Ezio Carboni

Amphetamine, cocaine, phencyclidine and nomifensine increase extracellular dopamine concentrations preferentially in the nucleus accumbens of freely moving rats

The effect of systemically administered amphetamine, cocaine, phencyclidine and nomifensine on the extracellular concentrations of dopamine in freely moving rats was estimated by microdialysis in the nucleus accumbens and in the dorsal caudate. All the drugs tested stimulated dopamine output in both areas but more effectively in the accumbens as compared to the caudate. Low doses of cocaine (1.0 mg/kg s.c.) stimulated dopamine output only in the nucleus accumbens. Nomifensine (1.25-5.0 mg/kg s.c.) increased by a similar extent peak dopamine output in the two dopaminergic areas but the duration of the effect was longer in the accumbens as compared to the caudate. The effect of cocaine, phencyclidine and nomifensine was prevented by systemic gamma-butyrolactone (700 mg/kg i.p.) and by omitting Ca2+ from the Ringer used for dialysis, the effect of amphetamine was insensitive to these manipulations. Thus, in contrast with amphetamine, cocaine, phencyclidine and nomifensine increase synaptic dopamine concentrations in vivo by a mechanism which depends on intact activity of dopaminergic neurons and by an exocytotic process.

Blockade of the noradrenaline carrier increases extracellular dopamine concentrations in the prefrontal cortex: evidence that dopamine is taken up in vivo by noradrenergic terminals.

Abstract: The effect of systemic administration of desmethylimipramine (DMI) and oxaproptiline (OXA), two inhibitors of the noradrenaline (NA) reuptake carrier, on the in vivo extracellular concentrations of dopamine (DA) was studied by transcerebral dialysis in the prefrontal cortex and in the dorsal caudate of freely moving rats. In the NA‐rich prefrontal cortex, either drug increased extracellular DA concentrations whereas in the dorsal caudate neither was effective. Haloperidol increased extracellular DA concentrations more effectively in the dorsal caudate than in the prefrontal cortex. Pre‐treatment with DMI or OXA. which failed to modify the effect of haloperidol in the dorsal caudate, potentiated its action in the prefrontal cortex. 6‐Hydroxydopamine lesioning of the dorsal NA bundle prevented the ability of OXA to increase DA concentrations. The results suggest that reuptake into NA terminals is an important mechanism by which DA is cleared from the extracellular space in a NA‐rich area such as the prefrontal cortex. The elevated extracellular concentrations of DA resulting from blockade of such mechanism by tricyclic antidepressants may play a role in the therapeutic effects of these drugs.

Increase of extracellular dopamine in the prefrontal cortex: a trait of drugs with antidepressant potential?

Drugs differing in their primary mechanism of action but having in common the ability to act as antidepressants such as fluoxetine (10 mg/kg SC), clomipramine (10 mg/kg IP), imipramine (10 mg/kg IP), desipramine (10 mg/kg IP) and (±)8-OHDPAT (0.03 mg/kg SC) increase extracellular concentrations of dopamine in the rat prefrontal cortex but not in the medial nucleus accumbens. Buspirone (1 mg/kg SC) increased dopamine both in the prefrontal cortex and in the nucleus accumbens. Extracellular 5HT was increased by fluoxetine, clomipramine and imipramine but not by desipramine while 8-OHDPAT and buspirone decreased it. These results raise the possibility that the property of stimulating dopamine transmission in the prefrontal cortex has a role in the antidepressant properties of these drugs.

Differential inhibitory effects of a 5-HT3 antagonist on drug-induced stimulation of dopamine release

The effects of a potent and specific antagonist of 5-HT3 receptors, ICS 205-930, on the dopamine (DA)-releasing properties of morphine (1.0 mg/kg s.c.), nicotine (0.6 mg/kg s.c.), ethanol (1.0 g/kg i.p.) and amphetamine (0.25 and 1.0 mg/kg s.c.) were studied in rats. DA release was estimated by trans-cerebral dialysis in the nucleus accumbens of freely moving rats. ICS 205-930 (15-30 micrograms/kg s.c.) failed to modify the basal output of DA and its metabolites, however, ICS 205-930 dose dependently reduced the stimulation of DA release by morphine, nicotine and ethanol. Thus, at doses of 30 micrograms/kg s.c., ICS 205-930 completely prevented the morphine-, nicotine- and ethanol-induced stimulation of DA release in the nucleus accumbens; doses of 15 micrograms/kg s.c. partially prevented the morphine-, nicotine- and ethanol-induced stimulation of DA release while doses of 7.5 micrograms/kg s.c. were ineffective. In contrast, ICS 205-930 (up to 30 micrograms/kg s.c.) failed to affect the amphetamine-induced stimulation of DA release in the nucleus accumbens. The inhibitory effects of ICS 205-930 (15 and 30 micrograms/kg s.c.) on the drug-induced stimulation of DA release could also be extended to the neuroleptic haloperidol (0.1 mg/kg s.c.). The results indicate that blockade of 5-HT3 receptors selectively prevents the stimulation of DA release induced by drugs known to stimulate the firing activity of DA neurons.

