results in a programming of dopaminergic neurotransmission in the nucleus accumbens (NAcc) of adult female rats. To answer this question, electrophysiological, neurochemical, cellular, molecular and behavioural techniques were used. The data show that frequency but not amplitude of the spontaneous excitatory postsynaptic current is significantly increased in NAcc medium spiny neurones of EV-treated rats. In addition, DA content and release are both increased in the NAcc of EV-treated rats, caused by an increased synthesis of this neurotransmitter. These results are functionally associated with a higher percentage of EV-treated rats conditioned to morphine, a drug of abuse, compared to controls. In conclusion, neonatal programming with oestradiol increases NAcc dopaminergic neurotransmission in adulthood, which may be associated with increased reinforcing effects of drugs of abuse.

Voltage-clamp analysis of the potentiation of the slow Ca2+-activated K+ current in hippocampal pyramidal neurons.

Exploring the principles that govern activity-dependent changes in excitability is an essential step to understand the function of the nervous system, because they act as a general postsynaptic control mechanism that modulates the flow of synaptic signals. We show an activity-dependent potentiation of the slow Ca2+-activated K+ current (sl(AHP)) which induces sustained decreases in the excitability in CA1 pyramidal neurons. We analyzed the sl(AHP) using the slice technique and voltage-clamp recordings with sharp or patch-electrodes. Using sharp electrodes-repeated activation with depolarizing pulses evoked a prolonged (8-min) potentiation of the amplitude (171%) and duration (208%) of the sl(AHP). Using patch electrodes, early after entering the whole-cell configuration (<20 min), responses were as those reported above. However, although the sl(AHP) remained unchanged, its potentiation was markedly reduced in later recordings, suggesting that the underlying mechanisms were rapidly eliminated by intracellular dialysis. Inhibition of L-type Ca2+ current by nifedipine (20 microM) markedly reduced the sl(AHP) (79%) and its potentiation (55%). Ryanodine (20 microM) that blocks the release of intracellular Ca2+ also reduced sl(AHP) (29%) and its potentiation (25%). The potentiation of the sl(AHP) induced a marked and prolonged (>50%; approximately equals 8 min) decrease in excitability. The results suggest that sl(AHP) is potentiated as a result of an increased intracellular Ca2+ concentration ([Ca2+]i) following activation of voltage-gated L-type Ca2+ channels, aided by the subsequent release of Ca2+ from intracellular stores. Another possibility is that repeated activation increases the Ca2+-binding capacity of the channels mediating the sl(AHP). This potentiation of the sl(AHP) could be relevant in hippocampal physiology, because the changes in excitability it causes may regulate the induction threshold of the long-term potentiation of synaptic efficacy. Moreover, the potentiation would act as a protective mechanism by reducing excitability and preventing the accumulation of intracellular Ca2+ to toxic levels when intense synaptic activation occurs.

The activity-dependent potentiation of the slow Ca2+-activated K+ current regulates synaptic efficacy in rat CA1 pyramidal neurons.

Activity-dependent modifications of neuronal excitability are of key functional importance because they accomplish general postsynaptic control of the flow of synaptic signals. We tested the modifications of synaptic efficacy evoked in rat CA1 hippocampal pyramidal neurons during the short-term activity-dependent reduction in excitability termed "response depression". The in vitro slice technique and recordings with sharp electrodes in the current- and voltage-clamp modes were used. Depression was induced by repeatedly stimulating the Schaffer collateral and stratum oriens. Repeated synaptic stimuli also depressed subsequent responses evoked by transmembrane current pulse injection and vice versa. Depression was characterised by a marked decrease in synaptic efficacy that outlasted stimuli for several minutes and was generalized to all pyramidal cells. The action potential frequency adaptation, the slow after-hyperpolarization and the underlying slow Ca2+-dependent K+ current (IAHP) were potentiated during depression. The potentiated IAHP caused depression by acting as a cumulative negative feedback that reduced synaptic efficacy by increasing the membrane conductance and hyperpolarizing the neurone. This depression may act as a homeostatic negative feedback mechanism to limit the rise in intracellular Ca2+ concentration and stabilize the membrane potential following intense synaptic activation.

Ionic components of the electrical response of chromaffin cells from the toad (Caudiverbera caudiverbera) adrenal gland.

1. Ultra fine tip microelectrodes (300 MOhm) were used to study the electrical properties of the chromaffin cell membrane in situ in the intact toad adrenal gland. 2. In the presence of physiologic [K+]o (2 mM) the resting membrane potential (Vm) was -53 +/- 3.2 mV. Vm depended on [K+]o as predicted by the constant field equation with PNa/PK of 0.16. 3. A small fraction (20%) of the impaled cells exhibited spontaneous electrical activity, though in all the cells examined, the injection of depolarizing current pulses elicited repetitive spikes. 4. Our measurements of the chromaffin cell input resistance (326 +/- 35 MOhm) is substantially smaller than the values reported for bovine isolated chromaffin cells, suggesting that the toad adrenal chromaffin cells might be electrically coupled. 5. Tetraethylammonium (TEA) increased the amplitude and duration of spikes, probably inhibiting outward K+ current. In the presence of tetrodotoxin (TTX) action potentials were abolished, although they reappeared if TEA was added, suggesting the participation of both Na+ and Ca2+ currents in the genesis of spikes. 6. As expected, acetylcholine (ACh) and nicotine depolarized the cells, though they did not always elicit electrical activity. 7. Muscarine (10-100 microM) had no effect on both Vm and on the depolarization induced by ACh or nicotine. Since muscarine inhibits catecholamine (CA) secretion induced by ACh and nicotine, we concluded that the inhibition of CA release by muscarine in the toad probably occurs at a level other than the membrane.