Facilitation of brain stimulation reward by mesencephalic injections of neurotensin-(1-13).

The effects on brain stimulation reward of neurotensin-(1-13) microinjected at different concentrations (2.5, 5, 10 and 20 micrograms/0.5 microliters) into the ventral mesencephalic region containing mesocorticolimbic dopamine neurons were tested in 12 male rats. Neurotensin lowered the stimulation frequency required to sustain threshold levels of responding for brain stimulation reward, suggesting that this neuropeptide is involved in modulating the activity of dopamine neurons that mediate behaviors motivated by positive reinforces. The magnitude of the facilitatory effect of neurotensin on brain stimulation reward was dependent on the concentration injected and to a significant extent also on whether the peptide was administered in an ascending or a descending order of concentration. The different effects of neurotensin depending on the order of administration may suggest long-lasting effects on the responsiveness of neurotensin receptors in this region after injection of high concentrations of the peptide. Subsequent injection of morphine (2.5-5 micrograms/0.5 microliter) into the same site produced a weaker facilitation of brain stimulation reward than expected, suggesting that local damage after multiple central injections or prior injections of neurotensin itself reduced the responsiveness of dopamine neurons to opiates. Taken together, the results are consistent with data indicating that activation of neurotensin receptors in the ventral mesencephalon stimulates dopamine cell firing and axonal dopamine release in limbic terminal fields and suggest that endogenous neurotensin is involved in the control of behavior motivated by positive reinforcement.     

Neurochemical investigations in vitro with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in preparations of rat brain

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in concentrations ranging from 10(-8) M to 10(-6) M induced a decrease, and at 10(-5) M an increase of both basal and electrically evoked tritium outflow from [3H]dopamine-prelabeled rat striatal slices. These effects of MPTP were almost abolished in the presence of nomifensine. Chromatographic separation of the released tritium compounds revealed that the decrease of tritium outflow was mostly due to a decrease in the outflow of the dopamine metabolite [3H]3,4-dihydroxyphenylacetic acid (DOPAC) and the increase of tritium outflow due to a massive release of [3H]dopamine. MPTP inhibited oxidative deamination of [3H]dopamine non-competitively in a crude mitochondrial preparation of rat brain, with an apparent Ki value of 4.5 microM. No relevant effect of MPTP on adenylate cyclase activity in homogenates and on basal and electrically evoked tritium outflow from [3H]choline-prelabeled slices of rat striatum could be detected. In contrast, MPTP facilitated both basal and electrically evoked tritium outflow from [3H]noradrenaline-prelabeled rat cerebral occipital cortex slices. Furthermore, MPTP counteracted the inhibitory effect of clonidine on evoked tritium outflow from rat cerebral occipital cortex slices. Moreover, in the presence of cocaine, the effect on basal, but not that on electrically evoked tritium outflow was attenuated. These results are compatible with the view that MPTP has no affinity to dopamine receptors but is preferentially taken up into dopaminergic nerve terminals by the nomifensine-sensitive uptake system where it reaches a concentration sufficient to inhibit intraneuronal monoamine oxidase (MAO). In contrast, the facilitatory effect of MPTP on evoked tritium outflow from [3H]noradrenaline prelabeled rat cerebral occipital cortex slices appears to result from antagonistic effects at presynaptic alpha 2-adrenoceptors. The observation that MPTP at lower concentrations (10(-8) to 10(-7) M) inhibits basal tritium outflow from rat cerebral occipital cortex slices suggests that this compound inhibits also intraneuronal deamination of noradrenaline by MAO in noradrenergic nerve terminals.     

