Roland S.G. Jones

The locus coeruleus: actions of psychoactive drugs

The locus coeruleus is one of the most thoroughly investigated mammalian brain areas. Its fibers innervate large parts of the neuraxis, in particular, areas involved in cognitive functions such as the cortex and the hippocampus. A role of locus coeruleus has been proposed in such processes as memory, the control of vigilance, blood pressure and others. Results obtained in this and other laboratories demonstrate that the firing rate of locus coeruleus neurons is affected by a great number of psychoactive agents such as antidepressants, minor tranquillizers, neuroleptics, psychostimulants and certain psychogeriatric drugs. We have attempted to correlate the data obtained on the cell bodies of locus coeruleus with studies reporting effects on terminal areas and thereby gain an overall view of the action of the above mentioned drugs on this cell system. The activity of noradrenergic neurons in locus coeruleus is thought to correlate with the level of cortical vigilance. Special emphasis is placed on the finding that a number of drugs which exert a positive effect on cognitive functions in man and animals increase the firing rate of the rat locus coeruleus neurons.

Electrophysiological and neurochemical investigations on the action of carbamazepine on the rat hippocampus.

Carbamazepine moderately depressed the input fiber volley resulting in attenuation of the dendritic epsp and the population spike in CA1 of rat hippocampal slices with a threshold concentration of 20 microM. The depressant effect on the population spike was not antagonized by the adenosine receptor blocker caffeine. Paired-pulse inhibition was not affected by carbamazepine (40 microM). Epileptic-like rhythmic discharge of CA1 neurons in medium containing low Ca2+/high Mg2+ was attenuated at even lower concentrations of carbamazepine (8 microM) indicating that there was also a postsynaptic site of action. Imipramine being significantly more potent than carbamazepine in the rabbit corneal test for local anaesthetic activity had no effect on the population spike (20 microM). In neurochemical studies, carbamazepine reduced the [22Na]- and [3H]L-glutamate efflux induced by potassium and veratridine from hippocampal slices with a threshold concentration of 10 microM. The drug (400 microM) failed to affect Na+-dependent binding of [3H]L-glutamate to hippocampal synaptic membranes. In conclusion, the present findings demonstrate pre- and postsynaptic depressant actions of carbamazepine in CAI of hippocampus.

The action of anticonvulsant drugs on the firing of locus coeruleus neurons: Selective, activating effect of carbamazepine

The action of various doses of intraperitoneally administered carbamazepine, ethosuximide, Na-valproate, phenobarbital and diphenylhydantoin on the neuronal firing rate of presumed noradrenergic neurons of the locus coeruleus was investigated in the anaesthetized rat. Carbamazepine was the only compound which produced a statistically significant, dose-dependent activation of these neurons. The other anticonvulsant drugs caused a small but non significant reduction in locus coeruleus cell firing. It is concluded that this brain nucleus is not a main target of anticonvulsant drugs.

Excitatory effects of ACTH on noradrenergic neurons of the locus coeruleus in the rat

Responses of presumed noradrenaline-containing neurons in locus coeruleus (LC) to iontophoretically applied ACTH were determined. The full sequence ACTH1-39 and the partial sequence ACTH1-24 were excitatory on the majority of neurons tested. The partial sequence ACTH27-39 was without effect on most neurons. The presence of ACTH-containing fibers in LC together with the present results may suggest a controlling influence of the peptide on the noradrenaline system.

Multiple changes in the sensitivity of cingulate cortical neurones to putative neurotransmitters in ageing rats: Substance P, acetylcholine and noradrenaline

The responsiveness of neurones in the anterior cingulate cortex to iontophoretically applied substance P(SP), acetylcholine (ACh), noradrenaline (NA) and GABA was compared in young (3-4 months) and old (24-30 months) rats. Neurones in the old rats were less sensitive to the depressant effects of NA but not GABA. These cells were also less sensitive to the excitatory actions of ACh but markedly more sensitive to those of SP. Such changes in responsiveness could be involved in the deficits in cerebral function which often occur in old age.

Reduced activity of locus coeruleus neurons in hypertensive rats

The effect of blood pressure on the neuronal activity of the locus coeruleus (LC) was investigated by means of electrophysiological techniques in rats anaesthetized with chloral hydrate. The mean neuronal discharge rate of noradrenergic neurons of the LC was reduced by 19% in spontaneously hypertensive rats (SHR) and by 25% in deoxycorticosterone acetate (DOCA)-salt hypertensive rats compared with their corresponding controls. The cellular activity of 27 out of 40 neurons was reversibly suppressed by acute, peripherally induced blood pressure increases in normotensive rats. Five neurons were reversibly activated and eight neurons were not affected. Conversely, acute decreases in blood pressure stimulated the neuronal activity of the LC in 10 out of 16 neurons. These findings support the hypothesis of the LC having a role in both short and long term regulation of blood pressure.

