C Cadoni

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.

Reciprocal changes in dopamine responsiveness in the nucleus accumbens shell and core and in the dorsal caudate–putamen in rats sensitized to morphine

In this study, we describe a model of opiate sensitization characterized by a brief schedule of treatment with repeated morphine administrations. In this model, we investigated the changes produced by repeated morphine treatment on dopamine transmission at the level of the two major terminal dopaminergic areas, the dorsolateral caudate-putamen and the nucleus accumbens in its two subdivisions, the shell and the core. Rats were treated twice a day for three days with increasing doses of morphine (10, 20 and 40 mg/kg, s.c.) or with saline. After 15 days of withdrawal, rats were challenged with 1 and 5 mg/kg (s.c.) of morphine, and dopamine transmission was monitored by microdialysis. In this model, we show that repeated morphine produces a strong behavioral sensitization accompanied by increased stimulation of dopamine transmission in the core of the nucleus accumbens and in the caudate-putamen, and by a decreased stimulation of dopamine transmission in the shell of the nucleus accumbens, as compared to control rats. Moreover, we administered to these animals amphetamine (0.5 mg/kg, s.c.) and cocaine (10 mg/kg, i.p.) to assess whether cross-sensitization occurs between opiates and psychostimulants in conditions independent of the context. In the present study, we did not observe either behavioral or biochemical sensitization to amphetamine and to cocaine in rats sensitized to morphine. These results suggest that rats behaviorally sensitized to morphine show opposite changes in the stimulant effect of morphine in the nucleus accumbens shell and core and in the dorsal caudate-putamen. Moreover, this study suggests that sensitization of the dopamine system to a given agent does not necessarily extend to drugs of abuse of different pharmacological classes.

Psychostimulant sensitization: differential changes in accumbal shell and core dopamine.

The nucleus accumbens has been subdivided into a shell and a core compartment on the basis of histochemical and connectional differences. Recently, we reported that behavioral sensitization to morphine is associated with an increased dopamine transmission in the caudate-putamen and in the nucleus accumbens core as well as a decreased response in the nucleus accumbens shell following acute morphine challenge. We have now performed a similar study in rats sensitized to amphetamine and to cocaine. Behavioral sensitization was induced by daily administration of a single dose of 1 mg/kg s.c. of amphetamine for 10 days or of 10 mg/kg i.p. of cocaine twice a day for 14 days. Microdialysis was performed 10-14 days after the last injection of amphetamine and 7-10 days after the last injection of cocaine. Both schedules resulted in robust behavioral sensitization in response to challenge with 0.25 and 0.5 mg/kg of amphetamine and to 5 and 10 mg/kg of cocaine, respectively. Subjects pre-exposed to amphetamine showed a sensitization of dopamine transmission in the nucleus accumbens core but not in the nucleus accumbens shell. Subjects pre-exposed to cocaine showed sensitization of dopamine transmission in the core only to the lower dose of cocaine. In the shell no change was observed after the lower dose of cocaine while a significant reduction of the dopamine response was observed after the higher dose. These results suggest that behavioral sensitization might result from reciprocal changes in the response of nucleus accumbens dopamine in the shell and in the core to drug challenge.

Differential changes in accumbens shell and core dopamine in behavioral sensitization to nicotine.

Repeated treatment with nicotine has been shown to sensitize rats to its locomotor stimulant effects and to its properties to stimulate mesolimbic dopamine transmission. We investigated the relationship between sensitization of nicotine induced locomotor stimulation and activation of dopamine transmission in the nucleus accumbens shell and core. Rats were administered daily for 5 days with 0.4 mg/kg s.c. of nicotine or with saline and 24 h later, dopamine was monitored by microdialysis in the shell and in the core of nucleus accumbens and behavioral activity was scored after challenge with nicotine (0. 4 mg/kg s.c.). Behavioral sensitization to nicotine was associated with a reduced response of dopamine transmission in the shell and with an increased one in the core of nucleus accumbens.

Selective psychostimulant sensitization by food restriction: differential changes in accumbens shell and core dopamine

