Partial and full dopamine D1 agonists produce comparable increases in ventral pallidal neuronal activity: contribution of endogenous dopamine

Systemic administration of the partial DA D1 agonist SKF38393 often increases the firing rate of neurons in the VP of rats. This study extended this finding by comparing responses to (+/-)SKF38393 with those produced by two D1 agonists that have greater intrinsic efficacy, (+/-)SKF82958 and (+/-)DHX. The role of endogenous DA in D1 agonist-induced effects also was examined. Extracellular recordings of single VP neurons were obtained in chloral hydrate-anesthetized male rats, to which equimolar doses of SKF38393, SKF82958 or DHX were administered i.v. Each of the agonists increased firing rate in about 45% of the neurons tested. Moreover, each agonist produced the same maximal increase in activity (161% to 178% of spontaneous rate). Acute decreases in synaptic DA, produced by either GBL or combined treatment with reserpine and AMPT, potentiated the maximal increase in activity evoked by SKF38393 or SKF82958. These DA-depleting treatments did not alter the percentage of neurons that displayed this response to D1 agonist challenge. Low doses of the selective D1 antagonists SCH23390 or SCH39166 generally attenuated the agonist-induced changes in firing rate, supporting the conclusion that D1 receptors were activated by SKF38393, SKF82958 and DHX. Thus, these three D1 agonists, which produce different maximal increases in striatal adenylyl cyclase activity, had comparable efficacy to increase VP neuronal activity. A reduction in endogenous DA enhanced the D1 agonist-induced effects, possibly through a reduction in inhibitory influences on VP neurons that are mediated by other DA receptor subtypes.     

Invasion depth diagnosis of depressed type early colorectal cancers by combined use of videoendoscopy and chromoendoscopy

The activation of rat mesocortical dopaminergic (DA) neurons evoked by the electrical stimulation of the ventral tegmental area (VTA) induces a marked inhibition of the spontaneous activity of prefrontocortical cells. In the present study, it was first shown that systemic administration of either clozapine (a mixed antagonist of D1, D2, and alpha1-adrenergic receptors) (3-5 mg/kg, i.v.), prazosin (an alpha1-adrenergic antagonist) (0.2 mg/kg, i.v.), or sulpiride (a D2 antagonist) (30 mg/kg, i.v.), but not SCH 23390 (a D1 antagonist) (0.2 mg/kg, i.v.), reversed this cortical inhibition. Second, it was found that following the systemic administration of prazosin, the VTA-induced cortical inhibition reappeared when either SCH 23390 or sulpiride was applied by iontophoresis into the prefrontal cortex. Third, it was seen that, whereas haloperidol (0.2 mg/kg, i.v.), a D2 antagonist which also blocks alpha1-adrenergic receptors, failed to reverse the VTA-induced inhibition, the systemic administration of haloperidol plus SCH 23390 (0.2 mg/kg, i.v.) blocked this inhibition. Finally, it was verified that the cortical inhibitions obtained following treatments with either "prazosin plus sulpiride" or "prazosin plus SCH 23390" were blocked by a superimposed administration of either SCH 23390 or sulpiride, respectively. These data indicate that complex interactions between cortical D2, D1, and alpha1-adrenergic receptors are involved in the regulation of the activity of prefrontocortical cells innervated by the VTA neurons. They confirm that the physiological stimulation of cortical alpha1-adrenergic receptors hampers the functional activity of cortical D1 receptors and suggest that the stimulations of cortical D1 and D2 receptors exert mutual inhibition on each other's transmission.     

beta-Phenylethylamine regulation of dopaminergic nigrostriatal cell activity

In the present paper, the action of beta-phenylethylamine on electrophysiological activity of dopaminergic nigrostriatal neurons is described. 10 s after its i.v. injection and during 2-4 min, beta-phenylethylamine decreased the firing rate, the number of spikes within and out of burst and the number of bursts per second of these neurons. This was a dose-related action with statistical differences starting from 1.4 mg/kg for total and out of burst firing rate and from 2.4 mg/kg for within burst firing rate and for the number of bursts per second. The standard deviation and the variation coefficient of inter-spike intervals increased in a dose-related way. The marked effect found after low-dose administration suggests that under physiological conditions endogenous beta-phenylethylamine levels regulate the nigrostriatal dopaminergic cell activity. After peripheral low dose administration, beta-phenylethylamine behaves as a dopaminergic agonist with a very fast and brief action.     

