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I S Hoffmann

Publications and source records attributed to I S Hoffmann.

33 records · Page 2Linked to original sources
PubMed1989

Differential effects of phorbol ester on prefrontal cortex and striatal dopamine terminals: dependence on rate and duration of stimulation.

Compared to the nigrostriatal dopamine (DA) neurons, the mesocortical DA neurons projecting to the prefrontal cortex (PFC) are able to sustain higher levels of release when driven at high stimulation frequencies. The effect of a well known activator of protein kinase C (PKC), 4-beta-phorbol-12, 13-dibutyrate (PDBu), were compared on PFC and striatal DA terminals. DA release was monitored from slices of the rabbit PFC and striatum obtained from the same animal. The PKC activator, PDBu (30-1000 nM) enhanced the stimulation-evoked release (SER) of DA from PFC and striatum. The magnitude of the facilitation of DA release produced by PDBu was much greater from the PFC than from the striatum. In the striatum, PDBu produced a bell-shaped dose-response curve, i.e., 0.03 and 1 microM PDBu enhanced SER of DA by 25%, whereas 0.1 and 0.3 microM PDBu enhanced DA release by 60 and 100%, respectively (1 Hz, 120 pulses). In the PFC, 0.03 microM enhanced the SER of DA by 70% and 1 microM by 250% (1 Hz, 120 pulses). In addition, in the PFC, PDBu enhance the basal release of DA (+65% at 1 microM); this effect was not seen in the striatum. The inactive isomer, 4-alpha-phorbol-12, 13-dibutyrate (0.03-1 microM) failed to increase the SER and the basal release of DA from PFC or striatum. The SER of DA was dependent on the rate and duration of stimulation. However, under all conditions of stimulation studied DA release from PFC was always greater than from the striatum.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Sustained high release at rapid stimulation rates and reduced functional autoreceptors characterize prefrontal cortex dopamine terminals.

The release of dopamine (DA) from mesocortical and nigrostriatal nerve terminal fields, as well as its modulation by auto- and heteroreceptors was investigated. Rabbit brain slices obtained from medial prefrontal cortex (PFC) and nucleus caudate (striatum) were prelabeled with [3H]DA in the presence of 0.3 microM desipramine. Neuronal depolarization was elicited by electrical stimulation. Higher stimulation-evoked overflow of [3H]DA (release) was observed from PFC than from striatal slices. At 0.3 Hz (120 pulses) release from the PFC was 60% higher than from the striatum, and at higher frequencies (10 Hz and 120 or 1200 pulses) the fraction of tissue radioactivity released from the PFC was 550% greater than that released from the striatum. These differences were not eliminated by blockade of autoreceptors with haloperidol, or by inhibition of neuronal uptake with nomifensine. These results suggest that the coupling between neuronal depolarization and DA release is more efficient in the PFC than in the striatum. This may allow the PFC terminals to sustain neurotransmission under continuous fast firing. Selective D2 agonists, as well as nonselective DA agonists, inhibited DA release in a concentration-dependent fashion from the PFC and the striatum. Their effects were blocked by l-sulpiride or haloperidol. SKF 38393, a selective D1 agonist, produced a small facilitation of release from both regions; its effects were blocked by SCH 23390 (a selective D1 antagonist). The latter was ineffective on its own. The maximal degree of inhibition of release produced by apomorphine, bromocriptine and LY-171555 was lower in the PFC than in the striatum; these differences were accentuated greatly at high stimulation rates. When the slices were stimulated at frequencies comparable to the "in vivo" firing rates for each neuronal group, apomorphine and LY-171555 were much weaker in inhibiting DA release from the PFC (10 Hz) than from the striatum (3 Hz). In the striatum, strong modulation of DA release by endogenous DA was observed; whereas little modulation was seen in the PFC. Nomifensine produced larger increases in the stimulation-evoked overflow of DA from PFC and there was no synergistic interaction between nomifensine and haloperidol in this structure. In the striatum, marked facilitation of DA overflow was observed when nomifensine and haloperidol were given together. Furthermore, haloperidol per se facilitated DA release from both brain regions; however, the degree of facilitation was frequency dependent in the striatum, but not in the PFC.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Effects of propranolol, clonidine and hydrochlorothiazide treatment and abrupt discontinuation on central and peripheral noradrenergic activity in essential hypertension.

