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The effects of various psychotropic drugs (benzodiazepines, antidepressants, neuroleptics and nootropic drugs, a family of cognition activator agents) on firing rates of septohippocampal neurons, identified by electrical antidromic stimulation, were studied in the medial septum-nucleus of the diagonal band of Broca of rats anaesthetized with urethan. Extracellular potentials from single septohippocampal neurons were recorded using glass pipettes. Drugs were applied by either microiontophoresis or intravenous injections (i.V.). Benzodiazepines produced a marked depression of spontaneous firing rates of septohippocampal neurons whether applied i.v. (diazepam) or iontophoretically (flurazepam, midazolam). In addition, diazepam had a potent depressant effect on the rhythmically bursting activity of the septohippocampal neurons. Baclofen also had an inhibitory effect. Antidepressant drugs (applied by iontophoresis) as well as amphetamine, had a depressant effect on spontaneous firing rates. Neuroleptics (i.v.) had less significant or consistent effects on septohippocampal neurons, although the effects of haloperidol were usually inhibitory. Nootropic drugs were generally ineffective. These data indicate that most psychotropic drugs tested (with the exception of nootropic drugs) have an inhibitory effect on the spontaneous activity of septohippocampal neurons. However, benzodiazepines seem to be more active than antidepressants or neuroleptics. Oxotremorine (i.v.) had a potent excitatory effect on septohippocampal neurons. Atropine (i.v.) increased the septohippocampal neurons' firing rate in some cases. These results are discussed in view of the possible implication of the involvement of septohippocampal neurons in the mediation of the effects of psychotropic drugs on the central nervous system and, more specifically, on the cholinergic systems.

The effects of the microiontophoretic application of five different peptides (cholecystokinin octapeptide sulfated form, cholecystokinin octapeptide non-sulfated form, vasoactive intestinal polypeptide, angiotensin-II and substance P) on cortical neurons were studied in rats anaesthetized with urethane. Vertical electrode penetrations were made in the first somatic sensory cortex and the laminar position of the neurons determined by the reconstruction of the tracks based on extracellular dye deposits. The first type of effect observed was an excitation of some cortical neurons. These neurons were mostly found in infragranular layers, specially in layer Vb. Pyramidal tract neurons were more often excited by peptides than the cortical population taken as a whole. Substance P excited the largest percentage of neurons, followed by vasoactive intestinal polypeptide and cholecystokinin octapeptide sulfated form, whereas angiotensin II and cholecystokinin octapeptide non-sulfated form were the least potent in terms of frequency of neurons excited as well as of amplitude of the responses. The vast majority of the neurons excited by a peptide could also be excited by acetylcholine. A second and independent effect of peptides was observed: the neuronal excitation induced by acetylcholine could be depressed by the simultaneous application of peptide. This depressing effect was also the most frequently observed with substance P, followed by cholecystokinin and vasoactive intestinal polypeptide.

Intracellular recording from hippocampal CA1 pyramidal cells was used to characterize the pharmacological properties of muscarinic responses. Results obtained with the M1 antagonist pirenzepine and the M2 antagonist gallamine suggest that an M1 muscarinic receptor is involved in the muscarinic-induced membrane depolarization and blockade of the afterhyperpolarization (AHP). On the other hand, an M2 receptor may be involved in the cholinergic depression of the EPSP and the blockade of the potassium current termed the M-current. Pretreatment of hippocampi with pertussis toxin did not prevent any of the muscarinic responses suggesting that a pertussis toxin-sensitive G-protein is not involved. The M-current, in contrast to the other muscarinic actions, was unaffected by muscarinic agonists which are weak at increasing phosphoinositide (PI) turnover and actually blocked the action of full agonists. This finding suggests that stimulation of PI turnover may be involved in the blockade of the M-current. Although activation of protein kinase C with phorbol esters has little effect on the M-current, intracellular application of inositol trisphosphate did reduce the M-current. We were unable to establish any clear relationship between biochemical effector systems and the muscarinic receptor subtypes.

The mechanisms by which neurotransmitter receptors are coupled to ion channels has been the focus of a great deal of research since the discovery that neurotransmitters can alter neuronal excitability by acting on voltage-dependent, as well as voltage-independent, ion channels. Using the in vitro hippocampal slice preparation we have examined the role of second messenger systems and GTP-binding proteins (G-proteins) in mediating the actions of a variety of neurotransmitters found in the hippocampus. Specifically we have examined the actions of norepinephrine (NE), acetylcholine (ACh), serotonin (5-HT), and baclofen (a GABAB receptor agonist).

The septo-hippocampal pathway is one of the best characterized cholinergic pathways of the mammalian central nervous system. It is very likely that this pathway is involved in the pathophysiology of dementia of the Alzheimer's type and perhaps of normal aging also. The properties of the septo-hippocampal neurons identified by their antidromic response to the electrical stimulation of the fimbria-fornix were altered in aged (27 months) rats as compared to young (2–3 months) controls: their pattern of spontaneous activity (including the frequency of occurrence of a rhythmically bursting activity) and their axonal conduction velocity were altered. The intensity of these changes was dependent on the presence of pituitary tumor which developed spontaneously in about1/3 of the animals. These results provide direct evidence of the involvement of septo-hippocampal neurons in the aging process.

The effects of verapamil, the phenylalkylamine calcium channel antagonist, have been studied on rat hippocampal pyramidal neurons, using intracellular recordings in an in vitro slice preparation. At low concentrations (1-10 microM), verapamil had no effect on these neurons. At higher concentrations (100-150 microM), it induced a progressive blockade of the slow component of the after-hyperpolarizing potential (AHP), but did not affect the fast one. Verapamil also blocked the slow inhibitory postsynaptic potential (sIPSP), but not the fast one. Pharmacological responses to the application of baclofen and serotonin were abolished, while the response to GABA was not. In addition, the size of the calcium spike was increased by verapamil, while the AHP and the sIPSP were already blocked. These results suggest that verapamil, applied at high concentrations, has an inhibitory effect on potassium conductances, independent of its calcium antagonist property.