We have recently reported that behavioural sensitization to morphine, amphetamine, cocaine and nicotine is associated with an increased response of dialysate dopamine to the same drugs in the nucleus accumbens core and/or a reduced response in the shell. Prolonged exposure to stressful stimuli also induces behavioural sensitization to drugs of abuse. We therefore investigated the effect of different drugs of abuse on behaviour and on dopamine transmission in the nucleus accumbens shell and core of rats stressed by 1 week schedule of food restriction. Food‐restricted rats (80% of their initial body weight) were implanted with microdialysis probes in the nucleus accumbens shell and core and challenged with cocaine (5 and 10 mg/kg i.p.), amphetamine (0.25 and 0.5 mg/kg s.c.), morphine (1 and 2 mg/kg s.c.), nicotine (0.2 and 0.4 mg/kg s.c.) and the changes in dialysate dopamine transmission were monitored together with the behaviour. Food restricted rats showed strong behavioural sensitization to cocaine and amphetamine but not to morphine or nicotine as compared to ad libitum fed controls. Behavioural sensitization to psychostimulants was associated with an increased response of dialysate dopamine in the core and with an unchanged or even reduced response in the shell. No significant differences were observed between controls and food‐restricted animals in the ability of morphine and nicotine to stimulate dopamine transmission in the shell and core. The present results indicate that a sensitized dopamine response in the nucleus accumbens core is a general feature of the expression of behavioural sensitization.

Role of vesicular dopamine in the in vivo stimulation of striatal dopamine transmission by amphetamine: evidence from microdialysis and Fos immunohistochemistry.

The role of vesicular and newly synthesized dopamine in the action of amphetamine was investigated by studying the effect of reserpine and alpha-methyl-p-tyrosine pretreatment on amphetamine-induced changes in extracellular dopamine and acetylcholine, estimated by brain microdialysis, and on c-fos expression, estimated by quantitative immunohistochemistry of the Fos antigene, in the dorsal caudate-putamen of rats. Blockade of dopamine synthesis by alpha-methyl-p-tyrosine pretreatment (1 or 2 h) only partially prevented the increase in extracellular dopamine concentrations elicited by 0.5 and 2 mg/kg s.c. of amphetamine. Inactivation of vesicular amine uptake by reserpine pretreatment (3 h) reduced the increase in extracellular dopamine by 2 mg/kg but not by 0.5 mg/kg of amphetamine. Combined pretreatment with reserpine (3 h) and alpha-methyl-p-tyrosine (1 h) drastically reduced the increase in extracellular dopamine by both doses of amphetamine (0.5 and 2 mg/kg s.c.). alpha-Methyl-p-tyrosine pretreatment reduced c-fos expression stimulated by amphetamine (2 mg/kg) in the dorsomedial and dorsolateral caudate-putamen while reserpine pretreatment reduced it only in the dorsolateral caudate-putamen. Amphetamine (2 mg/kg s.c.) stimulated acetylcholine release but this effect was not modified by reserpine or alpha-methyl-p-tyrosine pretreatment. The results indicate that blockade of dopamine synthesis, by itself, is insufficient to prevent the stimulation of dopamine transmission by amphetamine and, conversely, that inactivation of vesicular dopamine significantly reduces amphetamine effects at pre- and postsynaptic levels. Therefore, vesicular dopamine appears to contribute to the stimulation of dopamine transmission elicited by amphetamine in the dorsal caudate-putamen.

Calcium-dependent, tetrodotoxin-sensitive stimulation of cortical serotonin release after a tryptophan load.

The effect of intraperitoneal administration of tryptophan (50, 100, or 200 mg/kg) on extracellular concentrations of tryptophan, serotonin (5‐hydroxytryptamine, 5‐HT), and 5‐hydroxyindoleacetic acid (5‐HIAA) was studied in the cortex of freely moving rats by transcerebral dialysis. Rats were implanted with dialysis probes in the frontal cortex, and experiments were performed 24 h later. Tryptophan, 5‐HT, and 5‐HIAA were quantified in 20‐min samples of dialysate by HPLC with electrochemical detection after separation on reverse‐phase columns. Tryptophan administration resulted in a significant increase of tryptophan, 5‐HT, and 5‐HIAA levels in di‐alysates. The maximal increase of 5‐HT and 5‐HIAA output was ˜ 150% over basal values. Perfusion with Ringers solution containing tetrodotoxin (1 μM) reduced 5‐HT output by 90% and prevented the increase of 5‐HT and 5‐HIAA content after 100 mg/kg of tryptophan. Similar results were obtained after perfusion with Ringers solution without Ca2+. The results indicate that a tryptophan load stimulates the physiological release of 5‐HT.

