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Biomedical subjects

M Diana

Publications and source records attributed to M Diana.

At least 19 recordsLinked to original sources
PubMed1998

Mesolimbic dopaminergic decline after cannabinoid withdrawal.

The mesolimbic dopamine system has recently been implicated in the long-term aversive consequences of withdrawal from major drugs of abuse. In the present study we sought to determine whether mesolimbic dopamine neurons are involved in the neurobiologic mechanisms underlying withdrawal from chronic cannabinoid exposure. Rats were treated chronically with the major psychoactive ingredient of hashish and marijuana, Delta9-tetrahydrocannabinol (Delta9-THC). Administration of the cannabinoid antagonist SR 141716A precipitated an intense behavioral withdrawal syndrome, whereas abrupt Delta9-THC suspension failed to produce overt signs of abstinence. In contrast, both groups showed a reduction in dopamine cells activity as indicated by extracellular single unit recordings from antidromically identified meso-accumbens dopamine neurons. The administration of Delta9-THC to spontaneously withdrawn rats restored neuronal activity. Conversely, SR 141716A produced a further decrease of spontaneous activity in cannabinoid-treated although it was ineffective in control rats. These data indicate that withdrawal from chronic cannabinoid administration is associated with reduced dopaminergic transmission in the limbic system, similar to that observed with other addictive drugs; these changes in neuronal plasticity may play a role in drug craving and relapse into drug addiction.

Animals↗
PubMed1998

Haloperidol does not produce dopamine cell depolarization-block in paralyzed, unanesthetized rats.

A widely accepted theory postulates that chronic treatment with neuroleptics causes, in rats, the depolarization block of the majority of midbrain dopamine (DA) neurons. However, we reported that such treatment fails to reduce the number of spontaneously active DA neurons when the neuronal sampling is performed in the d-tubocurarine-paralyzed instead of chloral-hydrate anesthetized preparation. The present experiments were aimed at verifying whether the negative results might be due to the use of d-tubocurarine as paralyzing agent. Rats were chronically treated with haloperidol (0.5 mg kg-1 i.p., daily) for 3 to 4 weeks. Two to three hours after the last injection, the number of spontaneously active DA neurons in the ventral tegmental area (VTA) were sampled, and their discharging characteristics analyzed, both in animals under chloral hydrate anesthesia and in rats immobilized either with d-tubocurarine, gallamine or succinylcholine. The results indicate that chronic treatment with haloperidol reduced the number of spontaneously active VTA-DA neurons by about 65% in animals under chloral hydrate anesthesia, but failed to modify the number of spontaneously firing DA neurons in rats immobilized with d-tubocurarine, gallamine or succinylcholine. The results indicate that the depolarization block of DA neurons does not occur in the paralyzed preparation and raise doubts about the presence of this phenomenon in the intact non- anesthetized unrestrained animal.

Animals↗
PubMed1998

Cannabinoids activate mesolimbic dopamine neurons by an action on cannabinoid CB1 receptors.

The present study was designed to determine if cannabinoids share with other drugs of abuse the ability to stimulate mesolimbic dopaminergic neurons and if this effect is mediated by cannabinoid receptors. To this end, the effects of the prototypical cannabinoid, delta9 tetrahydrocannabinol ¿(-)-trans-(6aR,10aR)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl- 3-pentyl-6H-dibenzo[b,d]pyran-1-ol¿, and the two highly potent synthetic cannabinoids, ¿(R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)-methyl]pyrrolo[1,2,3-d e]-1,4-benzoxazin-6-yl, +(1-naphtalenyl)methanone¿ WIN 55,212-2 and ¿(-)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl )-cicloexan-1-ol¿ CP 55,940, on the spontaneous discharge rate of meso-accumbens dopamine (A10 dopamine) neurons were studied in rats. The intravenous administration of delta9-tetrahydrocannabinol, WIN 55,212-2 and CP 55,940 (0.0625-1.0 mg/kg) produced a dose-dependent increase in the spontaneous firing of A10 dopamine neurons both in non-anesthetized and anesthetized rats, with a maximal percent increase of 120, 187 and 155 in non-anesthetized and 33, 102 and 52, respectively, in anesthetized rats. The stimulant response to cannabinoids was suppressed by the specific cannabinoid receptor antagonist ¿N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide¿ SR 141716A, indicating a cannabinoid receptor-mediated effect. These findings support the contention that cannabinoids regulate mesolimbic dopamine transmission and may help to explain the addictive properties of marijuana.

