Gaetano Di Chiara

Nucleus accumbens shell and core dopamine: Differential role in behavior and addiction.

Drug addiction can be conceptualized as a disturbance of behavior motivated by drug-conditioned incentives. This abnormality has been explained by Incentive-Sensitization and Allostatic-Counteradaptive theories as the result of non-associative mechanisms acting at the stage of the expression of incentive motivation and responding for drug reinforcement. Each one of these theories, however, does not account per se for two basic properties of the motivational disturbance of drug addiction: (1). focussing on drug- at the expenses of non-drug-incentives; (2). virtual irreversibility. To account for the above aspects we have proposed an associative learning hypothesis. According to this hypothesis the basic disturbance of drug addiction takes place at the stage of acquisition of motivation and in particular of Pavlovian incentive learning. Drugs share with non-drug rewards the property of stimulating dopamine (DA) transmission in the nucleus accumbens shell but this effect does not undergo habituation upon repeated drug exposure, as instead is the case of non-drug rewards. Repetitive, non-decremental stimulation of DA transmission by drugs in the nucleus accumbens septi (NAc) shell abnormally strengthens stimulus-drug associations. Thus, stimuli contingent upon drug reward acquire powerful incentive properties after a relatively limited number of predictive associations with the drug and become particularly resistant to extinction. Non-contingent occurrence of drug-conditioned incentive cues or contexts strongly facilitates and eventually reinstates drug self-administration. Repeated drug exposure also induces a process of sensitization of drug-induced stimulation of DA transmission in the NAc core. The precise significance of this adaptive change for the mechanism of drug addiction is unclear given the complexity and uncertainties surrounding the role of NAc core DA in responding but might be more directly related to instrumental performance.

Role of dopamine in the behavioural actions of nicotine related to addiction

Experimental impairment of dopamine function by 6-hydroxydopamine lesions or by dopamine receptor antagonists shows that dopamine is involved in nicotines discriminative stimulus properties, nicotine-induced facilitation of intracranial self-stimulation, intravenous nicotine self-administration, nicotine conditioned place-preference and nicotine-induced disruption of latent inhibition. Therefore, nicotine depends on dopamine for those behavioural effects that are most relevant for its reinforcing properties and are likely to be the basis of the abuse liability of tobacco smoke. On the other hand, in vivo monitoring studies show that nicotine stimulates dopamine transmission in specific brain areas and in particular, in the shell of the nucleus accumbens and in areas of the extended amygdala. These effects of nicotine resemble those of a reward like food except that nicotine-induced release of dopamine does not undergo single-trial, long-lasting habituation. It is speculated that repeated non-habituating stimulation of dopamine release by nicotine in the nucleus accumbens shell abnormally facilitates associative stimulus-reward learning. Acute effects of nicotine on dopamine transmission undergo acute and chronic tolerance; with repeated, discontinuous exposure, sensitization of nicotine-induced stimulation of dopamine release in the nucleus accumbens core takes place while the response in the shell is reduced. It is speculated that these adaptive changes are the substrate of a switch from abnormal incentive responding controlled by consequences (action-outcome responding) into abnormal habit responding, triggered by conditional stimuli and automatically driven by action schemata relatively independent from nicotine reward. These two modalities might coexist, being utilized alternatively in relation to the availability of tobacco. Unavailability of tobacco disrupts the automatic, implicit modality of abnormal habit responding switching responding into the explicit, conscious modality of incentive drug-seeking and craving.

The role of dopamine in drug abuse viewed from the perspective of its role in motivation

Drugs of abuse share with conventional reinforcers the activation of specific neural pathways in the CNS that are the substrate of their motivational properties. Dopamine is recognized as the transmitter of one such neural pathway, being involved in at least three major aspects of motivation: modulation of motivational state, acquisition (incentive learning) and expression of incentive properties by motivational stimuli. Drugs of abuse of different pharmacological classes stimulate in the low dose range dopamine transmission particularly in the ventral striatum. Apart from psychostimulants, the evidence that stimulation of dopamine transmission by drugs of abuse provides the primary motivational stimulus for drug self-administration is either unconvincing or negative. However, stimulation of dopamine transmission is essential for the activational properties of drugs of abuse and might be instrumental for the acquisition of responding to drug-related incentive stimuli (incentive learning). Dopamine is involved in the induction and in the expression of behavioural sensitization by repeated exposure to various drugs of abuse. Sensitization to the dopamine-stimulant properties of specific drug classes leading to facilitation of incentive learning of drug-related stimuli might account for the strong control over behaviour exerted by these stimuli in the addiction state. Withdrawal from drugs of abuse results in a reduction in basal dopamine transmission in vivo and in reduced responding for conventional reinforcers. Although these changes are likely to be the expression of a state of dependence of the dopamine system their contribution to the motivational state of drug addiction is unclear.