VTA dopamine neuron activity distinguishes alcohol-preferring (P) rats from Wistar rats

The mesolimbic dopamine (DA) system is innately deficient in rats selectively bred for high alcohol drinking behavior compared with rats selectively bred for low alcohol drinking and unselected rats. In alcohol-preferring (P) rats, compared with alcohol-nonpreferring (NP) rats, this is evidenced by fewer DA neurons in the ventral tegmental area (VTA) projecting to the nucleus accumbens (ACB). Yet, despite this deficiency, DA release in the ACB is similar in P, NP, and Wistar rats. DA release is regulated by DA neuronal activity, and DA neurons fire tonically as well as in bursts. Burst firing has been shown to substantially enhance DA release compared with tonic firing. The present study was designed to test the hypothesis that the remaining VTA DA neurons in P rats have faster firing frequencies and/or burst fire more frequently than VTA DA neurons in Wistar rats. The spontaneous activity of VTA DA neurons was recorded in unanesthetized alcohol-naive P and Wistar rats. A conventional burst analysis on 500 consecutive action potentials revealed that P rats had a significantly (p < 0.05) greater percentage of action potentials in bursts when compared with Wistar rats (P: 50.9%, Wistar: 34.4%). Firing frequency and other burst parameters (burst interspike interval, burst length, interburst interval, and the number of action potentials per burst) did not distinguish the two groups of rats. The increased burst activity in P rats may represent a compensatory mechanism to maintain adequate basal levels of DA despite the deficiency in the mesolimbic DA system.     

Activity of presumed dopamine neurons in the ventral tegmental area during heroin self-administration

To assess the pattern of mesocorticolimbic dopamine (DA) activity associated with drug-seeking and drug-taking behavior, we monitored the firing rate of presumed DA neurons in the ventral tegmental area of trained rats during i.v. heroin self-administration (SA). Relative to a slow and irregular basal activity, the first SA of each session was preceded by a phasic increase and followed by a more persistent increase in discharge rate that peaked approximately 15-20 min later at the time of the second SA. All subsequent SAs were associated with a biphasic neuronal change: a transient decrease followed by a gradual increase that peaked just before the next SA. Our results support mesocorticolimbic DA activation in heroin-seeking behavior but suggest a transient inhibition of DA activity correlated with heroin reward.     

kappa-opioid regulation of neuronal activity in the rat supraoptic nucleus in vivo

We investigated the influence of endogenous kappa-opioids on the activity of supraoptic neurons in vivo. Administration of the kappa-antagonist nor-binaltorphimine (200 micrograms/kg, i.v.), increased the activity of phasic (vasopressin), but not continuously active (oxytocin), supraoptic neurons by increasing burst duration (by 69 +/- 24%) and decreasing the interburst interval (by 19 +/- 11%). Similarly, retrodialysis of nor-binaltorphimine onto the supraoptic nucleus increased the burst duration (119 +/- 57% increase) of vasopressin cells but did not alter the firing rate of oxytocin cells (4 +/- 8% decrease). Thus, an endogenous kappa-agonist modulates vasopressin cell activity by an action within the supraoptic nucleus. To eliminate kappa-agonist actions within the supraoptic nucleus, we infused the kappa-agonist U50,488H (2.5 micrograms/hr at 0.5 micrograms/hr) into one supraoptic nucleus over 5 d to locally downregulate kappa-receptor function. Such infusions reduced the spontaneous activity of vasopressin but not oxytocin cells and reduced the proportion of cells displaying spontaneous phasic activity from 26% in vehicle-infused nuclei to 3% in U50, 488H-infused nuclei; this treatment also prevented acute inhibition of both vasopressin and oxytocin cells by U50,488H (1000 micrograms/kg, i.v.), confirming functional kappa-receptor downregulation. In U50, 488H-infused supraoptic nuclei, vasopressin cell firing rate was increased by nor-binaltorphimine (100 and 200 micrograms/kg, i.v.) but not to beyond that found in vehicle-treated nuclei, indicating that these cells were not U50,488H-dependent. Thus, normally functioning kappa-opioid mechanisms on vasopressin cells are essential for the expression of phasic firing.     

