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G Di Chiara

Publications and source records attributed to G Di Chiara.

At least 19 recordsLinked to original sources
PubMed2003

Mu opioid receptor signaling in morphine sensitization.

We used a previously reported model of morphine sensitization that elicited a complex behavioral syndrome involving stereotyped and non stereotyped activity. To identify the mechanism of these long-lasting processes, we checked the density of mu opioid receptors, receptor-G-protein coupling and the cyclic AMP (cAMP) cascade. In morphine-sensitized animals mu opioid receptor autoradiography revealed a significant increase in the caudate putamen (30% versus controls), nucleus accumbens shell (16%), prefrontal and frontal cortex (26%), medial thalamus (43%), hypothalamus (200%) and central gray (89%). Concerning morphine's activation of G proteins in the brain, investigated in the guanylyl 5'-[gamma-(35)S]thio]triphosphate ([(35)S]GTPgammaS) binding assay, a significant increase in net [(35)S]GTPgammaS binding was seen in the caudate putamen (39%) and hypothalamus (27%). In the caudate putamen this was due to an increase in the amount of activated G proteins, and in the hypothalamus to a greater affinity of G proteins for guanosine triphosphate (GTP). The main second messenger system linked to the opioid receptor is the cAMP pathway. In the striatum basal cAMP levels were significantly elevated in sensitized animals (70% versus controls) and [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO) significantly inhibited forskolin-stimulated cAMP production in control (30%) but not in sensitized rats. In the hypothalamus no significant changes were observed in basal cAMP levels and DAMGO inhibition. These cellular events induced by morphine pre-exposure could underlie the neuroadaptive processes involved in morphine sensitization.

Animals↗
PubMed2002

Decrease in basal dopamine levels in the nucleus accumbens shell during daily drug-seeking behaviour in rats.

Accumbal dopamine (DA) is generally accepted to participate in the neural mechanisms underlying drug dependence. Recently the involvement of accumbal DA in drug-seeking behaviour has gained more experimental attention. To study an involvement of accumbal DA in drug-seeking behaviour within and between daily self-administration behaviour, changes in extracellular DA concentration in the nucleus accumbens (NAc) shell were measured during the daily dynamics of intravenous heroin and cocaine self-administration. Groups of drug naive rats were allowed to intravenously self-administer heroin (30 microg/infusion) and cocaine (30 microg/infusion) during five consecutive daily 3 h sessions. Extracellular DA concentrations in the NAc were measured before and after a single 3 h session (acute) and before and after 5 consecutive 3 h sessions (repeated). Following acute and repeated heroin and cocaine self-administration the extracellular DA concentration in the NAc shell was increased by two-fold to three-fold over baseline. These changes in DA concentrations are thought to reflect a direct effect of heroin and cocaine on DA neurotransmission in the NAC shell. Measurement of basal DA concentrations before the self-administration sessions revealed that just before the scheduled 5th self-administration session the (absolute) basal DA levels in the NAc in heroin or cocaine self-administering animals were decreased by approximately halve, as compared to drug-naive animals. It is assumed that just before a scheduled next session the (daily) desire for the drug is high. This decrease in basal DA neurotransmission in the NAc shell may, therefore, reflect an involvement of accumbal DA in drug-seeking behaviour during daily self-administration behaviour. The results demonstrate that initiation of i.v. heroin and cocaine self-administration is linked with changes in extracellular levels of DA in the NAc shell. Moreover, the present data suggest that accumbal DA might be involved in processes underlying the motivational aspects involved in daily drug-seeking behaviour, and that neuroadaptive changes in the mesolimbic DA system due to repeated drug intake lead to an tonic decrease in overall DA activity in the NAc.

Analgesics, Opioid↗
PubMed2001

A role for dopamine D1 receptors of the nucleus accumbens shell in conditioned taste aversion learning.

The involvement of dopamine (DA) in conditioned taste aversion (CTA) learning was studied with saccharin or sucrose as the conditioned stimulus (CS) and intraperitoneal lithium as the unconditioned stimulus (US). The dopamine D(1) antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390) (12.5-50 microg/kg, s.c.), given 5 min after the CS, impaired the acquisition of CTA in a paradigm consisting of three or a single CS-lithium association. SCH 23390 failed to impair CTA acquisition given 45 min after, 30 min before, or right before the CS. (-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5a-benzo-(d)-naphtho-(2,1b) azepine (SCH 39166) (12.5-50.0 microg/kg, s.c), a SCH 23390 analog that does not bind to 5HT(2) receptors, also impaired CTA. No significant impairment of CTA was obtained after administration of the specific D(2)/D(3) antagonist raclopride (100 and 300 microg/kg, s.c.). The ability of SCH 23390 to impair CTA learning was confirmed by its ability to reduce the conditional aversive reactions to a gustatory CS (sweet chocolate) as estimated in a taste reactivity paradigm. SCH 39166 impaired CTA also when infused in the nucleus accumbens (NAc) shell 5 min after the CS. No impairment was obtained from the NAc core or from the bed nucleus stria terminalis. The results indicate that D(1) receptor blockade impairs CTA learning by disrupting the formation of a short-term memory trace of the gustatory CS and that endogenous dopamine acting on D(1) receptors in the NAc shell plays a role in short-term memory processes related to associative gustatory learning.

