Search PubMed⌕ Search

Biomedical subjects

B J Hoffer

Publications and source records attributed to B J Hoffer.

At least 127 records · Page 7Linked to original sources
PubMed1986

Release of monoamines from striatum of rat and mouse evoked by local application of potassium: evaluation of a new in vivo electrochemical technique.

Local application of K+ via micropressure-ejection, coupled with in vivo electrochemical detection, was used to study stimulated release from monoaminergic nerve terminals in the striatum of anesthetized rats and mice. K+-evoked releases were reversible, reproducible, and dose-dependent. In contrast, releases of electroactive species could not be evoked by local ejection of Na+. The magnitudes and time courses of K+-evoked releases recorded from the caudate nucleus of mice were greater than those seen in rats. Local application of nomifensine, a putative catecholamine reuptake blocker, augmented the magnitudes and time courses of K+-evoked releases. Releases were also recorded from brain regions adjacent the striatum; these signals were always smaller than those seen in the caudate nucleus and had amplitudes that showed good correspondence to the relative degree of dopaminergic input to these areas. These data, taken together with other information in the literature, suggest that this new technique is well suited for in situ studies of monoamine release and reuptake in intact animals.

Amines↗
PubMed1986

Electrophysiological interactions of isomers of cyclazocine with the phencyclidine antagonist metaphit in rat cerebellar Purkinje neurons.

Metaphit, 1-(1-(3-isothiocyanatophenyl) cyclohexyl) piperidine, an analog of phencyclidine (PCP) has been shown previously to selectively block PCP receptors and to irreversibly antagonize the depressant effect of PCP in cerebellum. In this study, we examined the electrophysiological interactions of metaphit and naloxone with stereoisomers of cyclazocine, an agent known to have analgesic and psychotomimetic activity in behavioral studies, effects that have been ascribed to opiate and PCP receptor activity. A dose-dependent and reversible slowing of Purkinje neuron discharge was seen with local application of (+)- or (-)-cyclazocine. We found that the blockade of (-)-cyclazocine effects required both high doses of naloxone and the presence of metaphit, whereas the responses to (+)-cyclazocine were blocked by metaphit alone on most cerebellar Purkinje neurons. These findings suggest that the depressant reaction of (+)-cyclazocine in cerebellar Purkinje neurons is primarily mediated through PCP receptors. (-)-Cyclazocine responses, on the other hand, appear to be due to activity at both PCP and kappa opioid receptors.

Animals↗
PubMed1986

Investigation of the failure of parenterally administered haloperidol to antagonize dopamine released from micropipettes in the caudate.

An anomaly in the experimental data underlying the theory that neuroleptics act by blockade of dopaminergic neurotransmission is the repeatedly demonstrated failure in several laboratories of parenterally administered neuroleptics to antagonize electrophysiologic actions of locally applied dopamine (DA) in striatum. This failure is enigmatic since many investigators have successfully demonstrated antagonism when both dopamine and neuroleptic are applied directly to striatal neurons by microiontophoresis. We used multibarrel micropipettes to pressure-eject DA agonists onto rat caudate neurons while observing the ability of parenterally administered haloperidol to block the inhibitory actions of dopaminergic agonists on neuronal activity. Experiments performed at times of maximal behavioural effect of haloperidol did not demonstrate agonist-antagonist interaction. This result has been obtained by four other teams of investigators. A variety of pharmacologic manipulations were employed to help solve this enigma. Acute treatment with reserpine and alpha-methyl-paratyrosine, performed to minimize any possible interference by endogenous DA, did not permit blockade of dopamine by haloperidol. To see if this failure of antagonism could be generalized to other DA agonists, apomorphine, amphetamine, and phencyclidine (PCP) were also investigated. Although the direct dopaminergic agonist apomorphine was not antagonized by haloperidol, the indirect DA agonist PCP was successfully antagonized. Amphetamine, which has both direct and indirect actions when applied locally, was not antagonized. Antagonism of direct agonists was demonstrated in rats with unilateral 6-hydroxydopamine-induced lesions of the nigrostriatal pathway. In these preparations, parenterally administered haloperidol reversed the receptor-mediated supersensitivity to the inhibitory effects of locally applied DA and apomorphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗
PubMed1985

Interaction of norepinephrine with Purkinje cell responses to cerebellar afferent inputs in aged rats.