Neurobiology of opiate abuse

Opiates interact with cell surface receptors on neurons involved in the transmission of information along neural pathways that are related to behaviours essential for the life of the self and of the species. Opiates are provided with powerful and multifaceted rewarding properties that are fundamental for the acquisition, maintenance and relapse of opiate addiction. Gaetano Di Chiara and Alan North argue that both dopaminergic and non-dopaminergic systems are involved in opiate reward, and that opiate addiction results from adaptive and learning processes involving both positive reinforcing mechanisms related to the rewarding properties of opiates and negative reinforcing mechanisms related to the aversive properties of withdrawal in dependent subjects.

Modulatory functions of neurotransmitters in the striatum: ACh/dopamine/NMDA interactions

The striatum is viewed as a structure performing fast neurotransmitter-mediated operations through somatotopically organized projections to medium-size spiny neurons. This view is contrasted with another view that depicts the striatum as a site of diffuse modulatory influences mediated by cholinergic interneurons and by dopamine and N-methyl-D-aspartate receptors. These two operational and organizational modes both contribute, through their mutual interaction, to the function of basal ganglia. Detailed knowledge of the neural mechanisms by which such interactions take place and are expressed into behaviour, can provide new insight into the physiopathology and new clues for therapy of disorders of basal ganglia.

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.

Modulation of feeding-induced activation of mesolimbic dopamine transmission by appetitive stimuli and its relation to motivational state

We have previously shown in non‐deprived rats that feeding of an unfamiliar palatable food (Fonzies®) phasically stimulates in vivo dopamine (DA) transmission in the medial nucleus accumbens (NAc) and this effect undergoes habituation after a previous (24 h) Fonzies meal ( Bassareo & Di Chiara 1997 , J. Neurosci., 17, 851–861). The present study shows that an unfamiliar food (Kinder®) with a taste and composition (milk chocolate) different from that of Fonzies, also induces a release of DA in the NAc subjected to one‐trial habituation. Habituation was taste specific as no cross‐habituation was observed between Fonzies and Kinder. In undeprived rats, a 40‐min exposure to an intrinsic appetitive stimulus (food smell arising from a Fonzies‐filled plastic box) also prevented the increase in dialysate DA associated with Fonzies feeding, and this effect was partially reversed by food deprivation. Food deprivation also prevented habituation of Fonzies‐induced increase of dialysate DA in the NAc. Predictive association of an empty plastic box to Fonzies feeding resulted in the acquisition of appetitive properties by the box and in facilitation (rather than inhibition) of the phasic responsiveness of DA transmission to Fonzies feeding. A 10‐min pre‐exposure to appetitive olfactory stimuli intrinsic to Fonzies still prevented, like a 40‐min pre‐exposure, the NAc DA response to Fonzies feeding; however, a 5‐min pre‐exposure to these appetitive stimuli did not prevent the DA response in the NAc. These results show that the phasic responsiveness of NAc DA transmission to an unfamiliar palatable food is under strong modulatory control by primary (consummatory) and secondary (appetitive) stimuli, and that the sign and extent of this control depends on the nature of the appetitive stimulus, delay of reward and motivational state (deprivation).

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.

Depression of mesolimbic dopamine transmission and sensitization to morphine during opiate abstinence.

Abstract: To investigate the role of mesolimbic dopamine (DA) in the mechanism of drug dependence, extracellular DA was monitored by transcerebral dialysis in the caudal nucleus accumbens under basal conditions and after challenge with morphine (5 mg/kg s.c.) in control rats and in rats made dependent on and then deprived of morphine. Withdrawal from morphine resulted in a marked reduction of extracellular DA concentrations from control values at 1, 2, 3, and 5 days of withdrawal. After 7 days of withdrawal, DA output was less, but still significantly, reduced. Challenge with morphine resulted in stimulation of DA output in controls (maximum, 35%), no effect on the first day of withdrawal, and stimulation similar to controls’ on days 2 and 7 of withdrawal. On day 5 and, particularly, on day 3 of withdrawal, morphine‐induced stimulation of DA output was markedly potentiated (maximum, 100 and 160%, respectively). Changes in the sensitivity of DA transmission to morphine challenge were associated with changes in the behavioral stimulant effects of morphine, with tolerance on day 1 and marked sensitization on days 3 and 5 but also on day 7, when morphine‐induced stimulation of transmission was no longer potentiated. The results indicate that repeated morphine administration induces a state of dependence in DA neurons and a short‐lasting tolerance followed by an increased sensitivity to its stimulant effects on DA transmission. These changes might play an important role in the development of opiate addiction and in the maintenance of opiate self‐administration in dependent subjects.