A quantitative correlation between single unit activity and fluorescence intensity of dopamine neurones in zona compacta of substantia nigra, as demonstrated under the influence of nicotine and physostigmine

In order to investigate the possible relationship between neuronal activity and cellular fluorescence intensity, extracellular recordings of single unit activity and determinations of fluorescence intensity of dopamine (DA) neurones by histochemical microfluorimetry were performed in the same (rostral) part of zona compacta of substantia nigra in male rats. In urethane anaesthesia, zona compacta neurones characteristically showed a slow and fairly regular type of firing. Nicotine (1 mg/kg s.c.) induced a transient decrease in unit activity for 1 min followed by a sustained increase in firing rate. During that stage, 4-5 neurones/rat were recorded at different anteroposterior levels, each during 200 sec. Microfluorimetric examination of the fluorescence intensity developed at the end of the 30-min observation period by the DA neurones of the same area revealed a marked rise in cellular fluorescence intensity. Similar results were obtained with a lower dose of nicotine and/or a shorter observation period. Additional microiontophoretic experiments supported the view that extracellular recordings of the correlative electrophysiological-microfluorimetric investigation belonged to DA neurones. Release of DA from terminals was indicated by an increase in HVA concentration of caudate-putamen in rats subjected to the same nicotine treatment. When tested on one cell during a prolonged period of time, physostigmine (0.25 mg/kg i.p.) caused an initial increase in firing rate of zona compacta neurones (5-10 min) followed by a decrease of unit activity (15-23 min). In agreement with previous observations in mice, fluorescence intensity of nigral DA neurones likewise showed a biphasic change with an initial rise and subsequent decrease (examined at 9.5 and 22-23.5 min, respectively). When mean unit activity and mean fluorescence intensity of individual rats out of various experimental groups were related to each other, a highly significant positive correlation between neuronal fluorescence intensity and firing rate was found. The results obtained with physostigmine demonstrate that mean intensity closely paralleled mean unit activity in time, so that this correlation was maintained. These findings indicate that cellular fluorescence intensity of DA neurone groups can be used as an index of the level of neuronal activity, except for cases where a drug treatment interferes directly with catecholamine synthesis or storage mechanisms.     

Participation of the hypothalamus in regulation of the pituitary-adrenal system in accordance with the feedback principle

The multiunit activity and activity of pituitary-adrenocortical system were studied in chronic experiments on intact unrestrained rabbits injected with cortisol (1 mg/kg, i.v.). The pituitary-adrenocortical system was inhibited by cortisol (the level of corticosterone decreased) as well as the majority of the neuronal pools in the medial and lateral hypothalamus. The anterior hypothalamic neurons mostly responded to cortisol by a rise in firing rate. The changes observed suggest the existence of some electrophysiological correlates of the corticosteroid feedback mechanisms.     

The quality of the discharge planning process: the effect of a liaison nurse

Nitric oxide (NO) in brain has been implicated in neuronal regulatory processes and in neuropathologies. Previously we showed that NO modified quinpirole-induced yawning, a behavioral measure of dopamine (DA) D3 receptor activation in rats. The aim of this study was to characterize the effect of nitro-L-arginine methyl ester HCl (NAME) and L-arginine HCl on reactivity of rats to the DA D1 receptor agonist SKF 38393 and DA D1 antagonist SCH 23390 in intact and neonatal 6-hydroxydopamine (6-OHDA)-lesioned rats (134 micrograms of base ICV at 3rd day after birth). L-arginine HCl (300 mg/kg i.p.) increased the oral activity response in 6-OHDA-lesioned rats, like SKF 38393, and induced catalepsy in intact control rats, like SCH 23390. In contrast, NAME had no effect on oral activity or catalepsy, but fully attenuated SKF 38393-induced oral activity. These findings indicate that L-arginine HCl has no apparent effect at the DA D1 receptor, but that NAME is effective in attenuating a DA D1 agonist-induced effect. Consequently NO may be an intracellular second messenger for supersensitized receptors associated with DA D1 agonist-induced oral activity.     