Release of endogenous dopamine from rat isolated striatum: effect of clorgyline and (-)-deprenyl

High performance liquid chromatography with electrochemical detection was used to measure the release and content of dopamine and dihydroxyphenylacetic acid (DOPAC) from rat isolated striatum. The effects of the monoamine oxidase (MAO) inhibitors clorgyline and (-)-deprenyl on dopamine and DOPAC release and contents, and the IC50 values of these compounds for inhibition of dopamine deamination in rat striatum were determined. Dopamine release was significantly increased by elevated KCl (22 mM) in a Ca2+-dependent manner, and by ouabain (20 muM), whereas the release of DOPAC remained constant. The loss in striatal dopamine content during the incubation period (67% of initial content) was far greater than the amount of dopamine recovered in the incubation fluid (16% of initial content), suggesting that much of the DOPAC, released during incubation originated from the conversion of dopamine to DOPAC within the striatum. A concentration-dependent decrease in DOPAC efflux, both during rest and stimulation periods, was observed in the presence of clorgyline (10(-8)M-10(-7)M) and (-)-deprenyl (10(-5)M-10(-4)M). Higher concentrations of clorgyline (10(-7)M) and (-)-deprenyl (10(-4)M), which inhibited dopamine deamination by 85-90%, enhanced both the resting and KCl-induced release of dopamine. The total amount of dopamine plus DOPAC that was released in the presence of clorgyline or (-)-deprenyl did not differ from control values, suggesting that the increase in dopamine release elicited by MAO inhibitors might result from reduced degradation of dopamine to DOPAC.(ABSTRACT TRUNCATED AT 250 WORDS)     

The relationship between nerve terminal adenosine triphosphatases and neurotransmitter release: as determined by the use of antidepressant and other CNS-active drugs.

1 The role of adenosine triphosphatases (ATPases) in neurotransmitter release was studied using nerve terminals (synaptosomes) prepared from rat cerebral cortex as a model. 2 Amitriptyline, nortriptyline, protriptyline, desipramine and imipramine were found to inhibit ATPases at concentrations of 10(-5) M and above. The drugs inhibited both the basal and electrically evoked release of acetylcholine (ACh) and noradrenaline (NA) at concentrations of 10(-4) M and above. 3 At low concentrations of antidepressants (10(-8) and 10(-7) M) release of NA was enhanced but there was no effect on ACh release. 4 Other drugs which inhibit Na+, K+-ATPase increase basal NA release as did drugs which inhibited vesicular MG2+-ATPase. 5 A model is proposed suggesting that transmitter release/re-uptake depends on (1) active Na+, K+-ATPase at the presynaptic membrane and (2) an active synaptic vesicular MG2+-ATPase.     

Stereoisomers of apomorphine differ in affinity and intrinsic activity at presynaptic dopamine receptors modulating [3H]dopamine and [3H]acetylcholine release in slices of cat caudate

We investigated the effects of R(?)-apomorphine and S(+)-apomorphine on dopamine receptors modulating electrically evoked [³H]dopamine and [³H]acetylcholine release from slices of cat caudate nucleus. R(?)-Apomorphine inhibited the release of both [³H]dopamine and [³H]acetylcholine with an IC₅₀ of 20 nM, while S(+)-apomorphine was without inhibitory action on the electrically evoked release of either neurotransmitter at concentrations up to 1 μM. At a concentration of 1 μM, however, S(+)-apomorphine antagonized the inhibition by R(?)-apomorphine, producing a parallel five-fold shift to the right in the concentration-response curve to R(?)-apomorphine. These results indicate that S(+)-apomorphine is devoid of intrinsic activity to stimulate presynaptic dopamine receptors modulating the electrically evoked release of dopamine and acetylcholine. In addition, S(+)-apomorphine has an approximately ten-fold lower affinity for presynaptic dopamine receptors compared to R(?)-apomorphine.     

