In 1968, Aghajanian and colleagues studied freely moving rats with electrode implants in the raphe. LSD inhibited the spontaneous firing of neurons in the caudal midbrain raphe. Raphe units ceased firing within 1 to 2 minutes after the intravenous injections of 200 ug/kg LSD or within 5 minutes after the intraperitoneal injection (LSD 200 ug/kg). Once inhibited, raphe units did not return to original firing rates for at least 20 to 30 minutes. (G.K. Aghajanian, 1968)
In 1969, it was reported that LSD caused a cessation of dorsal or median raphe unit activity in anesthetized rat. A typical procedure consisted of locating a unit, observing its spontaneous activity for a period of 5-10 min and then giving an initial intravenous dose of either amphetamine or LSD. Figure 1 below shows a decrease in the spikes/min fired by a raphe neuron, when LSD was given as intravenous injection. In this case, the subsequent injection of amphetamine (A) caused the neuron to fire again. Most raphe cells showed a decrease and cessation of firing after LSD, and some units showed an increase in spontaneous firing rate to amphetamine, although in some cases, LSD and amphetamine had depressant effects on units in the reticular formation. (W.E. Foote, 1969)
|From LSD raphe neurons|
In preparations of decerebrate, unanaesthetized cat brain, LSD blocked the firing of brainstem neurons. With currents of 50 nA for periods of 5 min or longer, LSD reduced or completely blocked the excitatory effects of glutamate-excitation of brain stem neurons, more effectively than 2-bromo-LSD. (R.J. Boakes, 1969)
By 1970, in decerebrate cat preparations, it was found that iontophoretic release of LSD had a depressant action on 22 out of 35 neurons tested. LSD was found to antagonize the excitatory actions of glutamate, and no potentiation of glutamate excitation by LSD was ever observed. Figure 3 below shows the firing rate (y-axis) and glutamate current (x-axis) of a control neuron (open circles). In neurons exposed to LSD (closed circles), the curve is shifted to the right, indicating that larger pulses of glutamate were required to excite the neuron and increase its firing rate. In the LSD condition, firing rates were generally lower compared to the control neuron. (R.J.Boakes, 1970)
|From LSD raphe neurons|
An experiment in 1974 showed that dorsal raphe neurons are very sensitive to LSD, when compared with other neurons in the brain. Dorsal raphe neurons were compared with neurons that receive a serotonergic input, including the ventral lateral geniculate, amygdala, optic tectum and subiculum. Even though LSD inhibited neurons in these structures, the dorsal raphe nuclei neurons were inhibited at much lower ejection currents of LSD. (H.J. Haigler, 1974)
|From LSD raphe neurons|
LSD generally has a depressant effect on neurons, that is rarely excitatory. When a mesencephalon-diencephalon lesion was made, to ensure that no possible feedback pathways from the forebrain to the dorsal raphe nucleus existed, the responses recorded from the cell bodies of raphe neurons were basically the same – they were inhibited by LSD. This suggested that LSD affects electrical activity in the raphe dendrite bundle in the medulla, with subsequent effects on the firing of action potentials from the axons of raphe neurons.
In 1981, Trulson and others reported that LSD and mescaline are associated with a depression of raphe nuclei activity in freely moving, awake cats with implanted electrodes. (M.E. Trulson, 1981)
Aghajanian and colleagues in 1984 found that 5-HT and LSD had a similar inhibitory effect on 5-HT neurons in the dorsal raphe nucleus, and that this inhibitory effect on 5-HT neurons was caused by an increase in K+ conductance in the raphe neurons. The concentrations of 5-HT and LSD used were 80 uM and 80 nM. Serotonin or LSD caused a hyperpolarization of raphe neurons, which was not reversed by chloride-containing electrodes, suggesting that the inhibition of raphe neuron firing was caused by an increase in K+ conductance, and not mediated by chloride, which is typically a GABAA-receptor-related current. In slices of rat dorsal raphe nuclei, both 5-HT and LSD induce a hyperpolarization via K+ currents, but the LSD effect was longer-lasting and more pronounced than 5-HT, for example several hours were required for full recovery during washout. The main results suggested that 5-HT and LSD hyperpolarize serotonergic neurons predominantly through increasing potassium conductance. (G.K. Aghajanian, 1984)
In 1985, cats underwent surgery and were implanted with electrodes and a cyclic voltammetry device. An electrode array recorded from dorsal raphe neurons, while the cyclic voltammetry device measured 5-HT release in the striatum. Thus it was possible to simultaneously analyze the axonal 5-HT output in striatum in relationship to raphe spiking activity (field potentials) in the raphe medulla. In this research, a 50 ug/kg dose of LSD decreased raphe units activity by 50%, and LSD treatment produced a 88% decrease in the release of 5-hydroxyindole, a metabolite of 5-HT, measured by the voltammetric response. The authors concluded that LSD blocks the release of 5-HT from raphe neuron terminals. They speculated that LSD inhibits the metabolism of raphe neurons that so that less neurotransmitter is released at the synapse. (M.E. Trulson, 1985)
In 1987, LSD dose-dependently decreased the firing rate of 5-HT raphe neurons in anesthetized rats, and this effect was antagonized by pertussis toxin. Pertussis toxin is known to inactive the alpha subunits of G-proteins, thus it was inferred that the inhibition of raphe firing by LSD was dependent upon a mechanism involving G-proteins, particularly GABAB receptors which couple with K+ channels. It is possible that LSD activates local inhibitory neurons, which contribute to the inhibition of raphe neurons by releasing GABA. (R.B. Innis, 1987 )
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