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Biomedical subjects

G L Gessa

Publications and source records attributed to G L Gessa.

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 The administration of Delta9-THC to spontaneously withdrawn rats restored neuronal activity.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

Cannabinoid receptor CB1 mRNA is highly expressed in the rat ciliary body: implications for the antiglaucoma properties of marihuana.

We used RT-PCR to measure relative differences in cannabinoid receptor (CB) mRNAs in the rat eye, comparing CB1 or CB2 transcripts to that of the normalizing reference gene beta2 microglobulin (beta2m). Significantly higher levels of CB1 mRNA levels were found in the ciliary body (0.84+/-0.05% of beta2m) than in the iris, (0.34+/-0.04% of beta2m), retina (0.07+/-0.005% of beta2m) and choroid (0.06+/-0.005% of beta2m). CB2 mRNA was undetectable. This expression pattern supports a specific role for the CB1 receptor in controlling intraocular pressure, helping to explain the antiglaucoma property of cannabinoids.

Animals↗
PubMed1998

Cannabinoid modulation of intestinal propulsion in mice.

The effect of cannabinoid receptor activation and blockade on the propulsive activity in the mouse small intestine was assessed in the present study by measuring the transit of an orally administered, non-absorbable marker. The cannabinoid receptor agonist WIN 55,212-2 (R(+)-[2,3-dihydro-5-methyl-3[(morpholinyl)methyl]pyrrolo[1,2,3-de-1, 4benzoxazin-yl]-(1-naphthalenyl)methanone mesylate) inhibited, while the selective cannabinoid CB1 receptor antagonist SR 141716A (N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyraz ole-carboxamide) stimulated the marker transit. Furthermore, a per se non-effective dose of SR 141716A reversed WIN 55,212-2-induced reduction of the transit. The results of the present study suggest a role for cannabinoid CB1 receptors in the control of propulsive activity in the mouse small intestine.

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

Gamma-hydroxybutyric acid intake in ethanol-preferring sP and -nonpreferring sNP rats.

Gamma-hydroxybutyric acid (GHB) and ethanol share several pharmacological similarities, suggesting that GHB may exert ethanol-like effects in the central nervous system. The present study was designed to test whether selectively bred ethanol-preferring rats would, unlike ethanol-nonpreferring ones, self-administer GHB, consistent with their higher preference for ethanol. Male ethanol-naive Sardinian alcohol-preferring (sP) and Sardinian alcohol-nonpreferring (sNP) rats were used. In Experiment 1, GHB solution (1% (w/v) in water) was initially offered as the sole fluid available for 14 consecutive days and then presented under the two-bottle, free-choice regimen, one bottle containing water and the other the GHB solution, for an additional 14 consecutive days. During the free-choice phase, high preference for GHB and intake of pharmacologically relevant daily doses of GHB developed in both rat lines, presumably because the 14-day no-choice period would unmask the reinforcing properties of GHB and lead to acquisition of GHB preference also in the supposedly less susceptible sNP rats. In Experiment 2, the forced GHB drinking phase was reduced to 3 days. Under the subsequent free-choice regimen, daily GHB preference and intake were initially low in both sP and sNP rats; however, after approximately 10 days, GHB preference and intake in sP rats rose progressively and then stabilized to significantly higher levels than in sNP rats throughout the entire free-choice phase. It is likely that episodic binges of GHB intake occurring during the first 10 days resulted in experiencing the reinforcing properties of GHB by sP but not sNP rats. The results of the present study suggest that a) sP rats are genetically more sensitive to the reinforcing effects of both ethanol and GHB than sNP rats; and b) disclosure of the higher sensitivity of sP rats to the reinforcing effects of GHB is a function of the length of the induction procedure. The results are also discussed in terms of differences in GHB receptors contributing to the predisposition to ethanol preference and avoidance, respectively.

Alcohol Drinking↗
PubMed1998

Gamma-hydroxybutyric acid decreases intravenous cocaine self-administration in rats.