Drug Addiction as a Disorder of Associative Learning: Role of Nucleus Accumbens Shell/Extended Amygdala Dopamine

ABSTRACT: Conventional reinforcers phasically stimulate dopamine transmission in the nucleus accumbens shell. This property undergoes one‐trial habituation consistent with a role of nucleus accumbens shell dopamine in associative learning. Experimental studies with place‐ and taste‐conditioning paradigms confirm this role. Addictive drugs share with conventional reinforcers the property of stimulating dopamine transmission in the nucleus accumbens shell. This response, however, undergoes one‐trial habituation in the case of conventional reinforcers but not of drugs. Resistance to habituation allows drugs to repetitively activate dopamine transmission in the shell upon repeated self‐administration. This process abnormally facilitates associative learning, leading to the attribution of excessive motivational value to discrete stimuli or contexts predictive of drug availability. Addiction is therefore the expression of the excessive control over behavior acquired by drug‐related stimuli as a result of abnormal strenghtening of stimulus‐drug contingencies by nondecremental drug‐induced stimulation of dopamine transmission in the nucleus accumbens shell.

SCH 23390 blocks drug-conditioned place-preference and place-aversion: anhedonia (lack of reward) or apathy (lack of motivation) after dopamine-receptor blockade?

The influence of the D1 antagonist SCH 23390 on the motivational properties of rewarding (morphine, nicotine and diazepam) and aversive (naloxone, phencyclidine and picrotoxin) drugs was studied in the rat in a two-compartment place-conditioning paradigm, which included a pre-conditioning test for spontaneous place-preference. The specific D1 dopamine-receptor antagonist SCH 23390 (0.05 mg/kg SC), paired with both compartments or, separately, with the preferred or with the non-preferred compartment, failed to affect the spontaneous unconditioned preference of the animal. Pairing of morphine (1.0 mg/kg SC), nicotine (0.6 mg/kg SC) or diazepam (1.0 mg/kg IP) with the less preferred compartment induced significant preference for that compartment. Pairing of SCH 23390 (0.05 mg/kg SC) with both compartments completely blocked the place-preference induced by morphine, nicotine and diazepam. Naloxone (0.8 mg/kg SC), phencyclidine (2.5 mg/kg SC) or picrotoxin (2.0 mg/kg IP) paired with the preferred compartment elicited place-aversion. Pairing of SCH 23390 (0.05 mg/kg SC) with both compartments abolished also the place-aversion induced by naloxone, phencyclidine and picrotoxin. The results indicate that blockade of dopamine transmission blocks the motivational properties of rewarding as well as aversive stimuli. It is suggested that neuroleptics rather than simply blocking the rewarding impact of positive reinforcers (anhedonia, lack of pleasure) exert a more general influence on conditioned behaviour by blocking the affective impact of negative as well as positive reinforcers (apathy, lack of motivation).

5HT3 receptor antagonists block morphine- and nicotine-but not amphetamine-induced reward

The effect of two potent and specific antagonists of 5HT3 receptors, ICS 205-930 and MDL 72222, on the reinforcing properties of amphetamine, morphine and nicotine was studied in rats. Durg-induced reinforcement was assessed by measuring drug-conditioned place preference. ICS 205-930 and MDL 72222 dose-dependently reduced the place preference induced by morphine (1.0 mg/kg SC). At doses of 0.030 mg/kg SC the two antagonists completely blocked morphine-induced place preference while doses of 0.015 mg/kg SC significantly reduced it. ICS 205-930 and MDL 72222 at doses of 0.030 mg/kg SC also prevented the place preference induced by nicotine (0.6 mg/kg SC). In contrast, ICS 205-930 and MDL 72222 up to doses of 0.030 mg/kg SC failed to modify the place preference elicited by amphetamine (1.0 mg/kg SC). The results indicate that 5HT3 receptors are specifically involved in the reinforcing properties of morphine and nicotine.