Phenoxybenzamine blocks dopamine autoreceptors irreversibly: Implications for multiple dopamine receptor hypotheses

Phenoxybenzamine in μM concentrations increased the electrically evoked overflow of recently taken up [³H]dopamine from superfused slices of cat caudate nucleus, an effect which is also observed for dopamine receptor antagonists. The magnitude of the increase in electrically evoked [³H]dopamine release caused by 1 μM phenoxybenzamine was equal to that elicited by maximally effective concentrations of the specific dopamine receptor antagonist, S-sulpiride. Phenoxybenzamine (1 μM) completely antagonized the inhibition of [³H]dopamine release caused by the dopamine receptor agonist pergolide (10 nM). The α-adrenoceptor antagonist phentolamine (1 μM) had no effect on the electrically evoked overflow of [³H]dopamine, ruling out the possibility that the effect of phenoxybenzamine could be attributed to α-adrenoceptor blockade. A 20 min exposure to 1 μM phenoxybenzamine increased the electrically evoked [³H]dopamine overflow even after the tissue had been washed for two and a half hours. When the caudate slices were exposed for 30 min to the reversible dopamine receptor antagonist S-sulpiride (1 μM) and washed for two and a half hours, no similar increase in stimulation-evoked [³H]dopamine overflow was observed. When sulpiride (1 μM) was present during the exposure to phenoxybenzamine (1 μM), no increase in electrically evoked [³H]dopamine overflow was observed after the washout period. Thus phenoxybenzamine at 1 μM appears to block irreversibly the dopamine autoreceptor in the caudate nucleus. Phenoxybenzamine has been previously reported to block irreversibly dopamine-stimulated adenylate cyclase (D₁) and neuroleptic receptor binding (D₂). The present demonstration that phenoxybenzamine also blocks the dopamine autoreceptor irreversibly thus supports the view that all currently well-established dopamine receptors are sensitive to phenoxybenzamine.     

Influence of nitric oxide donors and of the alpha(2)-agonist UK-14,304 on acetylcholine release in the pig gastric fundus

This study in circular muscle strips of the pig gastric fundus aimed to measure the release of acetylcholine directly and to investigate whether NO and alpha(2)-adrenoceptor agonists can modulate acetylcholine release from cholinergic neurones. After incubation of the tissues with [(3)H]-choline, basal and electrically induced release of tritium and [(3)H]-acetylcholine were analyzed in a medium containing physostigmine (10(-5) M) as well as atropine (10(-6) M). The NO synthase inhibitor L-N(G)-nitroarginine methyl ester (3x10(-4) M), and the NO donors sodium nitroprusside (10(-5) M) and 3-morpholino-sydnonimine (10(-5) M) did not influence the basal release nor the electrically evoked release, indicating that NO does not modify [(3)H]-acetylcholine release. The alpha(2)-adrenoceptor agonist UK-14,304 (10(-5) M) significantly inhibited the electrically evoked release of [(3)H]-acetylcholine, and this effect was prevented by the alpha(2)-adrenoceptor antagonist rauwolscine (2x10(-6) M), suggesting that presynaptic alpha(2)-adrenoceptors are present on cholinergic neurones of the pig gastric fundus.     

Cardiovascular effects of neurotensin and some analogues on rats

When administered in vivo into the femoral vein of normotensive rats, neurotensin, neurotensin-(8-13), and [D-Lys8]neurotensin-(8-13) decreased diastolic blood pressure in a dose-dependent manner, without change in heart rate. All three peptides evoked tachyphylaxis and a triphasic depressor-pressor-depressor, response at higher doses. The rank order of potency was neurotensin greater than [D-Lys8]neurotensin-(8-13) greater than neurotensin-(8-13). In organ chamber experiments, both neurotensin and neurotensin-(8-13) at a range of concentrations which induced dose-dependent decreases in blood pressure, did not significantly change tension in rat aorta rings with or without endothelium. In contrast, [D-Lys8]neurotensin-(8-13) induced weak dose-dependent relaxation of both rings with or without endothelium. However, this effect was not obtained at concentrations able to decrease the blood pressure. Indomethacin did not change the vasodilator effect of [D-Lys8]neurotensin-(8-13). There was no correlation between the vasodilator effect of this peptide and its ability to decrease blood pressure. These experiments suggest that the hypotension was not due to a direct vasodilator effect on the smooth muscle. In addition, since the rank order of peptide potency was opposite of those found in previous studies of second messenger synthesis and binding to neural tissue, these data suggest that there is a second receptor for neurotensin or that neurotensin can also bind to a different unknown receptor.     