This study was undertaken to investigate further the CNS actions of commonly employed antihypertensive drugs. Measurements of cerebrospinal fluid (CSF) and plasma catecholamines (CA) were made in an attempt to estimate the activity of central and peripheral noradrenergic neurons during treatment with or after abrupt discontinuation of treatment with clonidine (CLO), propranolol (PRO), hydrochlorothiazide (HCTZ) or placebo, in patients with essential hypertension. A randomized, parallel, placebo-controlled, single-blind design was employed. BP reductions equal to or greater than 10 mmHg were observed with CLO (0.36 +/- 0.07 mg daily), PRO (160 mg +/- 0 mg daily) or HCTZ (70 +/- 12 mg daily). CLO reduced plasma norepinephrine (NE) by 64% and PRO increased it by 25%. Neither HCTZ nor placebo modified plasma NE. Plasma renin activity (PRA) was reduced by PRO (51%, P less than 0.01) and CLO (35%, P less than 0.05). CSF-NE levels (pg/ml) were significantly lower in the CLO group (CLO: 175 +/- 23; PRO: 278 +/- 35; HCTZ: 255 +/- 34; placebo: 203 +/- 7).

Adrenergic Fibers↗
PubMed1986

Dopamine autoreceptors modulate dopamine release from the prefrontal cortex.

Electrical stimulation (at 0.3, 1, or 10 Hz, 120 pulses each) produced a calcium-dependent overflow of radioactivity from slices of the rabbit prefrontal cortex preloaded with [3H]3,4-dihydroxyphenylethylamine ([3H]DA, [3H]dopamine) in the presence of desipramine. Flat frequency-release curves were observed. Apomorphine and LY-171555 inhibited in a concentration-dependent fashion the evoked overflow of DA, an effect antagonized by haloperidol. Stimulation frequencies comparable to normal firing rates of mesocortical neurons (10 Hz) drastically reduced apomorphine-induced inhibition of DA overflow. Haloperidol produced greater facilitation of DA overflow at 10 than at 1 Hz. Nomifensine, a neuronal uptake inhibitor, enhanced DA overflow. These results indicate that mesocortical DA neurons projecting to the prefrontal cortex have release modulatory autoreceptors of the D2 subtype.

Animals↗
PubMed1986

Interactions between endogenous dopamine and dopamine agonists at release modulatory receptors: multiple effects of neuronal uptake inhibitors on transmitter release.

The authors investigated the mechanisms by which inhibitors of the neuronal uptake (NUI) of dopamine (DA) and prolonged stimulations at high rates antagonize the inhibition of acetylcholine (ACh) release from rabbit striatal slices produced by DA receptor agonists. Nomifensine (1 microM) reduced the potency and efficacy of apomorphine (APO) in inhibiting the evoked release of ACh (0.3 Hz, 39 pulses) (noncompetitive kinetics). Highest inhibitory potency and efficacy of APO were obtained at 0.3 Hz and 39 pulses. Increases in stimulation rates and number of pulses (3 Hz and 120 pulses) reduced APO potency and efficacy for inhibition of ACh release (noncompetitive kinetics). At 10 Hz and 500 pulses APO efficacy was further reduced, and the APO concentration-effect curve was biphasic. Inhibition of DA and ACh release produced by other DA receptors agonists such as bromocriptine, piribedil and LY-171555 was also reduced by prolonged stimulations at high frequencies. Depletion of endogenous DA stores by reserpine pretreatment abolished the antagonism of APO produced by NUI and reduced considerably the antagonism produced by high pulses and high rates of stimulation of APO- and LY-171555-induced inhibition of ACh release. However, even after combined pretreatment with reserpine and alpha-methylparatyrosine, the potency and efficacy of APO in inhibiting ACh release at 10 Hz and 500 pulses were less than the values obtained in 0.3 Hz and 39 pulses and at 3 Hz and 120 pulses. The biphasic nature of the APO concentration-effect curve at 10 Hz and 500 pulses was no longer present after reserpine. Interestingly, reserpine pretreatment failed to modify APO-induced inhibition of ACh release at 0.3 Hz and 39 pulses, suggesting that the sensitivity of the DA release modulatory receptors was not affected by the pretreatment. These results indicate that the high synaptic concentration of DA achieved at low stimulation rates in the presence of NUI and at high stimulation rates reduces the potency and efficacy of DA agonists in inhibiting ACh release. However, for prolonged stimulations at high rates not all of the changes seen with DA agonists are mediated by endogenous DA. At high concentrations (10 microM), cocaine and nomifensine inhibited the evoked release of ACh even after depletion of tissue DA stores by reserpine in the absence or presence of a alpha-methylparatyrosine.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗
PubMed1984

Clonidine reduces elevated cerebrospinal fluid catecholamine levels in patients with essential hypertension.