Action Potentials↗
PubMed1998

Increase in meso-prefrontal dopaminergic activity after stimulation of CB1 receptors by cannabinoids.

The intravenous administration of the psychoactive constituent of marijuana, delta9-tetrahydrocannabinol (delta9-THC) (62.5-1000 microg/kg), and the synthetic cannabinoid agonist WIN 55212,2 (WIN) (62.5-500 microg/kg), produced a dose-related increase in the firing rate and burst firing in the majority of antidromically identified meso-prefrontal dopaminergic neurons. In a restricted number of neurons (n=4), WIN administration did not increase firing rate but produced an increment of bursting activity. These effects of the cannabinoids were reversed by the intravenous administration of SR 141716 A, a selective cannabinoid antagonist (1 mg/kg), per se ineffective to modify the electrical activity of dopaminergic neurons. The results indicate that stimulation of cannabinoid CB1 receptors produces an activation of meso-prefrontal dopaminergic transmission. Considering that supranormal stimulation of D1 dopamine receptors in the prefrontal cortex has been shown to impair working memory, the present results suggest that the negative effects of cannabinoids on cognitive processes might be related to the activation of dopaminergic transmission in the prefrontal cortex.

Action Potentials↗
PubMed1997

Spontaneous bursting activity of dopaminergic neurons in midbrain slices from immature rats: role of N-methyl-D-aspartate receptors.

Dopamine neurons in midbrain coronal slices from adult rats (40-70 days old) discharged only in pacemaker-like mode. Irregular or bursting mode was never observed. In contrast, dopamine neurons in slices from immature rats (15-21 days old) exhibited not only pacemaker-like firing (53.4% of neurons), but also irregular and bursting patterns (28.3 and 18.3%, respectively). Glutamate and kainate increased the firing rate but failed to induce bursts in dopamine neurons from either adult or immature rats. N-Methyl-D-aspartate augmented the firing rate in all neurons from adult rats and produced a modest increase of bursts in only three out of 18 cells. In slices from immature rats, N-methyl-D-aspartate activated the discharge rate in all neurons and also induced bursts in 37 and 53% of pacemaker and irregular neurons, respectively, and increased the occurrence of spikes in bursts in 76% of spontaneously bursting neurons. The selective N-methyl-D-aspartate receptor antagonist (+/-)2-amino,5-phosphonopentanoic acid prevented N-methyl-D-aspartate-induced changes and also reduced spontaneous bursts, suggesting that bursting discharge is mediated by N-methyl-D-aspartate receptor activation. While pacemaker neurons from immature and from adult rats exhibited the same sensitivity to N-methyl-D-aspartate-induced stimulation of firing rate, spontaneously bursting neurons were more sensitive than pacemaker neurons from either immature or adult rats. The present study indicates that spontaneous bursting, dependent on N-methyl-D-aspartate receptor activation, is present, and may be induced, in dopamine neurons in slices from immature rats. Its absence from cells in slices from adult rats may reflect a reduced sensitivity of N-methyl-D-aspartate receptors on dopamine or the loss of the N-methyl-D-aspartate-activated burst generator.

2-Amino-5-phosphonovalerate↗
PubMed1997

Effects of acute, chronic ethanol and withdrawal on dorsal raphe neurons: electrophysiological studies.

