M. Sabatino

Inhibitory control by substantia nigra of generalized epilepsy in the cat

Previous investigations have shown that the basal ganglia may exert a regulating influence on cortical epilepsy. Stimulation of the caudate nucleus enhances cortical penicillin (PCN) spikes. Stimulation of globus pallidus internus reduces cortical spike frequency. Since the substantia nigra pars reticulata (SNpr) seems to have an inhibitory action on the ventro-anterior (VA) and ventro-lateral (VL) thalamic nuclei and thalamic neurones send an excitatory influence to the cortex, we undertook an investigation to study nigral influence on cortical epilepsy induced by PCN. Experiments were conducted on encéphale isolé cats in which steady interictal activity was induced by means of parenteral PCN administration (feline generalized PCN epilepsy). Variations occurring in cortical PCN spikes following activation of either pars compacta (SNpc) or SNpr were analyzed. Electrical stimulation of SNpc reduced spike frequency and amplitude in 19% of the total number of stimulations; SNpr stimulation significantly inhibited cortical spikes, especially in the precruciate gyrus, in 80% of cases. The experimental findings constitute an electrophysiological feature of the control exerted by SNpr on the thalamo-cortical re-exciting loop. A putative preferential role of SNpr in the regulation of abnormal phenomena involving the neocortex is emphasized.

Substantia nigra-mediated anticonvulsant action: a possible role of a dopaminergic component.

A number of neural pathways may mediate nigral control of epilepsy. According to the literature, a GABAergic nigrotectal pathway may be responsible for the control exerted by the substantia nigra on the diffusion of discharges toward spinal targets, while the nigrothalamic projection may transfer nigral influence on premotor neocortical epilepsy. Since there is probably an anatomical nigrohippocampal pathway arising from dopaminergic cells in the substantia nigra, we tested the effects of stimulating the substantia nigra pars compacta (SNpc) on focal hippocampal epilepsy induced by penicillin injection in the cat. The possibility of dopamine involvement was further tested by studying the effects of intraperitoneal injection of haloperidol, a dopamine receptor blocking agent on nigrohippocampal influences, while to verify the precise site of action, in other groups of cats, sulpiride and apomorphine (D-receptor antagonist and agonist, respectively) were locally administered in the dorsal hippocampus. Furthermore, modifications of hippocampal epileptiform EEG were studied in control conditions and following SNpc electrolytic lesions. Results showed a strong nigral suppressive effect on focal hippocampal epilepsy. Nigral stimulation induced a significant decrease in both frequency and amplitude of hippocampal spikes, which disappeared either about 10 min after i.p. injection of haloperidol 1 mg/kg or about 5 min after intrahippocampal administration of sulpiride, and did not return during a further hour or more of experimental observation. It should be emphasized that in the absence of nigral stimulation, both haloperidol and sulpiride did not modify hippocampal spike frequency. Apomorphine application to dorsal hippocampus induced a marked reduction of hippocampal epileptiform activity parallel to the effect observed during SNpc stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of caudate nucleus on paroxysmal activity in hippocampus of cat

Electrically induced afterdischarges (ADs) were evoked in cats dorsal hippocampus. The effect of the conditioning prestimulation of the caudate head on AD duration was tested. A strong inhibitory action was observed when conditioning caudate stimulation immediately preceded hippocampal test stimulation. An increase in threshold values following caudate stimulation was also noted. The time course of the inhibitory phenomenon showed a decrease of the caudate conditioning effect when the interval between the two stimuli increased: complete disappearance of such effect was found to occur at about 600 msec. When caudate head stimulation followed the onset of hippocampal AD, this was inhibited only during caudate stimulation while presenting facilitation after caudate stimulation terminated. The results are discussed in terms of a possible explanation of the contrasting action of the pallidum, while previous findings attesting the facilitatory role of these structures are considered, as are the effects of caudate stimulation on hippocampal AD.

Striatal and septal influence on hippocampal theta and spikes in the cat

The experiments studied the modulation exerted by the septum and the caudate nucleus on hippocampal activity in the cat. Injections (i.v.) of sodium penicillin were performed in order to obtain a steady interictal epileptic activity. Hippocampal slow rhythmic activity showed a marked decrease either in duration or in frequency following penicillin activation. Both septal and caudate electrical stimulation inhibited spike frequency through a theta eliciting mechanism. Caudate stimulation failed to determine any sort of effect after medial septum lesions. The importance of the septum as modulation station between basal ganglia and hippocampus is emphasized.

Dopaminergic control of feline hippocampal epilepsy: A nigrophippocampal pathway

Substantia nigra is a mesencephalic structure inserted along several circuits which appear to play a key role in epilepsy. In previous researches we postulated that substantia nigra pars compacta (SNpc) may be the site of a precise control of hippocampal epilepsy while substantia nigra pars reticulata (SNpr) may exert a modulation of both neocortical epilepsy and spreading of hyperactivity toward a motor target. In order to better understand mechanisms subserving nigral action in feline hippocampal epilepsy we electrically stimulated SNpc (dopaminergic), before and after sulpiride (dopamine receptor-antagonist) intravenous injection. Furthermore we compared hippocampal epileptiform activity prior to and after apomorphine (dopamine receptor-agonist) intrahippocampal injection as well as prior to and after SNpc electrolytic destruction. Results showed that SNpc is able to regulate hippocampal epilepsy. This effect is selectively antagonized by sulpiride while apomorphine exerts, synergically with SNpc stimulation, inhibitory effects. On the contrary SNpc lesions induces a significant enhancement of hippocampal epileptiform spikes. Experimental findings suggest that SNpc represents a strategic region for the control of hippocampal excitability and that this regulation appears to be dopaminergic in nature.