Modulation of central serotonergic neurotransmission by risperidone: underlying mechanism(s) and significance of action

1. The effects of risperidone on brain 5-hydroxytryptamine (5-HT) neuronal activity were investigated using microdialysis in the frontal cortex (FC) or the dorsal raphe nucleus (DRN) as well as single cell recording in the DRN. 2. Systemic administration of risperidone (0.6 and 2.0 mg/kg, s.c.) dose-dependently increased 5-HT output in both the FC and the DRN. 3. Local cortical administration of both risperidone or idazoxan enhanced the 5-HT efflux in the FC, whereas local raphe administration of risperidone but not idazoxan increased the output of 5-HT in the DRN. 4. Systemic administration of risperidone (200 micrograms/kg, i.v.) or the selective alpha 1 adrenoceptor antagonist prazosin (400 micrograms/kg, i.v.) decreased, whereas selective alpha 2 adrenoceptor antagonist idazoxan (20 micrograms/kg, i.v.) increased the 5-HT cell firing in the DRN. 5. Pretreatment with the selective 5-HT1A receptor antagonist WAY 100,635 (5.0 micrograms/kg, i.v.) effectively antagonized the inhibition of 5-HT cells induced by risperidone, but failed to prevent the prazosin-induced decrease in 5-HT cell firing in the DRN. 6. The inhibitory effect of risperidone on 5-HT cell firing in the DRN was significantly attenuated in rats pretreated with the 5-HT depletor PCPA (p-chlorophenylalanine; 300 mg/kg/day i.p. for 3 consecutive days) in comparison with drug naive animals. 7. Consequently, the risperidone-induced increase in 5-HT output in the FC may be related to its alpha 2 adrenoceptor antagonistic action, an effect probably executed at the nerve terminal level, whereas the reduction in 5-HT cell firing by risperidone appears to be associated with increased availability of 5-HT in the somatodendritic region of the neurones leading to an enhanced 5-HT1A autoreceptor activation and, in turn, to inhibition of cell firing.     

Effects of small concentrations of volatile anesthetics on action potential firing of neocortical neurons in vitro

BACKGROUND: Volatile general anesthetics depress neuronal activity in the mammalian central nervous system and enhance inhibitory Cl- currents flowing across the gamma-aminobutyric acid A (GABA(A)) receptor-ion channel complex. The extent to which an increase in GABA(A)-mediated synaptic inhibition contributes to the decrease in neuronal firing must be determined, because many further effects of these agents have been reported on the molecular level. METHODS: The actions of halothane, isoflurane, and enflurane on the firing patterns of single neurons were investigated by extracellular recordings in organotypic slice cultures derived from the rat neocortex. RESULTS: Volatile anesthetics depressed spontaneous action potential firing of neocortical neurons in a concentration-dependent manner. The estimated median effective concentration (EC50) values were about one half the EC50 values for general anesthesia. In the presence of the GABA(A) antagonist bicuculline (20 microM), the effectiveness of halothane, isoflurane, and enflurane in reducing the discharge rates were diminished by 48-65%, indicating that these drugs act via the GABA(A) receptor. CONCLUSIONS: Together with recent investigations, our results provide evidence that halothane, isoflurane, and enflurane reduced spontaneous action potential firing of neocortical neurons in cultured brain slices mainly by increasing GABA(A)-mediated synaptic inhibition. At concentrations, approximately one half the EC50 for general anesthesia, volatile anesthetics increased overall GABA(A)-mediated synaptic inhibition about twofold, thus decreasing spontaneous action potential firing by half.     

