Gianluigi Tanda

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.

Self-administration behavior is maintained by the psychoactive ingredientof marijuana in squirrel monkeys

Many attempts to obtain reliable self-administration behavior by laboratory animals with delta-9-tetrahydrocannabinol (THC), the psychoactive ingredient in marijuana, have been unsuccessful. Because self-administration behavior has been demonstrated in laboratory animals for almost all other psychoactive drugs abused by humans, as well as for nicotine, the psychoactive ingredient in tobacco, these studies would seem to indicate that marijuana has less potential for abuse. Here we show persistent intravenous self-administration behavior by monkeys for doses of THC lower than doses used in previous studies, but comparable to doses in marijuana smoke inhaled by humans.

Reciprocal changes in prefrontal and limbic dopamine responsiveness to aversive and rewarding stimuli after chronic mild stress: implications for the psychobiology of depression.

BACKGROUND Chronic mild stress (CMS) has been reported to induce behavioral abnormalities that model human depression. To investigate the role in depression of phasic dopamine transmission in cortical and limbic areas, we studied the effect of CMS on the responsiveness of dopamine (DA) transmission to aversive and rewarding stimuli in rats by microdialysis of the nucleus accumbens (NAc) shell and of the medial prefrontal cortex (PFCX). METHODS Rats were subjected for 30 days to CMS and administered two trials of tail pinch as aversive stimulus and two feeding sessions of a highly palatable food as rewarding stimulus. Concentric microdialysis probes were implanted in the NAc shell and in the medial PFCX. RESULTS In unstressed rats, DA decreased in the NAc and increased in the PFCX on the first tail-pinch trial; on the 1st feeding trial, DA increased in the NAc and to a larger extent in the PFCX. In the second tail-pinch trial or feeding trial, these responses were maintained in the PFCX but underwent habituation in the NAc. CMS did not affect basal dialysate DA in the NAc or in the PFCX but influenced the responsiveness of Da transmission to tail pinches and to feeding in a reciprocal manner. Thus, in the tail-pinch trial, CMS reversed the inhibitory response of NAc DA transmission into a stimulatory one and potentiated the stimulatory response in the PFCX. By contrast, in the feeding trial, CMS blunted the stimulatory response of DA transmission in the NAc in the first trial and in the PFCX in the second trial. CONCLUSIONS CMS reciprocally affected DA responsiveness to motivational stimuli, facilitating or inducing a stimulatory DA response to aversive stimuli but blunting stimulatory responses to rewarding stimuli. Given the postulated role of phasic DA responsiveness in the NAc shell for learning and of DA transmission in the PFCX for expression of motivation, we hypothesize that depression is the result of defective learning and expression of aversive and appetitive motivation.

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.

A dopamine-μ1 opioid link in the rat ventral tegmentum shared by palatable food (Fonzies) and non-psychostimulant drugs of abuse

The role of μ1 opioid receptors in the stimulation of dopamine transmission in the rat nucleus accumbens by an unusual palatable food (Fonzies) and non‐psychostimulant drugs of abuse was investigated by the use of naloxonazine, a pseudo‐irreversible antagonist of μ1 opioid receptors. Feeding of Fonzies stimulated dopamine release in the medial prefrontal cortex and in the shell, but not in the core of the nucleus accumbens. Pretreatment with naloxonazine given systemically (15 mg/kg i.p. 20 h before) completely prevented the stimulation of dopamine release in the shell of the nucleus accumbens by Fonzies without affecting that in the prefrontal cortex. Systemic pretreatment with naloxonazine reduced or, depending on the dose, abolished, the stimulation of dopamine release in the nucleus accumbens shell by morphine, nicotine and ethanol, but did not affect that by haloperidol. Naloxonazine also prevented the stimulatory effects of Fonzies, nicotine and morphine on nucleus accumbens dopamine transmission when infused bilaterally in the ventral tegmental area. The results indicate that μ1 opioid receptors in the ventral tegmentum play a major role in the stimulant effects of food and drugs of abuse on mesolimbic dopamine transmission.