Gamma-hydroxybutyric acid (GHB) is an endogenous compound present in mammalian brain suggested as a putative neurotransmitter, which has been shown to affect several aspects of dependence from various classes of drugs of abuse. In the present study, two sets of experiments were performed to investigate the effects of acute pretreatment with GHB on intravenous cocaine self-administration in rats. In the first experiment GHB was administered intragastrically at the doses of 175, 350, and 700 mg/kg to Long-Evans rats trained to self-administer cocaine using nose-poke as operandum. In the second experiment, GHB was administered intraperitoneally at the doses of 100, 200, and 400 mg/kg to Wistar rats trained to self-administer cocaine intravenously using lever-pressing as operandum. In both experiments acute pretreatment with GHB significantly and dose dependently reduced cocaine self-administration. The effectiveness of GHB was similar in both experiments, indicating that the effect of GHB on cocaine self-administration is independent of animal strain. route of administration, and type of operant response required. These results indicate that GHB reduces cocaine-seeking behavior in rats, modulating the acute reinforcing effect of cocaine. The clinical effectiveness of GHB in dependence from various classes of abused drugs warrants further studies to evaluate the possibility that GHB might represent a useful therapeutic agent for cocaine addiction in humans.

Anesthetics, Intravenous↗
PubMed1998

Preprotachykinin-A gene expression in the forebrain of Sardinian alcohol-preferring and -nonpreferring rats.

Increasing evidence suggests that TKergic mechanisms might play a role in ethanol intake control. Preprotachykinin-A (PPT-A) mRNA brain levels were measured in Sardinian alcohol-preferring (sP) and Sardinian alcohol-nonpreferring (sNP) rats. PPT-A mRNAs were about 50% lower in sP than in sNP rats in the bed nucleus of the stria terminalis (BNST), whereas levels in the olfactory tubercle (Tu) were about 30% higher in sP than in sNP rats. Our findings suggest that altered PPT-A gene expression might contribute to the different ethanol preference and intake of sP opposite to sNP rats.

Alcohol Drinking↗
PubMed1998

Self-administration of the cannabinoid receptor agonist WIN 55,212-2 in drug-naive mice.

Marijuana is one of the most widely used illicit recreational drugs. However, contrary to the majority of drugs abused by humans, there is a general opinion that rewarding effects are not manifested by animals. We studied a synthetic cannabinoid agonist WIN 55,212-2 using an intravenous self-administration model in drug-naive mice. The results of this study show that WIN 55,212-2 was intravenously self-administered by mice in a concentration-dependent manner according to a bell-shaped curve. Thus, self-administration of WIN 55,212-2 significantly increased, with respect to the vehicle self-administration control group, at concentrations of 0.5 and 0.1 mg/kg per injection. However, at WIN 55,212-2 concentration of 0.5 mg/kg per injection, self-administration significantly decreased. The results obtained show how WIN 55,212-2 is able to elicit both rewarding and aversive effects depending on the concentration used. Pretreatment of mice with the cannabinoid CB1 receptor antagonist SR 141716A (0.25 mg/kg, i.p.) completely prevented WIN 55,212-2 (0.1 mg/kg per injection) self-administration, indicating that WIN 55,212-2 rewarding effects are specifically mediated by cannabinoid CB1 receptors.

Analgesics↗
PubMed1997

Psychiatric severity and treatment response in a comprehensive methadone maintenance treatment program.

The purpose of this study was to investigate the influence of the severity of concomitant psychiatric symptomatology on some selected measures of methadone maintenance treatment efficacy in a comprehensive methadone maintenance treatment program (MMTP). The cohort studied included 267 patients who entered a maintenance program in the years 1991-92. Two groups of patients differing in the severity of psychiatric symptomatology were obtained on the bases of the referral to the psychiatrist and the ascertainment of a current disorder. These two groups were compared for retention in treatment, urine tests positive for morphine while in treatment and methadone dose during an observation period of 2 years. The outcome of the study suggests that on these outcome parameters, patients on MMTP who are more psychiatrically ill can perform as well as the other patients.

Adult↗
PubMed1997

Opposite effects of stress on dopamine release in the limbic system of drug-naive and chronically amphetamine-treated rats.

The effects of repeated amphetamine administration on stress-induced dopamine release in the ventral striatum were examined in male Wistar rats treated with D-amphetamine (1.5 mg/kg; i.p./injection) or saline at 12 h intervals for 14 days. After 12 h as well as 7 days of amphetamine withdrawal, dopamine release was monitored by transverse microdialysis under basal conditions and during exposure to 60 min of restraint stress. Basal dopamine release was significantly suppressed relative to saline-pretreated controls after both 12 h and 7 days of amphetamine withdrawal. In control rats, restraint stress resulted in significantly increased dopamine efflux. In contrast, exposure to this stressor was associated with a significant suppression of dopamine release in rats chronically exposed to amphetamine. This effect was observed at both post-amphetamine test points. The results suggest that chronic amphetamine impairs the dopaminergic response to stress and that this dopaminergic deficit may play a role in stress-induced drug-seeking behavior and relapse.