Effects of neurotensin on midbrain dopamine neuronal activity

The effects of acute intracerebroventricular administration of the tridecapeptide, neurotensin, and a pseudopeptide analog of neurotensin-(8-13) were compared to the effects of haloperidol and clozapine on the spontaneous activity of dopamine cells in both the ventral tegmental area (A10) and the substantia nigra compacta (A9). Unlike the typical antipsychotic haloperidol, which causes a non-selective increase in both A9 and A10 cell activity, both neurotensin and a neurotensin analog, H-Lys (CH₂NH)Lys-Pro-Tyr-lle-Leu-OH, in like manner to clozapine, at low doses selectively increase the number of spontaneously active A10 dopamine cells. These data provide the first in vivo evidence that acute administration of neurotensin can produce changes in spontaneous activity of midbrain dopamine cells similar to the atypical antipsychotic, clozapine.     

Modulation of (–)-sulpiride-induced increase in electrically-evoked release of dopamine from rat striatal slices

Abstract— (–)-Sulpiride (10 Nm -10 μm ) in the superfusate, dose-dependently increased the electrically-evoked release of dopamine from rat striatal slices. (+)-Sulpiride had little effect on evoked release of dopamine up to 10 μm . Apomorphine inhibited electrically evoked release of dopamine, and this effect of apomorphine was antagonized by (–)-sulpiride. SCH23390 and forskolin had no effect on the (–)-sulpiride-induced increase in evoked release of dopamine. Treatment with the irreversible dopamine-receptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline caused a significant increase in evoked release of dopamine and prevented the (–)-sulpiride-induced increase in the evoked release of dopamine. These results indicate that the (–)-sulpiride-induced increase in evoked release of dopamine is due to antagonism of the activation of dopamine autoreceptors by endogenously released dopamine.     

(-)1-(Benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain

1. The brain constituents beta-phenylethylamine (PEA) and tryptamine enhance the impulse propagation mediated transmitter release (exocytosis) from the catecholaminergic and serotoninergic neurons in the brain ('catecholaminergic/serotoninergic activity enhancer, CAE/SAE, effect'). (-)Deprenyl (Selegiline) and (-)1-phenyl-2-propylaminopentane [(-)PPAP] are amphetamine derived CAE substances devoid of the catecholamine releasing property. 2. By changing the aromatic ring in PPAP we developed highly potent and selective CAE/SAE substances, structurally unrelated to the amphetamines. Out of 65 newly synthetized compounds, a tryptamine derived structure, (-)1-(benzofuran-2-yl)-2-propylaminopentane [(-)BPAP] was selected as a potential follower of (-)deprenyl in the clinic and as a reference compound for further analysis of the CAE/SAE mechanism in the mammalian brain. 3. (-)BPAP significantly enhanced in 0.18 micromol 1(-1) concentration the impulse propagation mediated release of [(3)H]-noradrenaline and [(3)H]-dopamine and in 36 nmol 1(-1) concentration the release of [(3)H]-serotonin from the isolated brain stem of rats. The amount of catecholamines and serotonin released from isolated discrete rat brain regions (dopamine from the striatum, substantia nigra and tuberculum olfactorium, noradrenaline from the locus coeruleus and serotonin from the raphe) enhanced significantly in the presence of 10(-12) - 10(-14) M (-)BPAP. BPAP protected cultured hippocampal neurons from the neurotoxic effect of beta-amyloid in 10(-14) M concentration. In rats (-)BPAP significantly enhanced the activity of the catecholaminergic and serotoninergic neurons in the brain 30 min after acute injection of 0.1 microg kg(-1) s.c. In the shuttle box, (-)BPAP in rats was about 130 times more potent than (-)deprenyl in antagonizing tetrabenazine induced inhibition of performance.     

Differential effects of nitric oxide donors on basal and electrically evoked release of acetylcholine from guinea-pig myenteric neurones.