The effect of a single intravenous administration of ethanol (0.25-1.0 g/kg) on the spontaneous activity of putative serotonin neurons of the dorsal raphe nucleus was studied in unanesthetized rats. Ethanol produced a slight but progressive decline in neuronal activity in 67% (six of nine) of all neurons tested. The remaining 33% (three of nine) were unresponsive. Upon withdrawal of chronic ethanol treatment (1-5 g/kg every 6 h for six consecutive days, 12 h from last ethanol administration), the mean firine rate of dorsal raphe neurons was found to be significantly reduced, by about 30% (n=71), as compared with the control group (n=83), whereas the cells/track index was unaltered. Under these conditions, ethanol administration further reduced firing rate in 67% (four of six) of all the neurons tested. In the remaining 33% (two of six), no response was observed. At 72 h after the last ethanol administration, the mean firing rate of dorsal raphe neurons was found to be within control values (n=90). Further, to evaluate the functional status of the autoreceptors under control conditions and after withdrawal from chronic ethanol, the selective serotonin-1A receptor agonist 8-hydroxy-(2-di-n-propylamino)tetralin was administered intravenously in cumulative doses (1-16 microg/kg) and dose-response curves were generated for both groups. Autoreceptor sensitivity of dorsal raphe neurons was found to be not statistically different in control and ethanol withdrawn rats (n=6 for both groups) as indexed by a similar potency displayed by 8-hydroxy-(2-di-n-propylamino)tetralin in reducing the spontaneous activity of dorsal raphe neurons. The results indicate that, in spite of the widespread use of serotonin transmission potentiating agents in the treatment of alcoholism, neither acute nor withdrawal from chronic ethanol administration produces drastic effects on dorsal raphe neurons. However, the inhibition of dorsal raphe neuronal activity after acute ethanol may be due to the reported ability of ethanol to increase serotonin release from terminal areas. This increased serotonin tone could, at the level of recurrent axon collaterals in the dorsal raphe nucleus, reduce the spontaneous activity of the cells. On the other hand, a similar reduction in spontaneous activity after withdrawal from ethanol correlates well with the reduction in serotonin levels observed under these conditions in microdialysis studies.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

Chronic administration of l-sulpiride at low doses reduces A10 but not A9 somatodentritic dopamine autoreceptor sensitivity.

The effect of chronic treatment (twice daily for 21 days) with low doses of l-sulpiride (2 mg/kg i.p.) on the apomorphine-induced inhibition of A10 and A9 dopaminergic neurons was compared with the effect of chronic administration of the classic antidepressant desipramine (20 mg/kg i.p. daily for 21 days). Intravenous administration of apomorphine (0.01-0.04 mg/kg), to rats treated chronically with l-sulpiride, produced a reduction of the spontaneous firing rate of A9 dopaminergic neurons not significantly different from that observed in control (saline-treated) rats. In contrast, apomorphine at the same doses was more potent in inhibiting A10 firing in control rats than in l-sulpiride-treated subjects. On the other hand, desipramine-treated rats were found normosensitive (as compared to saline-treated rats) to the inhibitory properties of apomorphine in both A9 and A10 dopaminergic neurons. It is suggested that chronic l-sulpiride-induced reduction of autoreceptor sensitivity in the A10 region may contribute to its clinical antidepressant effect.

Animals↗
PubMed1996

Repeated naltrexone administration accelerates resolution of morphine somatic withdrawal signs in morphine-dependent rats.

Morphine-dependent rats were divided into two subgroups. The first was allowed to develop a spontaneous withdrawal syndrome which was still present 33 h after the last morphine administration. The second subgroup received five injections of naltrexone. While the first two injections of naltrexone precipitated a marked somatic withdrawal syndrome, subsequent naltrexone failed to worsen the somatic signs. 24 h after the last morphine administration, naltrexone was completely ineffective. It is concluded that naltrexone shortens the duration of the morphine somatic withdrawal signs in dependent rats.

