The atypical excitation by opiates and opioid peptides of hippocampal pyramidal cells can be antagonized by iontophoresis of naloxone, the γ-aminobutyric acid antagonist bicuculline, or magnesium ion. The recurrent inhibition of these cells evoked by transcallosal stimulation of the contralateral hippocampus is blocked by enkephalin but only shortened by acetylcholine. The results suggest that the opioids excite pyramidal neurons indirectly by inhibition of neighboring inhibitory interneurons (probably containing γ-aminobutyric acid). This mechanism may be pertinent to the electrographic signs of addictive drugs.
The taurinate analog acamprosate (calcium acetylhomotaurinate) has received considerable attention in Europe for its ability to prevent relapse in abstained alcoholics. To determine the mechanism of acamprosate actions in the CNS, we superfused acamprosate onto rat hippocampal CA1 pyramidal neurons using an in vitro slice preparation. In current‐ and voltage‐clamp recordings, acamprosate (100 to 1000 μM) superfusion had little effect on resting membrane potential or input slope resistance. Acamprosate had no effect on Ca 2+ ‐dependent action potentials when tetrodotoxin was used to block Na + spikes. In whole‐cell voltage‐clamp recordings, and in the presence of tetraethylammonium and Cs + to block K + channels, acamprosate had little effect on a Cd 2+ ‐sensitive inward current likely to be a high voltage‐activated Ca 2+ current. However, in both current‐ and voltage‐clamp recordings, acamprosate significantly increased the N ‐methyl‐ d ‐aspartate (NMDA) component of excitatory postsynaptic potentials evoked by stimulation of Schaffer collaterals in the stratum radiatum, in the presence of the selective non‐NMDA (R.S)‐α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐proprionic acid kainate) glutamate receptor antagonist 6‐cyano‐7‐nitro‐quinoxaline‐2,3‐dione and the GABA A receptor antagonist bicuculline. Acamprosate had inconsistent or no effects on the stratum radiatum‐evoked non‐NMDA component of the excitatory postsynaptic potentials, in the presence of bicuculline and the NMDA antagonist dl ‐2‐amino‐5‐phosphonovalerate. Acamprosate, on average, had little effect on the late inhibitory postsynaptic potentials thought to be mediated by GABA B receptors. In the presence of tetrodotoxin to block synaptic transmission, acamprosate dramatically increased inward current responses in most CA1 neurons to exogenous NMDA applied by pressure or superfusion, with reversal on washout of acamprosate. These data suggest that acamprosate may act postsynaptically to increase the NMDA component of excitatory transmission to hippocampal CA1 pyramidal neurons. Considering the known interaction of ethanol with NMDA receptors, this acamprosate modulation of NMDA receptor‐mediated neurotransmission could provide a mechanism of action underlying the clinical efficacy of acamprosate.
A review of recent studies of the effects of corticotropin-releasing factor (CRF) on the electrical activity of central neurons indicates that CRF has predominantly excitatory actions in locus ceruleus, hippocampus, cortex, and some regions of hypothalamus. These brain areas are reported to contain immunoreactive CRF. Intracellular recordings in the hippocampal slice preparation demonstrate that the excitation in this preparation may arise from reduction of the afterhyperpolarizations (AHPs) following bursts of spikes. The postburst AHPs probably are produced by a Ca2+-dependent K+ conductance. Inasmuch as "Ca2+ spikes" recorded in the presence of tetrodotoxin are not diminished by CRF, this peptide appears to be acting either at the level of the Ca2+-dependent K+ conductance itself, or at the linkage between this conductance and Ca2+ influx or Ca2+ recognition sites. These excitatory effects are consistent with electroencephalographic recordings in awake animals, where intracerebroventricular CRF activates cortical and limbic areas and, at higher doses, evokes epileptiform activity in amygdala and hippocampus. However, predominantly inhibitory actions of CRF have been seen with extracellular single-unit recordings in a few central nervous system (CNS) areas such as lateral septum, thalamus, and the hypothalamic paraventricular nucleus. These findings, combined with those from immunohistochemical, biochemical, and behavioral studies, suggest 1) a possible neuromessenger role for CRF in extrahypothalamic regions and 2) a possible concerted function by CRF-containing elements in the CNS in an integrated behavioral response to stress.
Adenosine 3′,5′-monophosphate is localized in specific cerebellar neurons, as shown by fluorescence immunocytochemistry with a specific rabbit immunoglobulin. Positive staining is exhibited by Purkinje neurons and granule cells. The increase in concentration of cyclic adenosine monophosphate in the cerebellum, which is known to follow decapitation, is represented by greatly increased fluorescence of Purkinje neurons only. These immunofluorescence data provide the first evidence for localization of cyclic adenosine monophosphate in specific neurons and may permit further exploration into the role of this cyclic nucleotide in neuronal function.