Age-related differences in the modulatory actions of NE on the evoked activity of cerebellar Purkinje cells were examined in young (3 month) and old (18-20 month) Fischer 344 rats. We have previously shown that NE is more potent in young than in old rats, in terms of its ability to inhibit spontaneous activity. In this investigation complex spike excitation, simple spike excitation, and inhibition of Purkinje cell discharge were elicited by stimulation of climbing fibers, mossy fibers, and cerebellar parallel fibers, and quantified by computing post-stimulus time histograms of the neuronal response, recorded extracellularly. Histograms were compared before, during and after local ejection of NE from multibarreled micropipettes. In young rats NE preferentially inhibits spontaneous discharge more than evoked excitations. The inhibitory response of the Purkinje cell to activation of basket and stellate cell afferents is potentiated by NE with respect to the inhibition of spontaneous discharge. In old rats the NE-induced potentiation of both excitatory and inhibitory responses was significantly diminished. The loss of noradrenergic enhancement of the relative responsiveness of Purkinje neurons to afferent inputs in senescent animals may relate to behavioral deficits seen in aging.

Action Potentials↗
PubMed1984

Adrenergic transmission in hippocampus-locus coeruleus double grafts in oculo: demonstration by in vivo electrochemical detection.

In vivo electrochemical detection was used to study transmitter release from a synaptically or pharmacologically stimulated noradrenergic isolated pathway formed by double in oculo brain tissue grafts. Retinal illumination, which activates cholinergic nerve fibers that grow into intraocular grafts from the autonomic ground plexus of the iris, produced increases in the concentration of electroactive species in the hippocampal portion of intraocular locus coeruleus-hippocampus double grafts. This response was potentiated after cholinesterase inhibition, and mimicked by perfusion of carbachol, a muscarinic agonist. Much smaller increases in the electroactive species were measured in reserpinized animals, and this minimal response was completely eliminated by the subsequent inhibition of catecholamine synthesis with alpha-methyl-p-tyrosine. Taken together, the data suggest that synaptically released transmitter in these isolated brain circuits can be measured using in vivo electrochemical detection techniques, and lend further support to the hypothesis that in oculo locus coeruleus grafts develop a functional catecholaminergic input to sequentially grafted hippocampus.

Animals↗
PubMed1984

Effects of the selective noradrenergic neurotoxin DSP4 on cerebellar Purkinje neuron electrophysiology.

The effect of the adrenergic neurotoxin DSP4 on cerebellar electrophysiology was studied in the rat. DSP4, administered parenterally, depleted cerebellar norepinephrine by 76%. The depressant response of cerebellar Purkinje neurons to phencyclidine, a drug which acts on adrenergic presynaptic terminals to release NE, was markedly reduced after DSP4 pretreatment. In contrast with 6OHDA, which increased firing rates of the Purkinje cells, DSP4 did not change the rate or pattern of Purkinje cell discharge. Taken together these results suggest that DSP4 may be a valuable tool for studying central adrenergic pathways, but that this drug has properties which differ from 6OHDA.

Amines↗
PubMed1984

Neonatal cerebellectomy alters ethanol-induced sleep time of short sleep but not long sleep mice.

The effects of neonatal cerebellectomy on ethanol-induced sleep times in long sleep (LS) and short sleep (SS) mice were investigated. Cerebellectomy did not alter the ethanol sensitivity of LS animals for loss of righting reflex. In contrast, SS mice became more sensitive to alcohol after cerebellectomy. Even so, large differences were still observed between the alcohol-induced sleep times of cerebellectomized LS and SS mice. The data indicate that, while the cerebellum must have a prominant influence on alcohol sleep time in SS animals, this brain structure is not solely responsible for the observed differences in righting reflex sensitivity to ethanol in these two mouse lines. We postulate the existence of noncerebellar central neurons with differential sensitivities to the depressant effects of ethanol in LS and SS mice.

Animals↗
PubMed1984

Chronic lead exposure of the developing brain: electrophysiological abnormalities of cerebellar Purkinje neurons.