Behavioral sensitization to Δ9‐tetrahydrocannabinol and cross‐sensitization with morphine: differential changes in accumbal shell and core dopamine transmission

Although cannabinoid‐induced behavioral sensitization and cross‐sensitization with opiates has been recently demonstrated, no information is available on the associated state and responsiveness of dopamine (DA) transmission in the nucleus accumbens (NAc) shell and core. In this study we investigate by means of dual probe microdialysis, the effect of exposure to a sensitizing regimen of Δ9‐tetrahydrocannabinol (Δ9‐THC) and morphine on the extracellular concentrations of DA under basal conditions and after challenge with Δ9‐THC and morphine in the NAc shell and core. Different groups of male Sprague–Dawley rats were administered twice daily for 3 days with increasing doses of Δ9‐THC (2, 4, and 8 mg/kg i.p.), morphine (10, 20, and 40 mg/kg s.c.), and vehicle. After 14–20 days from the last injection, the animals were implanted with two microdialysis probes, one aimed at the NAc shell and the other at the core. The following day animals pre‐treated with Δ9‐THC and vehicle controls were challenged with 150 μg/kg i.v. of Δ9‐THC or 0.5 mg/kg i.v. of morphine. Animals pre‐treated with morphine and their vehicle controls were administered with 150 μg/kg i.v. of Δ9‐THC. Rats pre‐exposed to Δ9‐THC showed behavioral sensitization associated with a reduced stimulation of DA transmission in the NAc shell and an increased stimulation in the NAc core in response to Δ9‐THC challenge. Pre‐exposure to Δ9‐THC induced behavioral sensitization to morphine also, but only a reduced stimulation of DA transmission in the NAc shell was observed. Animals pre‐treated with morphine showed behavioral sensitization and differential changes of DA in the NAc shell and core in response to Δ9‐THC challenge with a decreased response in the shell and an increased response in the core. The results show that Δ9‐THC‐induced behavioral sensitization is associated with changes in the responsiveness of DA transmission in the NAc subdivisions that are similar to those observed in the sensitization induced by other drugs of abuse.

Homologies and differences in the action of drugs of abuse and a conventional reinforcer (food) on dopamine transmission: an interpretative framework of the mechanism of drug dependence.

Publisher Summary Drugs of abuse and Fonzies (palatable food) share the properties of stimulating dopamine (DA) transmission within the nucleus accumbens “shell,” as compared with the “core” Nonpsychostimulant drugs of abuse and food depend for their property of stimulating DA release in the shell of the nucleus accumbens on an activation of the μ 1 subtype of opioid receptors. Substances of abuse and Fonzies show differences in their ability to influence DA transmission in the prefrontal cortex. Fonzies activate DA release in the prefrontal cortex, but drugs of abuse, as a whole, do not activate DA transmission in the prefrontal cortex. Studies on Fonzies show that DA plays a different role in the prefrontal cortex and in the nucleus accumbens. It appears that while prefrontal DA transmission reacts to generically salient stimuli independently of motivational state, nucleus accumbens DA reacts to these stimuli only under a deprivation state. Under a nondeprivation state, nucleus accumbens DA reacts only to strong, unconditioned, novel, a d unpredicted stimuli. It is suggested that phasic stimulation of DA release in the shell of the nucleus accumbens by a conventional reinforcer such as food is not essential for the expression of incentive behavior and for the hedonic sensations arising from consumption of the reward. Thus, naloxonazine, a slowly reversible μ 1 antagonist, blocks the stimulation of DA release in the nucleus accumbens shell by morphine, nicotine, and ethanol, as well as by palatable food. Therefore, under nondeprivation conditions, stimulation of dopamine release in the shell of the nucleus accumbens might be related to the acquisition rather than the expression of motivated behavior.

Differences in dopamine responsiveness to drugs of abuse in the nucleus accumbens shell and core of Lewis and Fischer 344 rats

The use of inbred rat strains provides a tool to investigate the role of genetic factors in drug abuse. Two such strains are Lewis and Fischer 344 rats. Although several biochemical and hormonal differences have been observed between Lewis and Fischer 344 strains, a systematic comparison of the effect of different drugs of abuse on dopamine (DA) transmission in the shell and core of the nucleus accumbens of these strains is lacking. We therefore investigated, by means of dual probe microdialysis, the effect of different doses of morphine (1.0, 2.5, and 5.0 mg/kg), amphetamine (0.25, 0.5, and 1.0 mg/kg) and cocaine (5, 10, and 20 mg/kg) on DA transmission in the shell and in the core of nucleus accumbens. Behavior was monitored during microdialysis. In general, Lewis rats showed greater DA responsiveness in the NAc core compared to F344 rats except after 2.5 mg/kg of morphine and 20 mg/kg of cocaine. In the NAc shell, different effects were obtained depending on drug and dose: after 1.0 mg/kg of morphine no strain differences were observed, at 2.5 and 5.0 mg/kg Lewis rats showed greater increase in DA in the NAc shell. Following amphetamine and cocaine challenge, Lewis rats showed greater DA increase in the shell after 0.25 mg/kg of amphetamine and 20 mg/kg of cocaine. Behavioral activation was greater in Lewis rats in response to the lowest dose of morphine (1.0 mg/kg), to the highest dose of amphetamine (1.0 mg/kg) and to all doses of cocaine. These differences might be the basis for the different behavioral responses of these strains to drugs of abuse.