Animals↗
PubMed1996

Mesolimbic dopaminergic reduction outlasts ethanol withdrawal syndrome: evidence of protracted abstinence.

Rats chronically administered with ethanol every six hours for six consecutive days show, upon suspension of treatment, a marked somatic withdrawal syndrome characterized by classical neurological signs. The emergence of the behavioral syndrome coincides with a profound decline of dopaminergic mesolimbic neuronal activity which corresponds to a reduction of dopamine outflow in the nucleus accumbens [Diana et al. (1993) Proc. natn. Acad. Sci. U.S.A. 90, 7966-7969]. However, while the behavioral manifestation of the ethanol withdrawal syndrome recedes in about 48 h, electrophysiological indices of mesolimbic dopaminergic function are still reduced 72 h after ethanol discontinuation, thus outlasting the physical signs of ethanol withdrawal syndrome. Dopaminergic neuronal activity is reintegrated by anti-craving drugs such as ethanol itself and gamma-hydroxybutyric acid. It is postulated that the reduced spontaneous activity of mesolimbic dopaminergic neurons may form the neural basis of the dysphoric state which accompanies abrupt interruption of chronic ethanol administration. Pharmacological manipulations of dopaminergic activity targeted at restoring "normal" dopaminergic function after ethanol withdrawal may lead to way to the experimental basis of new therapeutic strategies of alcoholism.

Animals↗
PubMed1995

Ethanol withdrawal does not induce a reduction in the number of spontaneously active dopaminergic neurons in the mesolimbic system.

The effect of ethanol withdrawal, after chronic administration, on the electrophysiological properties of antidromically identified mesoaccumbens dopaminergic neurons was studied in two groups of rats with relative controls (withdrawal from chronic saline). The first group was anesthetized with chloral hydrate whereas the second was immobilized with D-tubocurarine. In chloral hydrate anesthetized rats, a significant reduction in the number of spontaneously active dopamine neurons was observed as compared with chronic saline withdrawn controls. In contrast, in ethanol-withdrawn D-tubocurarine treated rats, the number of spontaneously active dopamine neurons, as measured by the cells/track index, was found not different than chronic saline withdrawn controls. Further, intravenous administration of apomorphine, did not reverse the reduced cells/track index in chloral-hydrate anesthetized rats but consistently inhibited dopaminergic firing. Apomorphine-induced inhibition of firing was significantly more pronounced in ethanol withdrawn chloral-hydrate anesthetized rats. Firing rate and firing pattern were found decreased during ethanol withdrawal irrespective of experimental conditions. The results do not support the possibility that dopaminergic neurons of the mesoaccumbens pathway might be affected by depolarization inactivation during ethanol withdrawal. Rather, they confirm a reduction of neuronal activity already reported by previous studies. The reduced cells/track index observed in chloral hydrate anesthetized rats during ethanol withdrawal awaits an alternative explanation to the depolarization inactivation mechanism.

Anesthesia↗
PubMed1995

Biochemical and electrophysiological effects of 7-OH-DPAT on the mesolimbic dopaminergic system.

Systemic administration of the putative selective D3 receptor agonist 7-hydroxy-2-(N,N-di-n-propylamino)tetralin (7-OH-DPAT) consistently decreased extracellular dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the nucleus accumbens and dopaminergic neuronal activity in the ventral tegmental area. 7-OH-DPAT inhibited dopamine release in the nucleus accumbens also when locally perfused through the dialysis probe. The results suggest the possibility that stimulation of dopamine D3 receptors with 7-OH-DPAT mimic biochemical and electrophysiological actions previously ascribed to D2 autoreceptor stimulation; however the lack of selective D3 antagonist precludes any firm conclusion in this sense.

Animals↗
PubMed1995

Profound decrease of mesolimbic dopaminergic neuronal activity in morphine withdrawn rats.