This manuscript reviews our recent research concerning electrophysiological effects of chronic low-level lead exposure on developing brain. We found that, although growth, survival and histological organization of in oculo cerebellar grafts appear normal after perinatal exposure to blood lead levels of 450 to 550 micrograms/liter, the physiological activity of Purkinje neurons in these lead-treated grafts is abnormally low after discontinuation of lead treatment. On the other hand, chronic low-level lead exposure postnatally via systemic injections or perinatally via the drinking water did not alter in situ cerebellar Purkinje cell activity. Moderate systemic doses (2 mg/kg) did cause a persistent slowing of Purkinje neuron firing rates; however, this effect was much smaller than in intraocular cerebellar grafts. The slowing may be mediated by lead actions on various transmitter systems. We have found that chronic lead induces catecholaminergic neurons to hyperinnervate target areas. Perhaps this hyperinnervation is initiated by the postsynaptic lead-induced blockade of the electrophysiological effects of norepinephrine which we have previously observed in the cerebellum in situ and in cerebellar grafts in oculo.

Action Potentials↗
PubMed1984

Presynaptic dopaminergic activity of phencyclidine in rat caudate.

This study tested the hypothesis that phencyclidine (PCP) is an indirect dopamine (DA) agonist in the caudate nucleus. Single caudate neurons in rats anesthetized with urethane were recorded extracellularly with multibarrel micropipettes. Effects of drug solutions, applied by pressure microejection, were measured as changes in spontaneous and evoked neuronal activity. Caudate neurons were classified according to their latency-to-discharge in response to supramaximal cortical stimulation. PCP inhibited the spontaneous activity of 92% of neurons with latencies less than 13 msec, while DA inhibited 87%. Both drugs inhibited evoked activity significantly less than spontaneous activity (P less than .01). Neurons with latencies greater than 13 msec were excited by DA significantly more often (45%) than by PCP (13%; P less than .05). Receptor stereospecificity is suggested by the finding that the (+)-isomer of the 3-methyl piperidine derivative of PCP was significantly more potent than the (-)-isomer for inhibition of spontaneous activity. Mg++, which blocks presynaptic release of neurotransmitter, significantly antagonized inhibitory effects of PCP on spontaneous activity, which suggests a presynaptic effect of PCP. DA, which acts postsynaptically, was much less affected by Mg++. The potency of PCP was significantly less in rats treated with reserpine or 6-hydroxydopamine than in control rats, suggesting the endogenous DA is required for the action of PCP. Fluphenazine and (+)-butaclamol, potent DA-receptor antagonists, blocked the effect of PCP, but (-)-butaclamol did not. These results support the hypothesis that PCP facilitates release and/or inhibits reuptake of DA in nerve terminals and thereby acts as an indirect DA agonist in the caudate. However, there may be a subpopulation of caudate neurons in which PCP acts by a nondopaminergic mechanism.

Animals↗
PubMed1983

Normalization of spiroperidol binding in the denervated rat striatum by homologous grafts of substantia nigra.

Transplantation of embryonic substantia nigra into the adult rat brain decreases the motor asymmetry that is produced by dopamine receptor supersensitivity after a unilateral lesion of the substantia nigra. The authors report that this effect of transplantation is specific to grafts of substantia nigra. They also report that, in conjunction with the decrease in motor asymmetry, these grafts cause postsynaptic dopaminergic binding sites to return to normal density as measured by tritiated spiroperidol autoradiography. Thus, in animals with brain lesions, grafts of substantia nigra produce a long-term alteration in the functional status of host brain cell receptors that is associated with a reduction in the behavioral deficit.

Animals↗
PubMed1983

Postnatal lead exposure alters spontaneous cerebellar Purkinje neuron discharge.

The effects of early postnatal lead administration on the spontaneous activity of cerebellar Purkinje neurons were studied electrophysiologically in adult male Sprague-Dawley rats. Newborn rat litters were divided into three groups and injected daily from Day 1 to Day 20 after birth with 8 mg NaAc/kg, 1 mg PbAc/kg, or 8 mg PbAc/kg intraperitoneally. Purkinje neurons in all three groups showed regular and sustained discharge. However, the mean spontaneous firing rate was significantly lower in the 8-mg PbAc/kg group (26.13 +/- 1.28 Hz) compared to the NaAc controls (32.39 +/- 1.93, P greater than 0.01). Furthermore, the distribution of the firing rates of the Purkinje cells were different in the two groups, with an obvious loss of faster firing cells in the 8-mg PbAc/kg group. No differences were seen between the 1-mg PbAc/kg group and the NaAc controls. As the 8-mg PbAc/kg group weighed significantly less than the NaAc group, malnourished animals were produced by using oversized litters, to control for any changes caused by the lower body weight. However, when compared to concomitantly raised controls, no changes could be seen in Purkinje cell discharge in the malnourished animals. It is concluded that neonatal exposure to lead can cause permanent changes in spontaneous Purkinje cell discharge.