Monoaminergic modulation of the sensitivity of neurones in the cingulate cortex to iontophoretically applied substance P.

The interactions of noradrenaline (NA) and 5-hydroxytryptamine (5-HT) with substance P (SP) were studied on single neurones in the anterior cingulate cortex of the rat. Iontophoretic application of 5-HT potentiated the excitatory responses of some neurones to SP and reduced responses of others. However these effects were usually accompanied by parallel changes in baseline firing rate i.e. increase and decrease respectively. In studies where carbachol (CCh) was used as a control the excitatory responses to this substance were always altered in a similar fashion to those to SP. The effects of NA on SP-responses were more consistent. This amine caused a reduction of response to SP regardless of whether there was an increase, decrease, or no change in baseline firing rate. Responses to SP could be reduced on many cells in the absence of changes in response to CCh and even on some cells where CCh responses were concurrently enhanced. Lesions of the locus coeruleus which resulted in a depletion of NA in the ipsilateral cingulate cortex gave rise to a substantial increase in sensitivity of neurones to SP two weeks later. However, lesions of the median raphe(MR)-nucleus which strongly reduced cortical 5-HT had no detectable effect on SP-responses. The data indicate that both NA and 5-HT can alter cortical neurone-sensitivity to SP but that the former amine may be involved in a more specific and possibly a functional interaction.

Noradrenaline-octopamine interactions on cortical neurones in the rat.

The interactions of noradrenaline and octopamine were tested on spontaneously active neurones in the rat cerebral cortex. When applied with weak iontophoretic currents such that no change in baseline firing rate occurred, octopamine profoundly enhanced both depressant and excitatory responses to noradrenaline. Similar applications of octopamine did not alter depressant responses to dopamine or depressant or excitatory responses to iontophoretically applied 5-hydroxytryptamine. The results could support a role of octopamine as a co-transmitter or modulator of noradrenaline mediated neurotransmission.

Locus Coeruleus as a Target for Psychogeriatric Agents

Today the noradrenergic-containing nucleus locus coeruleus is probably one of the best documented neuronal systems in brain. The locus coeruleus is thought to be involved in various functions such as the control of attention,’ central blood pressure,’ anxiety: and processes related to memory and learning.‘ No unifying concept is available to explain the relative contribution and exact role of this small nucleus in these diverse functions. The role of the locus coeruleus in processes related to memory and learning has gained a lot of attention and has been intensively investigated in the past fifteen years but the issue remains controversial. Whereas earlier behavioral studies strongly supported a role of locus coeruleus in these processes,” more recent investigations militate against this hypothesis? However, although behavioral studies remain controversial, recent electrophysiological investigations give a more coherent picture pointing to a basic role of the locus coeruleus in information processing. Single-cell recording studies performed in freely moving mammals have demonstrated that neuronal activity in the locus coeruleus correlates with the level of vigilance.’&’’ Highest levels of neuronal activity are observed during wakefulness and lower firing rates occur when the animals are drowsy and in slow wave and paradoxical sleep. The neurons respond with transient, biphasic changes in discharge to auditory, visual, and somatosensory stim~li.’~~’’ These findings suggest that the locus coeruleus affects target cell systems concerned with processing of external stimuli. In keeping with this notion, it has been shown that noradrenaline differentially affects the activity of auditory cortex neurons in the awake monkey.’’ Iontophoretically applied noradrenaline reduced both spontaneous and evoked (acoustic stimulus) firing but the latter was relatively less affected.’’ In line with these findings, it has been shown in various brain areas that noradrenaline enhances neuronal responsiveness to natural stimulation of afferent pathways’’ or to microiontophoretically applied GABA16 and ACh” in various brain areas. In contrast we have shown that the amine can reduce cortical neuron sensitivity to substance P.’* These electrophysiological findings point to a modulatory role of noradrenaline in central information processing. A large consensus of data indicates that the central noradrenergic system displays a functional decline with advancing age. Both preand postsynaptic markers of noradrenergic activity show such changes. The spontaneous firing rate of locus coeruleus neurons declines” and the sensitivity of target neurons to noradrenaline attenuates in various brain areas with advancin age.’0*’‘ Endogenous noradrenaline levelsz2 and the stimulation of adenylate cyclase by noradrenaline were found to be k

A structure-activity profile of substance P and some of its fragments on supraspinal neurones in the rat

Responses of neurones in the cingulate cortex to iontophoretically applied substance P (SP) were compared to its various C-terminal fragments. Fragments as short as the hexapeptide sequence were at least as active in increasing neuronal firing as the parent molecule. The pentapeptide sequence was much less active and the tripeptide sequence inactive. Compared on a current basis the octa-, hepta- and hexapeptides all evoked larger responses than the full sequence SP. In addition, the nonapeptide N-terminal sequence of SP had no effect on any neurone on which it was tested.