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Biomedical subjects

B J Hoffer

Publications and source records attributed to B J Hoffer.

At least 145 records · Page 8Linked to original sources
PubMed1981

Noradrenergic responses in rat hippocampus: evidence for medication by alpha and beta receptors in the in vitro slice.

The effect of perfused norepinephrine (NE) on evoked potentials in CA1 of the in vitro rat hippocampus was examined. Weak and variable effects on population spike amplitude were observed, with lower doses of NE generally producing excitations and higher doses more often producing inhibitions. Clonidine, an alpha-receptor agonist, produced a dose-dependent inhibition of population spike amplitude; this inhibition was effectively antagonized by the alpha-antagonist, phentolamine. Isoproterenol (ISO), a beta-agonist, produced marked increases in population spike amplitude which could be antagonized by timolol, a beta-receptor antagonist. Phentolamine did not antagonize the excitations produced by ISO, and timolol had no effect on the inhibitions seen with clonidine. After pretreatment with either phentolamine or timolol, NE perfusion elicited robust and consistent elevations or reductions in the population spike, respectively. A potent cyclic AMP derivative, 8-p-chlorophenylthio cyclic AMP, produced large increases in population spike amplitude which appeared similar to the responses seen with beta-agonists. No changes in field EPSP amplitudes were observed with any of the drugs tested. Taken together, these results suggest that NE may interact with alpha-adrenergic receptors to decrease pyramidal cell excitability, and the beta-adrenergic receptors to increase pyramidal cell excitability; the beta-effect may involve cAMP.

Animals↗
PubMed1981

Effect of dopamine agonists and antagonists on the electrical activity of substantia nigra neurons transplanted into the lateral ventricle of the rat.

Pieces of fetal rat mesencephalon containing the substantia nigra were transplanted into the lateral ventricle of rats pretreated with 6-OHDA injections into the ipsilateral substantia nigra. Extracellular recordings from these grafts revealed spontaneously active neurons with action potential waveforms and firing rates similar to those found in substantia nigra zona compacta in situ. Furthermore, local application of dopamine agonists inhibited, while dopamine antagonists increased zona compacta activity, both in situ and of cells from nigral grafts. We conclude that substantia nigra grafts contain spontaneously active neurons similar to those of zona compacta in situ, and that some of the mechanisms regulating nigral neuronal activity in situ are also present in this preparation.

Action Potentials↗
PubMed1981

Electrophysiologic interactions of antipsychotic drugs with central noradrenergic pathways.

The pathway from the nucleus coeruleus to Purkinje neurons in rat cerebellar cortex was used to analyze effects of antipsychotic neuroleptic drugs on a central noradrenergic pathway. Fluphenazine and haloperidol produced a dose-dependent increase in Purkinje neuron spontaneous discharge. This effect was not seen in animals in which the noradrenergic input had been removed by the neurotoxin 6-hydroxydopamine. In contrast, the effects of neuroleptics were still present in animals which had received neonatal X-ray irradiation, which destroys intrinsic inhibitory and excitatory pathways in cerebellar cortex. Chlorpromazine produced the same increase in discharge rate, but was significantly less potent. alpha-Flupenthixol was equipotent with fluphenazine, but beta-flupenthixol, a behaviorally inactive stereoisomer, was without effect. The dose-response curves showed potencies similar to those in several animal behavioral paradigms. In addition, the rank order of potency was identical to that in clinical tests of antipsychotic activity. Three-week chronic administration of fluphenazine resulted in complete blockage of noradrenergic activity, with no further increase in Purkinje neurons spontaneous discharge rate by additional doses of drug. Thus, tolerance does not develop to the noradrenergic blocking effect of the neuroleptic. Taken together, this evidence suggests that antipsychotic neuroleptic drugs block noradrenergic neurotransmission in the CNS.

Animals↗
PubMed1981

Alkylxanthines elevate hippocampal excitability. Evidence for a role of endogenous adenosine.

The effects of four xanthines (theophylline, 8-phenyltheophylline, isobutylmethylxanthine (IBMX), and 7-benzyl-IBMX) were studied in the hippocampal slice in vitro. These agents increased the excitability of this preparation with 8-phenyltheophylline being the most potent, 7-benzyl-IBMX the least potent, and theophylline and IBMX having intermediate potencies. A similar rank order was observed in terms of the potencies of these xanthines in antagonizing a) electrophysiological responses to adenosine, and b) adenosine-stimulated cyclic AMP formation. These results indicate that the excitatory actions of xanthines in the vivo hippocampus can be most easily explained on the basis of their ability to block adenosine's actions; the CNS excitatory actions of these drugs in vivo may depend upon a similar mechanism of action.

Adenosine↗
PubMed1981

Changes in noradrenergic neurotransmission in rat cerebellum during aging.