1. The effects of the nitric oxide (NO) donors, 3-morpholino-sydnonimine (SIN-1), S-nitroso-N-acetylpenicillamine (SNAP) and sodium nitroprusside on basal and electrically evoked release of [3H]-acetylcholine were studied in myenteric plexus longitudinal muscle preparations of the guinea-pig small intestine preincubated with [3H]-choline. 2. The NO donors concentration-dependently increased basal release of [3H]-acetylcholine. The increase in release was calcium-dependent and was prevented in the presence of tetrodotoxin. Superoxide dismutase (150 u ml-1) potentiated the effect of SIN-1. The selective inhibitor of soluble guanylyl cyclase, 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ, 0.01-1 microM), antagonized the facilitatory effect of SNAP. 8-Bromo cyclic GMP and the cyclic GMP-specific phosphodiesterase inhibitor, zaprinast (both 0.1-1 mM), also enhanced basal [3H]-acetylcholine release. The effect of 10 microM SNAP was significantly enhanced in the presence of zaprinast. 3. The NO donors concentration-dependently inhibited the electrically evoked release of [3H]-acetylcholine, whereas 8-bromo cyclic GMP and zaprinast enhanced the evoked release. The inhibition of acetylcholine release by SNAP was not affected by ODQ (0.01-1 microM). 4. It is concluded that NO stimulates basal acetylcholine release from myenteric neurones through activation of guanylyl cyclase. In addition, NO inhibits the depolarization evoked release of acetylcholine by a presynaptic mechanism unrelated to cyclic GMP. The data imply that NO is not only an inhibitory transmitter to intestinal smooth muscles but also a modulator of cholinergic neurotransmission in the myenteric plexus.     

Antagonistic Effects of OPC-14597, a Novel Antipsychotic Drug,on Quinpirole- and (–)-Sulpiride-induced Changes in Evoked Dopamine Release in Rat Striatal Slices

The effects of a newly synthesized quinolinone derivative, 7-{4-(4-(2,3-dichlorophenyl)-1-piperazinyl) butoxy}-3,4-dihydro-2-(1H)-quinolinone (OPC-14597), a novel antipsychotic drug, on electrically evoked dopamine release in rat striatal slices were investigated. OPC-14597 (0.1–10 μm) had no effect on the dopamine release evoked in the striatal slices. The decrease induced by quinpirole, a dopamine receptor agonist, in evoked dopamine release was attenuated by supervision with OPC-14597 (1 and 10 μm) which by itself had no effect on evoked dopamine release. The increase induced by (–)-sulpiride, a dopamine receptor antagonist, in evoked dopamine release was, moreover, also attenuated by 1 and 10 μm OPC-14597. These findings indicate that OPC-14597 antagonizes both dopamine agonist- and antagonist-induced changes in evoked dopamine release in striatal slices in rats.     

Dopamine receptor mediated inhibition by pergolide of electrically-evoked 3H-dopamine release from striatal slices of cat and rat: Slight effect of ascorbate

Summary The dopamine receptor agonist pergolide inhibited the calcium-dependent, electrically evoked overflow of tritium from slices of the striatum of cat or rat prelabelled with ³H-dopamine. This inhibition of tritium overflow by nanomolar concentrations of pergolide was antagonized by the benzamide neuroleptic S-sulpiride (0.1 M). In millimolar concentrations, l- ascorbate had slight or no effects on this dopamine receptor mediated inhibition, in striatal slices of either the cat or the rat. Since these same concentrations of ascorbate have been reported to completely block the specific binding of ³H-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) and of ³H-apomorphine to presumed dopamine receptors, the present results suggest a dissociation between the characteristics of ³H-ADTN and ³H-apomorphine binding and the dopamine autoreceptor. Previous contradictory results concerning the existence of inhibitory dopamine receptors which modulate depolarization-evoked overflow of dopamine from the striatum of the rat are thus apparently not due to a species difference nor to the use of ascorbate, but rather to differences in experimental conditons.     