Cerebrospinal fluid (CSF) catecholamines were measured in normotensive patients and in patients with mild to moderate essential hypertension. CSF-norepinephrine (NE) concentrations were 50% lower in the normotensive individuals (127 +/- 28 vs. 240 +/- 23 pg/ml) (P less than 0.01). In hypertensive patients, CSF-NE was inversely related to age (r = -0.68; P less than 0.01) and directly related to plasma NE (r = 0.61; P less than 0.05). Clonidine (450 mcg/day for 2 weeks) significantly reduced CSF-NE (-40%) in hypertensive patients. In addition, it decreased blood pressure, plasma and urinary NE. Urinary VMA was not affected by clonidine. No correlation was observed between clonidine effects on BP and on plasma or CSF catecholamines. This study indicates that patients with essential hypertension have elevated levels of CSF-NE which are reduced after treatment with clonidine. The elevation of CSF-NE suggests that central (spinal?) noradrenergic activity may be increased in patients with mild to moderate essential hypertension, and that can be reduced by treatment with clonidine.

Adult↗
PubMed1984

Differential effects of bromocriptine on dopamine and acetylcholine release modulatory receptors.

Rabbit neostriatal slices were prelabeled with [3H]dopamine (DA) and [14C]choline and then superfused. The electrical stimulation-evoked release of DA and of acetylcholine (ACh) was abolished by 0.33 microM tetrodotoxin and by low calcium concentrations (0.13 mM). Bromocriptine, a selective D2-DA receptor agonist, inhibited in a concentration-dependent manner the evoked overflow of DA and ACh, without affecting the basal efflux of both transmitters. The effects of bromocriptine were antagonized by sulpiride, a specific antagonist of D2-DA receptors. With stimulation at 0.3 Hz and 120 pulses, bromocriptine was eight times more potent in inhibiting the evoked overflow of DA (IC50: 11 nM) than that of ACh (IC50: 83 nM). Stimulations at 3 Hz and 360 pulses markedly reduced the potency of bromocriptine in inhibiting DA and ACh release, and diminished its selectivity for presynaptic receptors. These results indicate that DA receptors that modulate the release of DA and ACh are of the D2 subtype. The greater potency of bromocriptine at pre- than at postsynaptic sites suggests that these receptors may be different in quantity and/or quality [D2-alpha (presynaptic) versus D2-beta (postsynaptic)]. Finally, marked differences in the potency and efficacy of DA agonist actions on DA and ACh release modulatory receptors are obtained, depending on the parameters of stimulation used.

Acetylcholine↗
PubMed1983

Frequency-dependent release of acetylcholine and dopamine from rabbit striatum: its modulation by dopaminergic receptors.

The release of [3H]dopamine (DA) and [14C]acetylcholine (ACh) was monitored from single slices of the rabbit striatum. In all cases, the evoked overflow of ACh showed a higher peak and was of shorter duration than that of 3H products. For ACh, the release per pulse showed a marked decline with increasing frequency of stimulation, whereas flat frequency-release curves were obtained for DA. At 0.1 and 1 Hz the evoked overflows of ACh were 15 and 7 times greater, respectively, than those of DA. Haloperidol (0.03 microM) and sulpiride (1 microM) produced large increases in the evoked overflow of DA and ACh at 3 and 10 Hz; little effect was observed at lower frequencies. These results indicate that the frequency-release curves for DA and ACh are different and that at high frequencies the slope of the curves is modified by activation of pre- and postsynaptic DA receptors. Apomorphine inhibited in a concentration-dependent fashion the evoked overflow of DA and ACh; greater inhibition was obtained at lower frequencies of stimulation. At 0.3 Hz the DA agonist was two times more potent in inhibiting DA than ACh overflow (IC50: 12.0 +/- 2.2 versus 22.0 +/- 2.8 nM; p less than 0.01). The greater sensitivity of pre- than postsynaptic sites to apomorphine was also seen at higher frequencies (3 Hz). Benztropine (1 microM) reduced the evoked overflow of ACh at 10 Hz, and enhanced that of 3H products at all rates of stimulation (0.3-10 Hz). These results suggest that the release of DA and ACh is regulated by dopaminergic receptors. They also indicate that the effects of DA agonists and antagonists and of uptake inhibitors on DA and ACh release are highly dependent on the frequency of stimulation used.

Acetylcholine↗
PubMed1983

Changes in the sensitivity to apomorphine of dopamine receptors modulating dopamine and acetylcholine release after chronic treatment with bromocriptine or haloperidol.