Serotonin release estimated by transcortical dialysis in freely-moving rats

The transcerebral dialysis method has been utilized for measuring extracellular brain concentrations of serotonin and 5-hydroxyindolacetic acid. Dialysis fibres were implanted transversally in the rat frontal cortex and perfused by Ringer. Serotonin and 5-hydroxyindolacetic acid were quantified by reverse phase high performance liquid chromatography with electrochemical detection. Experiments were performed in freely-moving rats 20-24 h after the implant of the fibre. Basal output of serotonin and 5-hydroxyindolacetic acid was 0.12 and 22.8 pmol in 20 min, respectively. The output of serotonin was calcium-dependent and tetrodotoxin-sensitive (1 micron in the Ringer) while was stimulated by veratridine (50 microns) and by high concentrations of K+ (60 and 100 mM). Serotonin output was increased in a concentration-dependent manner by chlorimipramine (1-10 microM) in the Ringer; this drug stimulated serotonin release also when administered s.c. (20 mg/kg) in a tetrodotoxin-sensitive manner. The irreversible monoamine-oxidase inhibitor pargyline (75 mg/kg, i.p.) strongly stimulated serotonin output while reduced 5-hydroxyindolacetic acid output. A proposed serotonin releaser, fenfluramine (25 mg/kg, s.c.), stimulated serotonin release and this effect was strongly potentiated by local application of tetrodotoxin (1 microM). Agonists of serotonin receptors such as lisuride (0.03 mg/kg, s.c.), 8-hydroxy-2-(di-n-propilamino)tetraline (0.25 mg/kg, s.c.) and 5-methoxy 3(1,2,3,6-tetrahydro-4-pyridinil)-1H indole succinate (1 mg/kg, s.c.) reduced serotonin release. It appears that brain dialysis is a suitable method for the study of serotonin release in the cortex of freely-moving rats.

PPAR-gamma-mediated neuroprotection in a chronic mouse model of Parkinson’s disease

Rosiglitazone is a commonly prescribed insulin‐sensitizing drug with a selective agonistic activity on the peroxisome proliferator‐activated receptor‐gamma (PPAR‐γ). PPAR‐γ can modulate inflammatory responses in the brain, and agonists might be beneficial in neurodegenerative diseases. In the present study we used a chronic 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine plus probenecid (MPTPp) mouse model of progressive Parkinson’s disease (PD) to assess the therapeutic efficacy of rosiglitazone on behavioural impairment, neurodegeneration and inflammation. Mice chronically treated with MPTPp displayed typical features of PD, including impairment of motor and olfactory functions associated with partial loss of tyrosine hydroxylase (TH)‐positive neurons in the substantia nigra pars compacta (SNc), decrease of dopamine (DA) and 3,4‐dihydroxyphenylacetic acid (DOPAC) content and dynorphin (Dyn) mRNA levels in the caudate‐putamen (CPu), intense microglial and astroglial response in the SNc and CPu. Chronic rosiglitazone, administered in association with MPTPp, completely prevented motor and olfactory dysfunctions and loss of TH‐positive cells in the SNc. In the CPu, loss of striatal DA was partially prevented, whereas decreases in DOPAC content and Dyn were fully counteracted. Moreover, rosiglitazone completely inhibited microglia reactivity in SNc and CPu, as measured by CD11b immunostaining, and partially inhibited astroglial response assessed by glial fibrillary acidic protein immunoreactivity. Measurement of striatal MPP+ levels 2, 4, 6 h and 3 days after chronic treatment indicated that MPTP metabolism was not altered by rosiglitazone. The results support the use of PPAR‐γ agonists as a putative anti‐inflammatory therapy aimed at arresting PD progression, and suggest that assessment in PD clinical trials is warranted.

On the preferential release of dopamine in the nucleus accumbens by amphetamine: further evidence obtained by vertically implanted concentric dialysis probes

Concentric dialysis probes were vertically implanted in rats in the nucleus accumbens (Acc) of one side and in the dorsal caudate-putamen (CPu) of the other side. On the day after the implant the output of dopamine was monitored and the changes elicited byd-amphetamine sulphate were compared in the two areas. Amphetamine preferentially stimulated dopamine release in the Acc in a wide range of doses (0.25, 0.5, 1.0, 2.0 mg/kg SC) when Acc probes were located in the medial aspect of the Acc. In contrast, no significant differences between the Acc and the dorsal CPu were obtained in response to amphetamine (0.5 mg/kg SC) when Acc probes were located about 0.7 mm lateral to the previous site. It is concluded that the preferential effect of amphetamine in the Acc is related to precise topographical boundaries. This in turn might be related to the existence of a sharp anatomical and functional heterogeneity within the Acc.