Effects of neurotensin on the isolated mouse distal colon

The effects of neurotensin were studied in the isolated mouse distal colon. This peptide had potent stimulatory effects which were of pre- or postjunctional origin according to the concentrations used. At low concentrations (10(-11)-10(-10) M) neurotensin induced neurogenic non-cholinergic contractions which seemed to result from the release of substance P (or substance P-like activity) by enteric excitatory nerves. At higher concentrations (10(-9)-10(-7) M) neurotensin elicited a biphasic effect consisting of transient relaxation rapidly followed by myogenic contraction. The bee venom toxin apamin inhibited the NT-induced relaxation while inhibition of prostaglandin synthesis by indomethacin abolished the contraction phase. All these responses were tightly related to the extracellular Ca2+ concentration. These properties of neurotensin point to a possible role for this peptide as a modulator of colonic motility.     

The contrasting effects of neuroleptics on transmitter release from the nucleus accumbens and corpus striatum

The effects of haloperidol, chlorpromazine and clozapine on transmitter release have been studied by measuring the simultaneous release of dopamine and acetylcholine from tissue slices of nucleus accumbens and striatum in vitro following in vivo drug application, either a single dose or daily for periods of up to 25 days. In the striatum, both single and chronic injections of haloperidol (1 and 2 mg. kg-1) caused a large and significant enhancement (up to 83%) of the K+-evoked release of [3H]acetylcholine synthesized from [3H]choline. In contrast, in the nucleus accumbens, the K+-evoked release of [3H]acetylcholine was not significantly affected by neuroleptics when compared with the controls which received injection of vehicle. Clozapine (50 mg.kg-1) also enhanced the K+-evoked release of [3H]acetylcholine relative to the resting release but the effect was smaller than that with haloperidol or chlorpromazine. The evoked release of preloaded [14C]dopamine from either nucleus accumbens or striatum was unaffected by treatment with haloperidol. However, chlorpromazine (25 mg.kg-1) and clozapine (50 mg.kg-1) significantly enhanced the evoked release of preloaded [14C]dopamine from tissue slices of striatum. A similar but reduced effect of enhancing release was also seen in the nucleus accumbens in response to chlorpromazine. In support of these results, dopamine itself applied in vitro induced an opposite effect to that of the neuroleptics. Thus in the striatum, dopamine (4 x 10(-4) M) markedly reduced the release of [3H]acetylcholine (45%). A smaller inhibition was also seen in the nucleus accumbens (25%).     

Cholinergic action in the nucleus accumbens: modulation of dopamine and acetylcholine release.

The action of oxotremorine and acetylcholine on the release of dopamine and acetylcholine from tissue slices of the rat nucleus accumbens was studied. Oxotremorine significantly enhanced the release of [14C]-dopamine evoked by 34 mMK+ and the EC50 for this action was 1.5 X 10(-7)M. A maximal enhancement (30%) for this effect was reached at 2 X 10(-7)M oxotremorine. A further enhancement of dopamine release occurred at concentrations of oxotremorine greater than 10(-4)M. The action of oxotremorine on [14C]-dopamine release was calcium-dependent and blocked by atropine (10(-4) M) but not mecamylamine (up to 10(-4) M). Oxotremorine affected [3H]-acetylcholine release differentially, inhibiting the K+-evoked release of [3H]-acetylcholine at concentrations greater than 10(-5) M. The IC50 for this process was 4.3 X 10(-5) M. Acetylcholine (8 X 10(-4) M) showed a similar pattern of action to oxotremorine: it enhanced the K+-evoked release of [14C]-dopamine (50%) and inhibited the K+-evoked release of [3H]-acetylcholine (30%). The mechanism of action of oxotremorine on dopamine release is discussed in terms of a presynaptic receptor-mediated process.     