Modulatory action of dopamine on acetylcholine-responsive striatal and accumbal neurons in awake, unrestrained rats

In ambulant rats, iontophoresis of low concentrations of dopamine (DA) enhances the response of neurons in striatum and nucleus accumbens to iontophoretic glutamate. In an extension of this line of investigation, we tested the effects of acetylcholine (ACh), a presumed modulator of neuronal function in these same brain regions, and assessed possible DA-ACh interactions. Data were obtained from spontaneously active neurons known to respond to ACh (5-30 nA) when the animals rested quietly with no overt movement. ACh iontophoresis either excited or inhibited striatal and accumbal activity but excitatory effects predominated in both areas. With multiple applications of ACh, especially at the lowest currents tested, either response often was interspersed with instances of no change in firing rate. Responsiveness to ACh also diminished during periods of spontaneous movement when basal firing showed phasic increases in activity. In fact, neurons with the highest rates of basal activity showed the smallest magnitude response to ACh. Prolonged applications (120-180 s) of DA attenuated basal firing as well as the iontophoretic effects of ACh both during the DA application itself and for up to 1 min after DA ejection offset. The result of these inhibitory effects was no net change in the relative magnitude of the ACh response. Thus, although ACh can modulate striatal and accumbal neuronal activity, DA does not regulate this effect in the same way that it regulates the neuronal responsiveness to glutamate.     

Blockade of (+/-) 12-chloroscoulerine on feed-back regulation of dopamine D2 autoreceptors

AIM: To verify whether (+/-) 12-chloroscoulerine (CSL) is antagonist or agonist effect to D2 autoreceptors. METHODS: The levodopa content accumulated in the rat striatum was measured by HPLC-ECD, and the DA neuron firing activity in the substantia nigra zona compacta (SNC) was recorded. RESULTS: The accumulated levodopa content induced by CSL 40 mg.kg-1 was much more than that of 1,4-butyro-lactone (BL) group (P < 0.01). After i.p. injection of apomorphine (Apo) 5 mg.kg-1, the levodopa content was decreased below that of BL group (P < 0.05). The Apo inhibition on levodopa content was completely reversed by CSL (40 mg.kg-1, i.p.) and then increased the levodopa content (2.5 +/- 1.1 micrograms.g-1) over that of Apo group (0.7 +/- 0.3 microgram.g-1, P < 0.01). In the electrophysiologic recording, Apo (15 micrograms.kg-1, i.v.) induced the decrease of SNC DA cell firing rate nearly to zero. At the accumulated dose of CSL up to 80 micrograms.kg-1 (i.v.), the inhibition of Apo was attenuated and the firing activity was restored to predrug level. CONCLUSION: CSL showed an antagonistic action, an action to D2 autoreceptors.     

Blockade of adenosine A2A receptors by SCH 58261 results in neuroprotective effects in cerebral ischaemia in rats

Blockade of adenosine receptors can reduce cerebral infarct size in the model of global ischaemia. Using the potent and selective A2A adenosine receptor antagonist, SCH 58261, we assessed whether A2A receptors are involved in the neuronal damage following focal cerebral ischaemia as induced by occluding the left middle cerebral artery. SCH 58261 (0.01 mg/kg either i.p. or i.v.) administered to normotensive rats 10 min after ischaemia markedly reduced cortical infarct volume as measured 24 h later (30% vs controls, p < 0.05). Similar effects were observed when SCH 58261 (0.01 mg/kg, i.p.) was administered to hypertensive rats (28% infarct volume reduction vs controls, p < 0.05). Neuroprotective properties of SCH 58261 administered after ischaemia indicate that blockade of A2A adenosine receptors is a potentially useful biological target for the reduction of brain injury.     