The release of dopamine (DA) and of acetylcholine (ACh) was monitored from rabbit striatal slices labeled with [3H]DA and [14C]choline. Chronic treatment with haloperidol (1 mg/kg b. wt. for 28 days, sacrifice 96 hr after last injection) increased the potency of in vitro apomorphine in inhibiting the release of DA and ACh evoked by electrical stimulation when compared to vehicle-treated rabbits. Potentiation of apomorphine effects was greater on DA than on ACh release. The effects of in vitro haloperidol on DA and ACh release and in antagonizing the inhibitory effects of apomorphine were not modified by chronic treatment with haloperidol. Bromocriptine (1.5 mg/kg b.wt. for 7 days, sacrifice 72 hr after last injection) did not affect the evoked release of DA and of ACh, or the sensitivity to apomorphine. However, 15 mg/kg b.wt. of bromocriptine for 7 days and sacrifice 72 hr after last injection, produced a 60 to 70% reduction in the evoked release of DA and ACh, and markedly antagonized the inhibition of DA and ACh release produced by apomorphine. These results indicate that the DA receptors which modulate the release of DA and of ACh play an important physiological role inasmuch as they develop adaptational changes after prolonged receptor activation or inhibition by DA agonists and antagonists, respectively. These adaptational changes affect the potency of DA agonists on release modulatory receptors without modifying that of DA antagonists. The possibility that bromocriptine has a residual agonistic effect on striatal DA receptors 3 days after the last injection cannot be ruled out.

Acetylcholine↗
PubMed1982

Rate and duration of stimulation determine presynaptic effects of haloperidol on dopaminergic neurons.

Superfused rabbit neostriatal slices prelabeled with [3H]dopamine ([3H]DA) were polarized with electrical pulses (12 V, 1 ms). Although transmitter release showed a proportional increase with a greater number of pulses (30-360 pulses), flat frequency-release curves were obtained. Haloperidol (0.03-0.3 micro M) enhanced 3H overflow without affecting its metabolism or time course, and antagonized apomorphine-induced inhibition of transmitter release. Maximal enhancement of release by haloperidol was obtained with 30-60 pulses delivered at a rate of 3 Hz, whereas much less facilitation of release was seen at 0.3 and 1 Hz (30-90 pulses) or with 360 pulses at either of the three frequencies. Therefore, the slope of the frequency-release curve was markedly increased by haloperidol. These results indicate that activation of presynaptic DA receptors, and thus facilitation of release by haloperidol was highly dependent on the rate and duration of stimulation of striatal dopaminergic terminals. In these neurons the feedback loop seems to act physiologically to depress the slope of the frequency-release curve.

Animals↗
PubMed1980

Presynaptic effects of 2-aminotetralins on striatal dopaminergic neurons.

The present study evaluated whether 2-amino-5,6-dihydroxy-1,2,3,4,-tetrahydronaphthalene (A-5,6 DTN) and its 6,7-dihydroxy isomer (A-6,7 DTN) had effects on striatal dopaminergic terminals in addition to their well known action as agonists on postsynaptic dopamine (DA)-receptors. The presynaptic effects of 2-aminotetralins were evaluated on rat striatal tissue slices prelabeled with [3H]DA. Both, A-5,6 and A-6,7 DTN enhanced the basal efflux of radioactive products in a concentration-dependent fashion. Benztropine (1 microM) antagonized the releasing effects of low concentrations of both drugs (0.1-3.0 microM). Apomorphine and A-5,6 DTN (alpha rotamers, trans conformation) were 3 to 5 times more potent than A-6,7 DTN (beta rotamer, trans conformation) in inhibiting rat striatal monamine oxidase. This effect could account for the 50-fold greater potency of A-6,7 than A-5,6 DTN in enhancing the efflux of [3H]dihydroxyphenylacetic acid. A-5,6 DTN, A-6,7 DTN and apomorphine (0.3 microM each), reduced by 30% the depolarization elicited overflow of radioactive products. In summary, A-5,6 and A-6,7 DTN seem to enter DA-terminals and storage vesicles to accelerate the efflux of [3H]DA and 3H-dihydroxyphenylacetic acid and act upon presynapatic receptors to inhibit transmitter release. A greater selectivity for monamine oxidase inhibition was found with the alpha rotameric agents. The present study indicates that A-5,6 and A-6,7 DTN have marked presynaptic effects on rat striatal DA-containing neurons in addition to their well known effects as agonists on postsynaptic DA receptors.

2-Naphthylamine↗