This study compared the electrophysiological effects of locally applied cyclic adenosine-mono-phosphate (N6cAMP) between Purkinje neurons from young (4-month) and old rats (15-months and older). Purkinje neurons from young rats were significantly more sensitive to locally applied norepinephrine and N6cAMP than neurons from old rats. GABA sensitivity between the two groups was unaltered. Our results suggest that the locus of the adrenergic subsensitivity observed in older animals may reside to a large extent at or beyond the level of cAMP generation.

Aging↗
PubMed1981

Electrophysiological response of cerebellar Purkinje neurons to leukotriene D4 and B4.

The biological effects of leukotrienes B4 and D4, two recently characterized products of arachidonic acid metabolism, were studied on the guinea-pig ileum in vitro and on rat cerebellar Purkinje cells in vivo. Leukotriene D4 induced contraction of the ileum and a prolonged excitation of Purkinje cells. Both of these effects were antagonized by the "slow reacting substance" end-organ antagonist, FPL 55712. Leukotriene B4 had no central electrophysiological effects at the doses used and no effects on the guinea-pig ileum at doses below 0.2 microM. Taken together with previous studies, these data suggest that leukotrienes with slow reacting substance activity may modulate the excitability of central neurons as well as peripheral smooth muscle tone.

Action Potentials↗
PubMed1980

Kindling induces long-lasting alterations in response of hippocampal neurons to elevated potassium levels in vitro.

The cellular basis of kindling was studied electrophysiologically with slices of guinea pig hippocampus. Normally, epileptiform activity can be induced in the slices only by combined exposure to elevated potassium levels and a chemical convulsant such as penicillin. In hippocampal slices from pentylenetetrazole-kindled animals, however, elevated potassium alone can induce seizures. These data suggest that kindling elicits long-term changes in neuronal excitability that may involve ionic mechanisms.

Animals↗
PubMed1980

Restoration of dopaminergic function by grafting of fetal rat substantia nigra to the caudate nucleus: long-term behavioral, biochemical, and histochemical studies.

Motor deficits produced in rats by unilateral substantia nigra lesions have been found to be reduced by grafts of fetal rat substantia nigra to the dopamine denervated caudate nucleus. In the present study these grafts were examined behaviorally, histochemically, and biochemically over six to 10-month periods. The grafts were found to survive in a healthy condition and contain catecholaminergic cells and fibers after eight to ten months. Concentrations of dopamine in adjoining parts of the caudate nucleus were increased when examined six months after grafting. Apomorphine induced rotation was reduced by the grafts, and these reductions persisted for at least six months. Although signs of aging were observed in the brains of the host animals when sacrificed eight to ten months after grafting, the grafts remained healthy and showed no signs of aging or deterioration. It is concluded that substantia nigra grafts can become permanent, functional constituents of the brains of host animals with prior substantia nigra lesions.

Animals↗
PubMed1980

Conditions for adrenergic hyperinnervation in hippocampus: I. Histochemical evidence from intraocular double grafts.

The developing hippocampal anlage of rats was homologously grafted to the anterior chamber of the eye of adult recipients. After intraocular maturation of the hippocampal graft and removal of the sympathetic innervation of the eye by ipsilateral superior cervical ganglionectomy, four types of monoamine neurons were transplanted to the eye chamber: Peripheral sympathetic neurons, central adrenergic neurons of locus coeruleus, central dopaminergic neurons of substantia nigra, and central 5-hydroxytryptamine neurons of the lower raphe nuclei. All four classes of monoamine neurons were able to reinnervate the hippocampal graft, but the fiber ingrowth differed markedly. Although peripheral sympathetic neurons produced a pattern of adrenergic innervation in the hippocampal graft which resembled innervation of the hippocampus by the locus coeruleus in the brain, locus coeruleus neurons themselves produced an extremely dense plexus of fibers within the graft. This hyperinnervation remained intact for up to 9 months, the longest period of time studied. The locus coeruleus graft itself received fibers from the hippocampus graft, as demonstrated by the retrograde transport of horseradish peroxidase. We conclude that the hippocampal graft exerts a much stronger growth stimulation on the locus coeruleus neurons than on the peripheral sympathetic neurons. The difference between innervation patterns suggest that both presynaptic and postsynaptic influences determine fiber ingrowth in the central nervous system.

Adrenergic Fibers↗
PubMed1980

Conditions for adrenergic hyperinnervation in hippocampus: II. Electrophysiological evidence from intraocular double grafts.