Insulin-induced hypoglycemia does not impair the surge of luteinizing hormone secretion in the proestrous rat

Dopamine (DA) neurons in the ventral tegmental area and substantia nigra pars compacta were induced to fire in bursts with application of N-methyl-D-aspartate (NMDA, 20 microM) and apamin (100 nM) while recording intracellularly in the rat brain slice. L-Arginine (300 microM), a substrate for nitric oxide (NO) production, increased both the number of spikes per burst and the magnitude of interburst hyperpolarizations. Nitric oxide synthase inhibitors N-nitro-L-arginine methyl ester (L-NAME, 100 microM), N-nitro-L-arginine, and 7-nitroindazole inhibited NMDA-induced burst firing by reducing the number of spikes per burst. Moreover, L-arginine (100 microM) reversed the inhibition of burst firing produced by L-NAME. These findings suggest that NO facilitates NMDA-induced burst firing in DA neurons.     

Nicotine-induced activation of locus coeruleus neurons--an analysis of peripheral versus central induction

Previous electrophysiological experiments have shown that the marked but short-lasting excitation of locus coeruleus (LC) neurons seen after systemic administration of low doses of nicotine is of a peripheral origin. In addition, nicotine induces a weak but more long-lasting activation of LC neurons which is preferentially observed following administration of high doses of the drug. In the present study this latter activation was pharmacologically analysed. Whereas low intravenous doses of nicotine caused a marked but short-lasting excitation of most LC cells recorded from, higher doses of nicotine were associated with a moderate but durable (> 20 min) activation. In contrast to the short-lasting activation of the LC, the long-lasting effect of the drug was not counteracted by chlorisondamine (0.3 mg/kg, i.v.; n = 5). On the other hand, administration of mecamylamine (4 mg/kg, i.v.; n = 5) rapidly and effectively decreased the elevated spontaneous firing rate of LC neurons (as observed following repeated nicotine injections) to the original baseline firing rate. Intravenous administration of tetramethylammonium (TMA, 50-800 mg/kg, i.v.), activated most LC neurons in a manner resembling that of nicotine at low doses, i.e. a marked but short-lasting excitation with no tachyphylaxis. However, in contrast to nicotine, TMA administered in higher doses did not affect the baseline firing rate of LC neurons.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of trigeminal neurons by intravenous administration of the serotonin (5HT)1B/D receptor agonist zolmitriptan (311C90): are brain stem sites therapeutic target in migraine?

Migraine is a common and debilitating condition. Its treatment has received considerable attention in recent times with the introduction into clinical use of the serotonin (5HT)1B/D-like agonist sumatriptan. It is known from human studies that the intracranial blood vessels and dura mater are important pain-sensitive structures since mechanical or electrical stimulation of these vessels, such as the superior sagittal sinus, causes pain. We have developed a model of craniovascular pain by stimulating the superior sagittal sinus and monitoring trigeminal neuronal activity using electrophysiological techniques. In this study we determined the effect of intravenous administration of the novel anti-migraine compound zolmitriptan (311C90) upon evoked neuronal activity in trigeminal neurons. Nine adult cats were anaesthetised with alpha-chloralose (60 mg/kg, i.p.; 20 mg/kg, i.v., 2-hourly) with all surgery being conducted under halothane (1-3%). The superior sagittal sinus was isolated for electrical stimulation. Recordings were made from caudal trigeminal neurons at the C2 level of the cervical spinal cord with tungsten-in-glass microelectrodes. Signals were amplified and analysed by a custom-written program that enabled software filtering and extraction of both evoked potential and single cell data. Data were collected before and after administration of zolmitriptan. Electrical stimulation of the superior sagittal sinus resulted in activation of neuronal elements within the trigeminal nucleus that could be monitored as single unit activity or as evoked potentials, the latter reflecting both primary afferent and trigeminal cell body activity. The evoked potential recorded from the trigeminal nucleus was 207 +/- 14 microV and was reduced by zolmitriptan (100 micrograms/kg, i.v.) to a mean of 98 +/- 17 microV. Similarly, the probability of firing for trigeminal neurons was reduced from a control level of 0.63 +/- 0.1 to 0.13 +/- 0.05 after a dose of 100 micrograms/kg intravenously. These effects were dose-dependent and were significantly different from the effect of vehicle (P < 0.05). These data demonstrate that systemically administered zolmitriptan can inhibit evoked trigeminovascular activity within the trigeminal nucleus. This inhibition of trigeminal activity may play a role in the anti-migraine actions of this compound and offers the prospect of a third pathophysiologically consistent target site for anti-migraine drug effects.     