Effect of buflomedil (4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxy phenyl)-1-butanone hydrochloride) on the function of striatal dopaminergic neurons

Effect of buflomedil (4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxy phenyl)-1-butanone hydrochloride) on the release and uptake of dopamine (DA) and the function of DA receptors in the striatum was investigated using male Wistar rats. In vitro addition of buflomedil (10(-5)-10(-8) M) had no effect on the uptake of [3H]-DA in striatal slices. On the other hand, buflomedil (10(-5)-10(-7) M) increased the spontaneous as well as high K+ (30 mM)-evoked releases of [3H]DA from striatal slices. Buflomedil inhibited the bindings of [3H]SCH23390, [3H]spiperone and [3H]apomorphine to striatal D1, D2 and D3 receptors only at a high concentration. On the other hand, buflomedil inhibited [3H]quinuclidinyl benzilate (QNB) binding to striatal muscarinic cholinergic receptors, which was similar to the action of carbachol. Pretreatment with scopolamine (0.5 mg/kg) in vivo inhibited the facilitation of striatal DA turnover induced by oral administration of buflomedil (300 mg/kg). In contrast, continuous oral administration of buflomedil (30 mg/kg x 7 days) to rats had no significant effect on the specific bindings of [3H]SCH23390, [3H]spiperone, [3H]apomorphine and [3H]QNB to synaptic membrane preparations obtained from the striatum. These results suggest that buflomedil may enhance striatal DA release by stimulating muscarinic cholinergic receptor and that DA receptors may not be involved in the enhancing effect of buflomedil on DA release.     

Unrestricted free-choice ethanol self-administration in rats causes long-term neuroadaptations in the nucleus accumbens and caudate putamen

In the present study, the reactivity of striatal dopamine and dopamine-sensitive neurons in superfused striatal slices of ethanol-experienced rats was compared to that of ethanol-naive rats, 3 weeks after oral ethanol self-administration. During the acquisition phase (17 days), rats were offered increasing concentrations of ethanol (from 2 to 10%, 24 h per day) on an alternate-day schedule in a free choice with water. Following 2 weeks of unrestricted 10% ethanol consumption, the highest and lowest drinkers (representing about 25% of the upper and lower extremes of the total population) were selected. Preliminary experiments revealed that both groups of rats displayed a profound increase in ethanol consumption and preference 3 weeks after cessation of ethanol self-administration (deprivation effect). This deprivation effect was associated with an increase in electrically evoked release of [³H]dopamine from superfused nucleus accumbens slices, whereas the evoked [³H]dopamine release from caudate putamen slices remained unchanged. In slices of the caudate putamen, but not in nucleus accumbens slices, postsynaptic dopamine D₁ receptor-stimulated cyclic AMP production was also enhanced. In addition, prior ethanol consumption enhanced the electrically evoked release of [¹⁴C]acetylcholine release in both striatal regions. Interestingly, the magnitude of these long-term neuroadaptations correlated with the amount of daily ethanol consumption, i.e. neuronal hyperresponsiveness in the striatum was more profound in the high than in the low ethanol drinkers. These data show for the first time that unrestricted free-choice ethanol consumption in rats is associated with a long-term increase in dopaminergic and cholinergic neurotransmission in the nucleus accumbens and caudate putamen. These (and other) neuroadaptations may underlie the enhanced motivation to self-administer ethanol and the maintenance of ethanol consumption long after deprivation. Received: 14 April 1998/Final version: 15 June 1998     

The effects of glutamate receptor agonists on neurotensin release using in vivo microdialysis

In the present study, extracellular concentrations of neurotensin were measured from the striatum, nucleus accumbens and the medial prefrontal cortex in the awake, freely moving rat. Using a highly sensitive solid phase radioimmunoassay, basal concentrations of neurotensin were 2-5 pg/sample. In each region, glutamate receptor agonists, N-methyl-D-aspartate (NMDA) and kainic acid, increased neurotensin release 2-3-fold. Preincubation with the Na(+) channel blocker tetrodotoxin abolished the glutamate receptor agonist-induced increases except in the striatum following kainic acid infusion. These findings indicate that activation of glutamate receptors may indirectly stimulate neurotensin release.