Following sequential intraocular transplantations of areas containing NE cell bodies (locus coeruleus or superior cervical ganglion) and of NE fiber target areas (hippocampus), both pieces mature in a manner analogous to that observed for individual transplants. NE-containing nerve fibers, derived from either LC or SCG transplants, can be seen to invade the hippocampal formation. When LC is used, the invading fibers markedly hyperinnervate the hippocampus while SCG-derived fiber densities approximate those seen with innervation from the adrenergic ground plexus of the iris. Electrophysiological recordings from neurons in the LC reveal an atropine-sensitive excitatory response to illumination, suggesting innervation of the LC by cholinergic nerve fibers from the iris. This is supported by the fact that dense cholinesterase-positive staining can be found in the LC piece. Application of an epileptogenic agent, such as penicillin, results in a marked excitation of neurons in the LC without inducing epileptiform activity in the hippocampus. In contrast, single hippocampal grafts seize readily after penicillin. Local application of the inhibitory agent GABA into the LC allows penicillin-induced epileptiform activity to generate in the hippocampus, suggesting that functional inhibitory innervation develops between NE fibers derived from LC and pyramidal neurons in the hippocampus. Supporting this, subsequent excitation of LC neurons by iontophoresis of glutamate terminates the hippocampal seizure. Prior administration of reserpine (2.5 mg/kg) disrupts the inhibitory influence of LC innervation on the hippocampal EEG following penicillin. After reserpine, the hippocampal portions of double grafts behave like single hippocampal transplants. It is concluded that sequential transplantations of cell body and target regions of the CNS to the anterior chamber of the eye creates a functional, yet isolated, neuronal pathway which can be utilized to study the development of neuronal connections.

Adrenergic Fibers↗
PubMed1980

GABA facilitation by noradrenaline shows supersensitivity in cerebellum after 6-hydroxydopamine.

Alterations of cerebellar Purkinje cell responses to microiontophoretically applied noradrenaline (NA) were studied in rats after the destruction of NA-containing afferents and terminals by 6-hydroxydopamine (6-OHDA). An enhanced efficacy of NA action after 6-OHDA treatment was indicated by a significant reduction in the mean iontophoretic current required for a threshold depressant response to NA. A potentiation of gamma aminobutyric acid (GABA)-mediated inhibition by administration of NA, similar to that previously observed in control animals, was also reliably elicited in 6-OHDA pretreated rats. In addition, Purkinje cells appeared to demonstrate an increase in sensitivity to such facilitating actions of NA, defined here as "modulatory supersensitivity". In contrast to the prolonged synergistic interactions between NA and GABA observed in control animals, however, the enhancement of the amino acid response in 6-OHDA treated animals did not persist beyond the period of NA ejection and converted instead to a period of rebound insensitivity to GABA action. These results provide electrophysiological evidence for the emergence of supersensitivity to NA action in cerebellum after the loss of noradrenergic input from locus coeruleus.

Animals↗
PubMed1980

Leukotriene C elicits a prolonged excitation of cerebellar Purkinje neurons.

Leukotriene C-1 (LTC-1), a recently characterized potent agonist in bioassays for the slow reacting substance of anaphylaxis (SRS-A), was tested for electrophysiological effects on central neurons. LTC-1 consistently elicited a unique prolonged excitatory action on cerebellar Purkinje (P) cells when administered locally by pressure ejection from a multibarreled micropipette. This excitation could be reversed by subsequent pressure ejection of FPL 55712 (FPL), a SRS-A end-organ antagonist. Prior application of FPL prevented the LTC-1-induced responses altogether. Heat-inactivated LTC-1 had no effect on P cell discharge. These data suggest that LTC-1, as has been recently found with many other peripherally acting neurohormones, may also function to regulate excitability of central neurons.

Action Potentials↗
PubMed1980

Adenine nucleotides and synaptic transmission in the in vitro rat hippocampus.

1 The effects of adenosine and various derivatives were examined in the in vitro hippocampal slice preparation from rat.2 The amplitudes of extracellularly recorded field potentials from the CA1 region were depressed by adenosine, and this effect could be antagonized by methylxanthines. Because presynaptic field potentials were unaffected by adenosine, while the field e.p.s.p. was depressed, adenosine would appear to act at a synaptic site to depress transmission.3 Adenosine deaminase, which breaks down adenosine to inosine, increased the amplitude of synaptic responses, while hexobendine, which blocks reuptake of adenosine, had a depressant effect. This strongly suggests that the endogenous release of adenosine from the hippocampal slice preparation is sufficient to exert a tonic inhibitory influence on the amplitude of synaptic responses.4 Cyclic adenosine 3',5'-monophosphate (cyclic AMP) and its dibutyryl derivative had depressant effects on the amplitude of field responses which were blocked by theophylline, suggesting that they are able to act at the extracellular adenosine receptor. (-)-Isoprenaline (which raises tissue cyclic AMP levels), and the 8-p-chlorophenylthio derivative of cyclic AMP both increased the amplitude of population spike responses, and these effects were not blocked by theophylline, suggesting that the physiological effects of adenosine are not mediated via a cyclic AMP-dependent mechanism.5 Since adenosine is not the transmitter at this CA1 pyramidal cell synapse, but is apparently present in the extracellular compartment in sufficient concentrations to affect the synaptic physiology of this region, this provides strong evidence in favour of the concept of a neuromodulatory role for adenosine in the central nervous system.

Adenine Nucleotides↗