Effects of substantia nigra and pallidum stimulation on hippocampal interictal activity in the cat

In the present work the role played by substantia nigra pars compacta and globus pallidus pars interna on hippocampal bioelectrical activity is studied. Injections of sodium penicillin (i.v.) produce steady interictal spikes in the hippocampus. Substantia nigra stimulation induces regular theta rhythm and inhibits the spikes. Pallidal stimulation, on the contrary, appears to strongly enhance epileptiform activity, proceeding to generalized seizure activity. The results are discussed in the light of the interrelationships between basal ganglia and hippocampus, hypothesizing a putative feedback loop from striatal to limbic centers.

Striatonigral suppression of focal hippocampal epilepsy.

Both caudate nucleus (CN) and substantia nigra (SN) appear to be involved in the control of epileptogenic events. Previous investigations had demonstrated that both CN and SN stimulations are able to induce hippocampal theta (theta) rhythm and an inhibition of epileptiform spikes. Since the two structures are reciprocally linked by fibre pathways, experiments were carried out to test the possibility that CN influences the hippocampus via SN or vice versa. To this end, changes in penicillin-induced hippocampal spikes by CN or SN stimulation were studied before and after destruction of SN and CN respectively. Steady interictal activity was induced in the hippocampus of encéphale isolé cats by local injection of penicillin. Stimulations of both CN and SN induced statistically significant reduction of hippocampal spike frequency, and in some cases a clear and regular theta-rhythm. These effects were unchanged by the destruction of either CN or SN. The results add further information to the role played by the basal ganglia and SN in the control of epilepsy, and underline the possibility that caudate and nigral influences on the hippocampus are mediated by different pathways.

Locus coeruleus noradrenaline system and focal penicillin hippocampal epilepsy: Neurophysiological study

Previous experimental investigations have shown that several neuronal systems modulate the spontaneous and paroxysmal electric activity of the hippocampus. The locus coeruleus-noradrenaline (LC-NA) system exerts an inhibitory influence on several brain areas including the ipsilateral hippocampus. Selective destruction of the LC increases the susceptibility to epileptiform phenomena in different models of experimental epilepsy. Our experiments were conducted on 34 rats in which a steady epileptiform interictal activity of the hippocampus was obtained by means of intrahippocampal administration of penicillin. Electrical stimulation of LC caused a significant decrease of penicillin spiking of hippocampus. Stimulation sessions given 10-15 min after i.p. propranolol administration (2 mg/kg) failed to induce any significant modification in the hippocampal spiking frequency. Intrahippocampal injection of L-noradrenaline mimicked the inhibitory effect of LC electrical stimulation on hippocampus. Finally, intrahippocampal administration of isoproterenol HCl, a beta-adrenoceptor agonist, caused a significant decrease of hippocampal penicillin spiking; this effect was antagonised by i.p. propranolol administration. The experimental data show a modulating influence of the LC-NA system on penicillin focal hippocampal epilepsy that probably involves beta-adrenoceptors.

Effects of desipramine and alprazolam in the forced swim test in rats after long-lasting termination of chronic exposure to picrotoxin and pentylenetetrazol

Rats were treated for 5 weeks with three subconvulsant doses of picrotoxin (PTX) and pentylenetetrazol (PTZ) per week to induce a persistent reduction of the GABAA receptor function which results in chemical kindling. Fifteen days after termination of this treatment schedule, the effect of desipramine (DMI) and alprazolam (ALP) on immobility time in the forced swim test (FST) was evaluated. Chronic PTX and PTZ did not alter the immobility time. Acute PTX and PTZ reduced the immobility of rats chronically treated with vehicle but not of those exposed chronically to PTX and PTZ. Chronic PTX did not influence the anti-immobility effect of DMI, but blocked that of ALP. Chronic PTZ markedly potentiated the anti-immobility effect of DMI but blocked that of ALP. Concomitant administration of chlordiazepoxide prevented the effects of chronic PTX and PTZ. These findings suggest that a long-lasting reduction in GABAA receptor function, unlike acute reduction, does not play an important role in the mobility of rats in the FST and in the anti-immobility effect of DMI while it blocks that of ALP.

Relay stations and neurotransmitters between the pallidal region and the hippocampus

The effects of internal pallidum and lateral habenula stimulation on epileptiform activity of cats hippocampus were studied. A steady interictal activity was induced by locally applied sodium penicillin (PCN) solution. Both pallidal and habenular electrical stimulation caused an increase in spike frequency and amplitude. Intraperitoneally injected atropine sulphate failed to modify pallidal and habenular influences. Intraperitoneal methysergide bimaleate (5-HT antagonist) suppressed the effects of habenular stimulation. In contrast to the effects of pallidal and habenular stimulation, raphe electrical stimulation inhibited hippocampal spiking and intra-raphal muscimol (a GABA receptor agonist) enhanced hippocampal-based epilepsy. After muscimol, raphe stimulation at the same threshold parameters failed to affect hippocampal activity. In cats with habenular lesions hippocampal spike frequency and amplitude were reduced and intra-raphal muscimol did not affect the hippocampus. The results are discussed in the light of a complex interrelationship between basal ganglia and hippocampus. The role of the lateral habenula and of the medial raphe as relay stations between the two regions is emphasized.