Differential effects of GABA(A) and GABA(B) agonists on sensitization to the locomotor stimulant effects of ethanol in DBA/2 J mice

Contemporary theories of drug abuse suggest that behavioral sensitization plays an important role in addiction. However, few studies have examined the mechanisms underlying behavioral sensitization to ethanol. The present study examined the ability of THIP (2, 4, or 8 mg/kg) and baclofen (5.0, 6.25, or 7.5 mg/kg), GABA(A) and GABA(B) agonists, respectively, to prevent development of sensitization to the locomotor stimulant effects of ethanol (2 g/kg) in DBA/2 J mice. Ethanol was administered immediately before four 5-min activity trials conducted at 48-h intervals. Administration of ethanol on each of the four trials resulted in behavioral sensitization in control groups. While having few effects on activity when given alone, both GABA agonists completely blocked the acute stimulant response to ethanol on the first trial. Administration of THIP prior to ethanol on each trial failed to prevent development of sensitization. In contrast, all doses of baclofen blocked sensitization. Assessment of blood ethanol levels 15, 50 and 100 min after administration of ethanol indicated that baclofen did not change the pharmacokinetics of ethanol. These results indicate an important role for GABA(B) receptors, but not GABA(A) receptors, in development of sensitization to the locomotor stimulant effects of ethanol.     

Increased expression of NGFI-A mRNA in the rat striatum following burst stimulation of the medial forebrain bundle

Using in situ hybridization, we examined the mRNA expression for several immediate early genes in dopamine-innervated brain areas following electrical burst vs. regular stimulation of the medial forebrain bundle in anaesthetized rats. Two hours after 5 Hz burst stimulation, the expression of the nerve growth factor-inducible clone A (NGFI-A) mRNA was increased in the medial part of the striatum. This increase was prevented by pretreatment with the dopamine-D1 receptor antagonist, SCH23390 (0.1 mg/kg i.p.). After 8 Hz burst stimulation, NGFI-A mRNA expression was increased in the medial, central and lateral parts of the striatum. Induction occurred predominantly in cells expressing mRNAs for the dopamine-D1 receptor, substance P and dopamine and cAMP-regulated phosphoprotein (DARP-32). Regular stimulation had no effect on NGFI-A mRNA expression. The induction of NGFI-A was related to the levels of dopamine released by burst or regular stimulation as demonstrated with in vivo amperometry. Two hours after stimulation, the expression of none of the other genes studied was altered. One hour after 8 Hz burst stimulation, the expression of NGFI-A, NGFI-B and jun-B mRNAs was increased in the striatum and that of NGFI-A, NGFI-B, c-fos, fos-B and jun-B mRNAs was variably increased in the nucleus accumbens and lateral septum. These results provide additional support for the physiological importance of burst firing activity in midbrain dopamine neurons for the activation of their target cells. They demonstrate a spatial and temporal specificity as regards the brain region, the gene activated, the receptor involved and the phenotype of the cells affected.     

Effects of different doses of apomorphine on GAD activity in rat substantia nigra

The effects of different doses of the dopamine (DA) receptor agonist apomorphine on the activity of the gamma-aminobutyric acid (GABA)-synthesizing enzyme glutamic acid decarboxylase (GAD, EC 4.1.1.15) were investigated in rat substantia nigra in comparison with haloperidol and sulpiride, two DA receptor blocking agents. Results obtained show that low doses (10,35 microgram/kg, s.c.) of apomorphine induce a decrease in nigral GAD activity whilst an opposite effect is observed with the highest dose (1000 microgram/kg, s.c.). No significant change is observed following injection of the intermediate doses (100 and 500 microgram/kg, s.c.). Moreover, sulpiride at the dose used (2 mg/kg, i.p.) induces an increase in GAD activity whilst no effect follows systemic injection of the same dose of haloperidol. The results are discussed in light of recent neurochemical and behavioral data.