Action Potentials↗
PubMed1983

Survival and growth of neurons with enkephalin-like immunoreactivity in fetal brain areas grafted to the anterior chamber of the eye.

Areas of fetal rat brain and spinal cord known to contain enkephalin-like immunoreactive cell bodies and/or terminal fields were transplanted to the anterior chamber of the eye of adult rats. Enkephalin-like immunoreactive neurons survive and produce an enkephalin-like immunoreactive fiber network within grafts of spinal cord, ventral medulla oblongata, ventrolateral pons, tectum, locus coeruleus, substantia nigra and the areas containing columna fornicis and globus pallidus. Although single intraocular grafts of neocortex do not apparently contain enkephalin-like immunoreactive fibers, such grafts contain a variable amount of sparsely distributed enkephalin-like fibers when sequentially grafted in oculo with either locus coeruleus or spinal cord. Combinations of locus coeruleus and globus pallidus contained a rich enkephalin fiber network in the locus coeruleus part and a sparse innervation of the globus pallidus part. We conclude that enkephalin-like immunoreactive neurons in small areas of fetal rat brain can be successfully transplanted to the anterior chamber of the eye. They are able to survive and develop to maturity in complete isolation from the rest of the brain. In general, the enkephalin-like immunoreactive fiber density in the various single grafts approximated that of their brain counterparts in situ. Fiber formation can be reinitiated in mature enkephalin-like immunoreactive neurons by addition of new brain target areas. Thus, the technique permits establishment of isolated, defined enkephalin systems and pathways accessible to functional analysis.

Animals↗
PubMed1983

Modulatory interactions between enkephalin and catecholamines: anatomical and physiological substrates.

The anatomical and electrophysiological basis of enkephalin-catecholamine interactions was studied in the central nervous system of the Sprague-Dawley rat. Sections of fetal rat brain were treated alternatively with antibodies raised against enkephalin or tyrosine hydroxylase (EC 1.14.16.2). Enkephalinergic fibers were found to innervate almost all brain areas known to contain catecholamine cell bodies or terminal fields. The possible electrophysiological correlates of such an overlap in enkephalin and catecholamine terminal fields was investigated in frontal neocortex. Parenteral administration of antipsychotic agents known to block catecholamine receptors, such as spiroperidol, alpha-flupenthixol, and (+)-butaclamol, reversibly antagonized enkephalin-induced depressions of neuronal activity. The biochemically inactive isomers of these antipsychotics, beta-flupenthixol and (-)-butaclamol, manifested no such activity. Unilateral lesions of the catecholaminergic projections to frontal cortex produced by interstitial injection of 6-hydroxydopamine resulted in an ipsilateral decrease in enkephalin efficacy and in an elimination of the antagonisms of enkephalin depressions by antipsychotic agents. It is hypothesized that catecholamines may act as modulators to augment responsiveness to peptides such as enkephalins.

Animals↗
PubMed1982

The effect of local application of homocysteine on neuronal activity in the central nervous system of the rat.

Homocysteine, a monocarboxylic, sulfur-containing amino acid, produces convulsions in rats and mice when administered systemically. Convulsions and high serum concentrations of homocysteine are among the symptoms that characterize patients with homocystinuria, a hereditary disorder of amino acid metabolism. In order to evaluate the effects of homocysteine on the central nervous system directly, extracellular recordings were made from neurons in rat cerebral cortex, cerebellum and midbrain during local application of homocysteine by pressure ejection or iontophoresis. Both methods of drug delivery produced dose-dependent increases in the activity of neurons in every area tested. Activity was increased by D,L-homocysteine and L-glutamate in 67 percent of cells tested with both drugs. The doses required to produce equivalent excitations in this group of cells were similar, suggesting that homocysteine is at least as potent as glutamate. The excitatory effects of both homocysteine and glutamate were antagonized by local application of betaine, a biological methyl donor which blocks convulsions produced by systemic administration of pentylenetetrazol and electroshock as well as homocysteine. The effects of local application of homocysteine were also blocked by local application of the glutamate antagonist glutamate diethylester (GDEE). In 6 of 7 cells tested, GDEE appeared to preferentially affect homocysteine-induced excitations. These data indicate that homocysteine has an excitatory action on neurons, a finding which may account for some of the symptoms associated with certain disorders of amino acid metabolism.

