Hyperpolarisability

For the linear response of the dipole to an electric field, this calculation is fairly straightforward. However, the dipole can also be calculated for a range of magnitudes of applied field to obtain higher order hyperpolarisabilities such as j . 

Quadratic hyperpolarisability DCJTB 4-(Dicyanomethylene)-2-tert-butyl-6 (l,l,7,7-tetrametbyljulolidyl-9-enyl)-4H-pyran Disperse red 1 HOMO-LUMO gap Electroluminescence Indium-tin-oxide Nonlinear optic... 

An inhibitory input increases the influx of Cl to make the inside of the neuron more negative. This hyperpolarisation, the inhibitory postsynaptic potential (IPSP), takes the membrane potential further away from threshold and firing. It is the mirror-image of the EPSP and will reduce the chance of an EPSP reaching threshold voltage. 

SKca and M channels are not the only K+ channels regulated by transmitters. As noted above, transmitters can also close, or open, other K+ channels that do not directly regulate excitability but instead determine the resting potential of the neuron, and hence depolarise or hyperpolarise the neuron. 

ANOTHER PACEMAKER CHANNEL HYPERPOLARISATION-ACTIVATED CATION CHANNELS ( h-CHANNELS )... 

Figure 2.9 Hyperpolarisation-activated cation current 4 and its role in pacemaking in a guinea-pig thalamic relay neuron. (Adapted from Figs 2 and 14 in McCormick, DA and Pape, H-C (1990) J. Physiol. 431 291-318. Reproduced by permission of the Physiological Society.) (a) Records showing the time-dependent activation of the h-current by hyperpolarisation and its deactivation on repolarising, (b) Interpretation of rhythmic activity in a thalamic relay neuron. (1) The inter-spike hyperpolarisation activates 7h to produce a slowly rising pacemaker depolarisation. (2) This opens T-type Ca " channels to give a more rapid depolarisation, leading to (3) a burst of Na" spikes (see Fig. 2.8). At (4) the depolarisation has closed (deactivated) the h-channels and has inactivated the T-channels. The membrane now hyperpolarises, assisted by outward K+ current (5). This hyperpolarisation now removes T-channel in-activation and activates 7h (6), to produce another pacemaker potential...

Alternative mechanisms are equally likely. One possibility arises from evidence that activation of a2-adrenoceptors reduces Ca + influx this will have obvious effects on impulse-evoked exocytosis. In fact, the inhibition of release effected by a2-adrenoceptor agonists can be overcome by raising external Ca + concentration. Finally, an increase in K+ conductance has also been implicated this would hyperpolarise the nerve terminals and render them less likely to release transmitter on the arrival of a nerve impulse. Any, or all, of these processes could contribute to the feedback inhibition of transmitter release. Similar processes could explain the effects of activation of other types of auto-or heteroceptors. 

The M2 and M4 receptors also show struetural similarities. Through G-protein (Gi) they inhibit cyclic AMP production and open K+ ehannels while activation of another G-protein (Go) closes Ca + channels. The latter effeet will cause membrane hyperpolarisation as will the Gpinduced inerease in K+ efflux. The reduction in cAMP production, although possibly leading to depolarisation, is more likely to explain the presynaptie reduction in ACh release assoeiated with the M2 receptor. 

Ml and M3 receptors mediate the excitatory effects and since this postspike hyperpolarisation is blocked by phorbol esters and is therefore presumably dependent on IP3 production, one would expect it to be mediated through M] receptors (see above), especially as these are located postsynaptically. Unfortunately it does not appear to be affected by pirenzapine, the Mi antagonist. By contrast, muscarinic inhibition of the M current is reduced by the Mi antagonist but as it is not affected by phorbol esters is not likely to be linked to IP3 production, an Mi effect. 

ACh can sometimes inhibit neurons by increasing K+ conductance and although it has been found to hyperpolarise thalamic neurons, which would normally reduce firing, strong depolarisation may still make the cell fire even more rapidly than normal. This appears to be because the hyperpolarisation counters the inactivation of a low-threshold Ca + current which is then activated by the depolarisation to give a burst of action potentials (McCormick and Prince 1986b). 

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 Di 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). 

Although the distribution of these receptors is widespread in the brain, they are found postsynaptically in high concentrations in the hippocampus, septum and amygdala and also on cell bodies of 5-HT neurons in the Raphe nuclei. They are negatively coupled, via Gj/o/z proteins, to adenylyl cyclase such that their activation reduces production of cAMP. In turn, this leads to an increase in K+ conductance and hyperpolarisation of... 

Glycine is the simplest of all amino acids. It is involved in many metabolic pathways, is an essential component of proteins, and is found throughout the brain. A neurotransmitter role for glycine was first identified in the spinal cord, where it was found to be differentially distributed between dorsal and ventral regions and shown to cause hyperpolarisation of motoneurons (Werman et al. 1967). This inhibitory action of glycine is distinct from its... 

There is a good deal of evidence that the therapeutic effects of antidepressants could involve adaptive changes in 5-HTia receptors. Postsynaptic 5-HTia receptor responses became implicated because the hyperpolarisation of hippocampal CA3 pyramidal neurons that follows ionophoretic administration of 5-HT was found to be increased after chronic treatment with most (but not all) antidepressants (Chaput, de Montigny and Blier 1991). Others suggested that antidepressants attenuate postsynaptic 5-HTja responses because the hypothermia, evoked by their activation, is diminished by antidepressants (Martin et al. 1992). 

---