The spontaneous neuronal activity of meso-accumbens dopaminergic neurons was recorded in unanesthetized rats withdrawn from chronic morphine administration (15 days) by means of single cell extracellular recording techniques coupled with antidromic identification from the nucleus accumbens. Twenty-four h after last morphine administration, firing rate and burst firing were found to be drastically reduced and the relative refractory periods of the same neurons were prolonged in morphine-dependent rats as compared with chronic saline-treated controls. The number of spontaneously active dopaminergic neurons, however, did not differ between the two groups. Administration of morphine restored electrophysiological parameters. When rats were tested 2 h after last morphine administration, i.v. challenge with the opiate antagonist naloxone caused an abrupt and virtually complete reduction of dopaminergic firing rate, burst rate and a prolongation of the relative refractory period. These effects were not observed in control rats. The results indicate that the mesolimbic dopaminergic system is tonically reduced in its activity during morphine withdrawal syndrome and considering its role in the reinforcing properties of opioids, its depressed activity during the morphine withdrawal syndrome may bear relevance for the dysphoric state associated to morphine withdrawal in humans.

Animals↗
PubMed1995

Depolarization inactivation of dopamine neurons: an artifact?

A widely accepted theory postulates that, in rats, chronic treatment with neuroleptics causes the depolarization inactivation of the majority of midbrain dopamine (DA) neurons. The present study was aimed to verify whether general anesthesia and/or other factors might contribute to the depolarization inactivation of A9 and A10 DA neurons. To investigate on the possible role played by DA receptor subtypes, three representatives DA antagonists were used: haloperidol (a mixed D1/D2), (-)-sulpiride (a selective D2) and SCH 23390 (a selective D1). In agreement with previous studies, where neuronal sampling was carried out in animals under chloral hydrate anesthesia, chronic treatment with haloperidol (0.5 mg/kg daily for 21-28 d) produced a profound reduction (about 80%) in the number of spontaneously active A9 DA neurons. However, when neuronal sampling was performed in unanesthetized rats, the single administration of haloperidol, (-)-sulpiride, or SCH 23390 (0.5, 25, and 0.3 mg/kg respectively 2-3 hr beforehand) increased the number of spontaneously active A9 and A10 DA neurons and their firing rate, whereas the chronic administration of these drugs (daily for 21-28 d) failed to reduce the number of spontaneously active A9 and A10 DA neurons. The inhibitory effect of apomorphine on the firing rate of A9 and A10 DA neurons was prevented 3-4 hr after the acute or last injection of chronic haloperidol or (-)-sulpiride. However, the inhibitory effect was potentiated 24 hr after the last administration of the chronic regimen with these neuroleptics, but it was not influenced by either acute or chronic treatment with SCH 23390.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Failure of chronic haloperidol to induce depolarization inactivation of dopamine neurons in unanesthetized rats.

Chronic treatment with neuroleptics has been reported to induce a status of depolarization inactivation of the majority of midbrain dopamine neurons. The present study was aimed at determining whether general anesthesia might be a contributory cause of depolarization inactivation of substantia nigra dopamine neurons. In agreement with previous studies, where neuronal sampling was carried out in animals under chloral hydrate anesthesia, chronic treatment with haloperidol (0.5 mg/kg daily for 21-28 days) produced a marked reduction (about 80%) in the number of spontaneously active dopamine neurons. However, when neuronal sampling was performed in unanesthetized rats, chronic administration of haloperidol (daily for 21-28 days) failed to reduce the incidence of active dopaminergic neurons. The results suggest that depolarization inactivation of dopamine neurons is not present in the intact animal but is probably produced during the neuronal sampling procedure as a consequence of neuroleptic-induced hyperexcitability of dopamine neurons combined with their stimulation by general anesthetics.

Analysis of Variance↗
PubMed1994

Carotid artery endarterectomy in patients with contralateral carotid artery occlusion: perioperative hazards and late results.