Animals↗
PubMed1982

Hippocampal noradrenergic responses in vivo and in vitro. Characterization of alpha and beta components.

Pressure ejection of l-norepinephrine (NE) in the in vivo rat hippocampus generally produced depression of pyramidal cell spontaneous activity. In addition, both excitation and biphasic responses were observed. NE-induced inhibition of firing rate was effectively antagonized by concurrent administration of the alpha antagonist phentolamine, but was largely unaltered by the beta antagonist timolol. On the other hand, NE-induced elevation in spontaneous firing rate was effectively blocked by timolol, and largely unaffected by phentolamine. Another beta antagonist, sotalol, did not selectively antagonize either NE-induced inhibition or NE-induced excitation. The beta agonist 2-fluoro-NE produced increases in pyramidal cell firing rates in most cells studied, while the alpha agonist 6-fluoro-NE inhibited the majority of cells examined. The effects of sotalol were also examined on alpha and beta receptor-mediated field responses in the in vitro hippocampal slice. Sotalol was shown to be a selective beta antagonist in this system, blocking excitation evoked by the beta agonist isoproterenol while having no effect on inhibition elicited by the alpha agonist clonidine; however, the potency of sotalol (Ki = 3.5 microM) was considerably less than that of timolol (Ki = 50 nM). Taken together, these results suggest that NE-induced depression and elevation in hippocampal pyramidal cell spontaneous discharge in vivo are mediated via alpha and beta adrenoceptors, respectively.

Animals↗
PubMed1982

Interactions between phencyclidine and cholinergic excitation of hippocampal pyramidal neurons.

The interaction between phencyclidine and acetylcholine-evoked responses of hippocampal pyramidal neurons was investigated in normal and catecholamine-depleted rats. Phencyclidine antagonized the acetylcholine-induced excitations in both preparations. However, in the majority of cases, this effect was observed only at doses of phencyclidine which also manifested nonspecific membrane stabilization. In contrast, phencyclidine-induced decreases in firing rate, which have been shown to be mediated by catecholamines, occurred at doses of phencyclidine which do not cause local anesthesia. Taken together, these data suggest that the catecholaminergically-mediated effects of phencyclidine may be more important in the hippocampus.

Acetylcholine↗
PubMed1982

Noradrenergic responses in rat hippocampus: electrophysiological actions of direct- and indirect-acting sympathomimetics in the in vitro slice.

The effects of perfusion of postulated direct- and indirect-acting sympathomimetics on evoked potentials in the CA1 region of the in vitro rat hippocampus were examined. A selective alpha agonist, 6-fluoronorepinephrine, produced depressions of population spike amplitude which were antagonized by the alpha antagonist phentolamine, but not by the beta antagonist timolol. The selective beta agonist, 2-fluoronorepinephrine, produced increases in population spike amplitude which were antagonized by timolol but not by phentolamine. Weak and variable responses were seen to the indirect-acting sympathomimetic tyramine, with lower doses producing increases and higher doses producing decreases in population spike amplitude, respectively. As with 2-fluoronorepinephrine, increases in spike amplitude elicited by tyramine were blocked by timolol but not by phentolamine. Another indirect-acting sympathomimetic, d-amphetamine, produced only increases in population spike amplitude which were blocked by timolol. Phencyclidine, an agent which may produce some of its central effects via noradrenergic synapses, was virtually ineffective in producing catecholamine-like responses in this system. Only nonspecific, local anesthetic effects were observed. Taken together with previous studies, these results support the hypothesis that activation of alpha and beta receptors decreases and increases, respectively, pyramidal cell excitability. Furthermore, although both alpha and beta receptors appear to be capable of interacting with endogenously released norepinephrine, the beta response may predominate.

Action Potentials↗