Anandamide administration alone and after inhibition of fatty acid amide hydrolase (FAAH) increases dopamine levels in the nucleus accumbens shell in rats

Although endogenous cannabinoid systems have been implicated in the modulation of the rewarding effects of abused drugs and food, little is known about the direct effects of endogenous ligands for cannabinoid receptors on brain reward processes. Here we show for the first time that the intravenous administration of anandamide, an endogenous ligand for cannabinoid receptors, and its longer‐lasting synthetic analog methanandamide, increase the extracellular dopamine levels in the nucleus accumbens shell of awake, freely moving rats, an effect characteristic of most drugs abused by humans. Anandamide produced two distinctly different effects on dopamine levels: (1) a rapid, transient increase that was blocked by the cannabinoid CB1 receptor antagonist rimonabant, but not by the vanilloid VR1 receptor antagonist capsazepine, and was magnified and prolonged by the fatty acid amide hydrolase (FAAH) enzyme inhibitor, URB597; (2) a smaller delayed and long‐lasting increase, not sensitive to CB1, VR1 or FAAH blockade. Both effects were blocked by infusing either tetrodotoxin (TTX, 1 µm) or calcium‐free Ringers solution through the microdialysis probe, demonstrating that they were dependent on the physiologic activation of dopaminergic neurotransmission. Thus, these results indicate that anandamide, through the activation of the mesolimbic dopaminergic system, participates in the signaling of brain reward processes.

Contribution of blockade of the noradrenaline carrier to the increase of extracellular dopamine in the rat prefrontal cortex by amphetamine and cocaine.

This study was performed to investigate the relative role of noradrenaline (NA) and dopamine (DA) carrier blockade in the effects of psychostimulants on DA transmission in the rat prefrontal cortex (PFCX). To this end, changes of extracellular DA and NA in the PFCX and of extracellular DA in the nucleus accumbens (NAc) were measured following the administration of amphetamine and cocaine, which are known to bind to both DA and NA carriers, or GBR 12909, a selective DA carrier blocker. After non‐intravenous injection, amphetamine (0.25 and 0.5 mg/kg, s.c.) and cocaine (5 and 10 mg/kg, i.p.) increased extracellular DA in the PFCX to a larger extent than in the NAc, while the reverse applied to GBR 12909 (2.5 and 5 mg/kg, i.p.). These differences were obtained in spite of the fact that the three drugs elicited at each dose level a similar peak increase of extracellular DA in the NAc. Amphetamine and cocaine also increased extracellular NA in the PFCX and this effect was quantitatively similar to that on extracellular DA in the same area. Intravenous doses of cocaine and GBR 12909, corresponding to those which maintain self‐administration in the rat, while equieffective in raising extracellular DA in the NAG, had different effects on extracellular DA in the PFCX. In fact, in contrast to cocaine, GBR 12909 increased extracellular DA in the PFCX to a lesser extent than in the NAc or did not modify it at all. The peak increase of extracellular DA in the PFCX was highly correlated to that of NA in the same area but was poorly correlated to the increase of extracellular DA in the NAc. These results suggest that amphetamine and cocaine increase extracellular DA in the PFCX largely through the blockade of the NA carrier. Direct evidence for this hypothesis was provided by the observation that, when the NA carrier was blocked by reverse dialysis of the PFCX with desipramine (1 μM), cocaine and GBR 12909 lost their differences in the ability to increase extracellular DA in the PFCX.

Differential effects of caffeine on dopamine and acetylcholine transmission in brain areas of drug-naive and caffeine-pretreated rats.

The effects of caffeine on extracellular dopamine and acetylcholine have been studied in freely moving rats implanted with concentric microdialysis probes in the nucleus accumbens shell and core and in the medial prefrontal cortex. Intravenous administration of caffeine (0.25, 0.5, 1.0, 2.5 and 5.0 mg/kg) dose-dependently increased dopamine and acetylcholine dialysate concentrations in the medial prefrontal cortex, while it did not affect dialysate dopamine in the shell and core of the nucleus accumbens. Intraperitoneal administration of caffeine (1.5, 3, 10, 30 mg/kg) also failed to affect DA in the shell and core of the nucleus accumbens. Such effects were duplicated by intravenous administration of DPCPX, a selective antagonist of adenosine A1 receptors, and of SCH 58261, an antagonist of A2a receptors. The effect of caffeine on prefrontal dopamine and acetylcholine transmission was also studied in rats chronically administered with caffeine (25 mg/kg, twice a day for seven days). At the end of this treatment rats became tolerant to the locomotor stimulating effects of a dose of 1 and 2.5 mg/kg i.v. of caffeine; these doses, however, still increased dialysate acetylcholine but did not affect dopamine in the prefrontal cortex. Therefore, in rats made tolerant to the locomotor stimulant effects of caffeine, tolerance developed to the dopamine stimulant but not to the acetylcholine stimulant effect of caffeine in the prefrontal cortex. The lack of acute stimulation of dopamine release in the nucleus accumbens shell by caffeine is relevant to the issue of its addictive properties and of the role of DA in drug- and substance-addiction. On the other hand, the dissociation between tolerance to the locomotor effects of caffeine and stimulation of acetylcholine release in the prefrontal cortex suggests that this effect might be correlated to the arousing effects of caffeine as distinct from its locomotor stimulant properties.

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.