Synaptic Effects

Because DA is very much localised to one brain area (striatum) and as there is such a pronounced DA pathway from the substantia nigra to the striatum it would be reasonable to assume that the effect of this pathway on striatal neuron activity is well established. Unfortunately this is not the case.

Over the years a large number of studies using extracellular recording in the striatum have shown that iontophoretic DA depresses 75-100% of all neurons responding to it, irrespective of whether spontaneous, excitatory amino acid-induced, or synaptic-evoked activity was being monitored. This inhibitory response is slow in onset (up to 15 s) and long in duration (possibly minutes). Stimulation of the substantia nigra can produce inhibition, excitation or mixed effects but it is possible, despite the high proportion of

DA neurons in this nucleus, that not all the effects are elicited by the release of DA. Most neuroleptics block the inhibitory effects of applied DA but some, e.g. haloperidol, are less active against SN-evoked inhibition. Generally these studies lacked specific agonists and antagonists used microintophoresis which is not really quantitative and with extracellular recording gave little information on the state of polarisation of the neuron.

Unfortunately the picture was not clarified by intracellular recordings from striatal neurons which, as these need to be large to take an electrode, are not necessarily typical (only 10%) of most striatal neurons innervated by DA afferents. Stimulation of the substantia nigra invariably produces a monosynaptic depolarisation in them that is blocked by haloperidol, but which may proceed to a hyperpolarisation, if the stimulus is strong enough. DA iontophoresced onto the same neuron may also cause depolarisation (Kitai, Sugimori and Kocsis 1976) but can still reduce its discharge. Mixed effects are often seen with DA and when it is infused in increasing concentrations into the striatum through a push-pull cannula it generally depresses extracellularly recorded cell firing but low concentrations can produce excitation or bimodal excitation-inhibition (Schoener and Elkins 1984). Voltammetry studies with an electrode that can also be used for recording neuronal firing have shown that increasing nigrostriatal stimulation induces not only an increase in DA release but also an inhibition of neurons (after some initial but variable excitation of large neurons), which outlasts the rise in extracellular DA. Thus the effects of endogenous DA appear to be critically dependent on its extracellular concentration and it may be that while synaptic effects can be excitatory, extrasynaptic ones are inhibitory. Some of this effect may also be indirect through reducing the release of excitatory NTs such as glutamate from cortico-striatal fibres or ACh from intrinsic neurons.

In view of the known cellular actions of DA, such as increased K+ efflux and reduced Ca2+ currents associated with D2 receptor activation in cell lines, inhibition would be the expected response to DA, especially as cyclic AMP, which is increased by Di receptor activation also inhibits striatal neurons. In fact although many DA synaptic effects are blocked by D2 antagonists like haloperidol, the role of D1 receptors should not be overlooked.

Iontophoretic studies on rat striatal neurons (Hu and Wang 1988) showed that while the release of DA by low currents facilitated glutamate-induced activation, high current efflux inhibited it. Although these effects were reduced by the D2 antagonist haloperidol it was the D1 agonist SKF 38393 which mimicked them, causing activation when released by low currents but inhibition at higher ones. Both effects were abolished by the D1 antagonist SCH 23390. By contrast, the D2 agonist quinpirol produced a less marked biphasic effect in which inhibition dominated.

A number of studies in fact show clear D1 effects. Intracellular recording from striatal neurons in rat brain slices show a cAMP-mediated D1-dependent (blocked by SCH 23390) suppression of a voltage-dependent sodium current which make the cell less responsive.

Repetition of some of these approaches using more modern techniques, e.g. whole cell and patch-clamp recording from dissociated striatal neurons, shows a similar mixed picture. An observed D1-sensitive suppression of the sodium current and a shift of the inactivating voltage in a hyperpolarising direction, together with a depression of certain Ca2+ currents, would make the neuron less excitable. The D2 effect in these measures is less clear with reports of both a depolarising and hyperpolarising shift of the

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Figure 7.5 Rate recording of the dose-dependent inhibitory effects of apomorphine (^g/kg) on the spontaneous activity of a neuron in the medial prefrontal cortex of the halothane anaesthetised rat and its antagonism by haloperidol (HAL, 0.5mg/kg). Time scale is 50min intervals. Reproduced by permission from Dalley (1992)

Figure 7.5 Rate recording of the dose-dependent inhibitory effects of apomorphine (^g/kg) on the spontaneous activity of a neuron in the medial prefrontal cortex of the halothane anaesthetised rat and its antagonism by haloperidol (HAL, 0.5mg/kg). Time scale is 50min intervals. Reproduced by permission from Dalley (1992)

inactivation curves and an increased opening of a potassium conductance (see Calabresi et al. 1987).

What is clear from all these experiments is that DA can have a bimodal effect depending on how much is applied or released, and which receptors are involved. Excitation is more common at low concentrations and inhibition at higher ones. What happens in vivo is not clear but in vivo voltammetry certainly suggests that the extracellular concentration of DA can be very high and this would favour the more commonly observed inhibition.

In other brain areas which receive a DA input, such as the nucleus accumbens and prefrontal cortex, it appears to be inhibitory and predominently D2-mediated. This is clear from Fig. 7.5 which shows inhibition by apomorphine (mixed D2, D1 agonists) of the firing of neurons in the medial prefrontal cortex of the anaesthetised rat and its antagonism by the D2 antagonist haloperidol.

These are, of course, extracellular recordings but more recent intracellular studies in both rat and guinea pig accumbens slices show that DA produces a D2-mediated depolarisation and a D1 hyperpolarisation which appear to be dependent on decreased and increased K+ conductances respectively. This would certainly fit in with the belief that DA mediates the positive effects of schizophrenia by a D2-mediated stimulation of the nucleus accumbens (see Chapter 17).

It is perhaps not surprising that DA produces such mixed effects. The D1 receptor is primarily linked to the activation of adenylate cyclase and then protein kinase A. The response to its activation will therefore depend on the ion channels and other proteins modulated by the kinase which can vary from one neuron to another. Since the D2 receptor is not so closely associated with just one G-protein, this gives it the potential for even more effects (see Greenhoff and Johnson 1997).

Drugs And Brain Function

AMPHETAMINE (indirect)


Continue reading here: Pharmacology Of The Dopamine Synapse

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