The aim of this study was to analyze and compare the perioperative hazards and late results of internal carotid endarterectomy (CEA) in patients with and without contralateral internal carotid artery occlusion. From March 1980 to April 1990, 375 consecutive patients underwent 439 CEAs at the First Department of Vascular Surgery of Padova Medical School. Patients were divided into two groups; group 1 (61 patients) had contralateral internal carotid artery occlusion and group 2 (314 patients) did not (378 CEAs, 64 bilateral). Indications for CEA were similar in both groups. The only significant difference in patient characteristics was a higher rate of previous stroke in group 1 (11% vs. 3%, p < 0.001). General anesthesia, continuous EEG monitoring, selective intraluminal shunt, and arteriotomy closure with a polytetrafluoroethylene patch (PTFE) were used routinely in both groups. An intraluminal shunt was inserted more frequently in group 1 than in group 2 (69% vs. 17%, p < 0.001). Major perioperative stroke occurred in one patient in each group (1.7% vs. 0.31%, respectively; NS). Early fatal stroke rates were 0% and 0.95% in groups 1 and 2, respectively (NS). All patients had neurologic examinations and duplex scans every 6 months (range 6 to 118 months; mean 42 months). Kaplan-Meier survival curves were virtually identical in the two groups; the majority of deaths were caused by myocardial infarction and cancer. There were no stroke-related deaths in group 1 as compared with 8.2% in group 2 (NS). New neurologic symptoms appeared in 4.7% of patients in group 1 and 6% in group 2 (NS) whereas the late stroke rates were 0% and 3.1%, respectively (NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

Profound decrement of mesolimbic dopaminergic neuronal activity during ethanol withdrawal syndrome in rats: electrophysiological and biochemical evidence.

Activity of the mesolimbic dopaminergic system was investigated in rats withdrawn from chronic ethanol administration by single-cell extracellular recordings from dopaminergic neurons of the ventrotegmental area, coupled with antidromic identification from the nucleus accumbens, and by microdialysis-technique experiments in the nucleus accumbens. Spontaneous firing rates, spikes per burst, and absolute burst firing but not the number of spontaneously active neurons were found drastically reduced; whereas absolute and relative refractory periods increased in rats withdrawn from chronic ethanol treatment as compared with chronic saline-treated controls. Consistently, dopamine outflow in the nucleus accumbens and its acid metabolites were reduced after abruptly stopping chronic ethanol administration. All these changes, as well as ethanol-withdrawal behavioral signs, were reversed by ethanol administration. This reversal suggests that the abrupt cessation of chronic ethanol administration plays a causal role in the reduction of mesolimbic dopaminergic activity seen in the ethanol-withdrawal syndrome. Results indicate that during the ethanol-withdrawal syndrome the mesolimbic dopaminergic system is tonically reduced in activity, as indexed by electrophysiological and biochemical criteria. Considering the role of the mesolimbic dopaminergic system in the reinforcing properties of ethanol, the depressed activity of this system during the ethanol-withdrawal syndrome may be relevant to the dysphoric state associated with ethanol withdrawal in humans.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Lack of tolerance to ethanol-induced dopamine release in the rat ventral striatum.

The effect of ethanol challenge on the extracellular concentrations of dopamine, 3,4-dihydroxy-phenylacetic acid and homovanillic acid was studied in the ventral striatum of rats repeatedly treated with ethanol. Ethanol-treated animals (1 g/kg i.p. twice a day for 12 days) developed marked tolerance to the behavioral signs of ethanol intoxication when challenged with ethanol (2 g/kg i.p.). However, in ethanol-treated animals the increased output of dopamine and metabolites after ethanol challenge (1 or 2 g/kg i.p.) was not statistically different from that observed in saline-treated rats. These results indicate that tolerance does not develop to the ethanol-induced stimulation of dopamine release and support the hypothesis that activation of the mesolimbic dopamine system contributes to the reinforcing properties of ethanol.

3,4-Dihydroxyphenylacetic Acid↗