Amphetamine↗
PubMed1997

Dizocilpine prevents the enhanced locomotor response to quinpirole induced by repeated electroconvulsive shock.

Repeated administration of electroconvulsive shock, as expected, potentiated the locomotor stimulant response to quinpirole (0.3 mg/kg s.c.), a dopamine D2-like receptor agonist. Chronic, but not acute, treatment with the NMDA receptor non-competitive antagonist dizocilpine (0.3 mg/kg i.p.) prevented electroconvulsive shock-induced potentiation of quinpirole locomotor response. These results suggest that NMDA receptor activation is necessary for the development of supersensitivity to dopamine receptor agonists produced by repeated electroconvulsive shock. The relevance of this observation in regard to the mechanism of electroconvulsive shock therapeutic effect is discussed.

Animals↗
PubMed1997

Inhibition of hippocampal acetylcholine release by cannabinoids: reversal by SR 141716A.

Two synthetic cannabinoids, WIN 55,212-2 {R-(+)-(2,3-dihydro-5-methyl-3-[{4-morpholinylmethyl]pyrol [1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl)methanone monomethanesulfonate} (5.0 and 10 mg/kg i.p.) and CP 55,940 {[1a,2-(R)-5-(1.1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-phenol} {[1a,2-(R)-5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-phenol} (0.5 and 1.0 mg/kg i.p.), inhibited acetylcholine release in the rat hippocampus. The inhibition was prevented by the cannabinoid receptor antagonist, SR 141716A {N-(piperidin-1-yl)-5-(4- chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide} HCl, at the dose of 0.1 mg/kg i.p. Higher doses of SR 141716A (1.0 and 3.0 mg/kg i.p.) themselves increased hippocampal acetylcholine release, suggesting that acetylcholine output is tonically inhibited by endogenous cannabinoids. The results also suggest that the negative effects of marijuana on learning and memory may depend on cannabinoid receptor-mediated inhibition of acetylcholine release.

Acetylcholine↗
PubMed1997

Chronic morphine and naltrexone fail to modify mu-opioid receptor mRNA levels in the rat brain.

Previous radioligand-binding studies have reported conflicting results concerning the effect of chronic morphine administration on the regulation of mu-opioid receptor (MOR) density. On the other hand, chronic administration of an opioid antagonist, such as naltrexone, has been shown to increase the density of the MOR. In order to determine if the changes in the MOR are associated with alterations in receptor mRNA levels, we investigated MOR gene expression following chronic treatment with morphine and/or naltrexone. MOR mRNA levels, determined by the ribonuclease protection assay (RPA), were unchanged with respect to control during chronic morphine treatment and morphine withdrawal in each of the analysed brain areas. Furthermore, chronic administration of naltrexone did not result in changes of MOR mRNA levels in rat striatum of naive and morphine-dependent rats, suggesting that the up-regulation of the MOR density, at least in this tissue, is not regulated at transcriptional level.

Animals↗
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

Role of D1 and alpha1 receptors in the enhanced locomotor response to dopamine D2-like receptor stimulation induced by repeated electroconvulsive shock.

We previously reported that, in rats chronically treated with the antidepressant drug imipramine, the enhanced locomotor response to the D2-like receptor agonist quinpirole became less sensitive to the inhibitory effect of the D1 receptor antagonist SCH 23390 and more sensitive to the inhibitory effect of the alpha1 receptor antagonist prazosin. In this study, we show that in electroconvulsive shock-treated rats these antagonists behave in the opposite manner to that observed in imipramine-treated rats, with SCH 23390 being highly effective and prazosin ineffective in antagonizing the locomotor response to quinpirole. The possibility that these differences may reflect some of the clinical characteristics of these antidepressant treatments is discussed.

Animals↗
PubMed1997

Evolution of the dopaminergic system and its relationships with the psychopathology of pleasure.

This paper summarizes the fundamental steps in the evolution of the dopaminergic system. A rudimentary dopaminergic system is present in primitive creatures, already able to select information processing, modulate "emotional" behaviours and react to perturbations in environmental conditions. Pharmacological manipulations of the dopaminergic transmission are able to modify basic behaviours present in all animals from fishes to lizards to mammals. The ability to put the organism in motion and the hedonic capacity of giving pleasure, would justify the conservation through evolution of such a neuronal system. The fact however that the dopaminergic system has remained identical for the last several centuries, while many external conditions which interfere with its physiology have dramatically changed, may contribute to explain the transition from the original vital advantages of the dopaminergic system to its crucial role in the psychopathology of pleasure.

Animals↗