Animals↗
PubMed2001

Delta9-tetrahydrocannabinol enhances cortical and hippocampal acetylcholine release in vivo: a microdialysis study.

The intravenous administration of synthetic cannabinoid agonists was recently shown to dose dependently increase acetylcholine release from the rat prefrontal cortex and hippocampus (Eur. J. Pharmacol. 401 (2000) 179]. We report here that the active ingredient of cannabis preparations, delta9-tetrahydrocannabinol, administered at 10, 37.5, 75 and 150 microg/kg, dose dependently stimulated acetylcholine release from rat prefrontal cortex and hippocampus estimated by means of in vivo brain microdialysis with vertical concentric probes. At these doses, delta9-tetrahydrocannabinol induced behavioural stimulation. The administration of the CB1 receptor antagonist, ([N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3carboxamide]HCl) SR 141716A (200 microg/kg i.p.) significantly reduced the effect of delta9-tetrahydrocannabinol (75 microg/kg i.v.) on acetylcholine release from rat prefrontal cortex and hippocampus.

Acetylcholine↗
PubMed2001

Cocaine and amphetamine increase extracellular dopamine in the nucleus accumbens of mice lacking the dopamine transporter gene.

Behavioral and biochemical studies suggest that dopamine (DA) plays a role in the reinforcing and addictive properties of drugs of abuse. Recently, this hypothesis has been challenged on the basis of the observation that, in mice genetically lacking the plasma membrane dopamine transporter [DAT-knock out (DAT-KO)], cocaine maintained its reinforcing properties of being self-administered and inducing place preference, despite the failure to increase extracellular dopamine in the dorsal striatum. Here we report that, in DAT-KO mice, cocaine and amphetamine increase dialysate dopamine in the medial part of the nucleus accumbens. Moreover, reboxetine, a specific blocker of the noradrenaline transporter, increased DA in the nucleus accumbens of DAT-KO but not of wild-type mice; in contrast, GBR 12909, a specific blocker of the dopamine transporter, increased dialysate dopamine in the nucleus accumbens of wild-type but not of DAT-KO mice. These observations provide an explanation for the persistence of cocaine reinforcement in DAT-KO mice and support the hypothesis of a primary role of nucleus accumbens dopamine in drug reinforcement.

Adrenergic Uptake Inhibitors↗
PubMed2001

Intravenous administration of ecstasy (3,4-methylendioxymethamphetamine) enhances cortical and striatal acetylcholine release in vivo.

The effect of intravenous administration of 3,4-methylendioxymethamphetamine (MDMA), in a range of doses (0.32-3.2 mg/kg) that have been shown to maintain self-administration behaviour in rats, on in vivo acetylcholine release from rat prefrontal cortex and dorsal striatum was studied by means of microdialysis with vertical concentric probes. Intravenous administration of MDMA dose-dependently increased basal acetylcholine release from the prefrontal cortex to 57+/-21%, 98+/-20%, 102+/-7% and 141+/-14% above baseline, at doses of 0.32, 0.64, 1.0 and 3.2 mg/kg, respectively. MDMA also stimulated striatal acetylcholine release at the dose of 3.2 mg/kg i.v. (the maximal increase being 32+/-3% above baseline) while at the dose of 1 mg/kg i.v., MDMA failed to affect basal acetylcholine output. Administration of MDMA also dose-dependently stimulated behaviour. The results of the present study show that MDMA affects measures of central cholinergic neurotransmission in vivo and suggest that at least some of the psychomotor stimulant actions of MDMA might be positively coupled with an increase in prefrontal cortical and striatal acetylcholine release.

Acetylcholine↗
PubMed2001

Behavioural sensitization after repeated exposure to Delta 9-tetrahydrocannabinol and cross-sensitization with morphine.

RATIONALE: Repeated exposure to several drugs of abuse has been reported to induce behavioural sensitization. So far no evidence has been provided that such a phenomenon also applies to cannabinoids. OBJECTIVES: In this study we investigated if repeated exposure to Delta(9)-tetrahydrocannabinol (Delta(9)-THC) induces behavioural sensitization. In addition we tested the possibility of cross-sensitization between Delta(9)-THC and morphine. METHODS: Male Sprague-Dawley rats were administered for 3 days, twice daily, with increasing doses of Delta(9)-tetrahydrocannabinol (2, 4 and 8 mg/kg i.p.) or increasing doses of morphine (10, 20 and 40 mg/kg s.c.) or vehicle. After a washout of 14 days the animals were challenged with Delta(9)-THC (75 and 150 microg/kg i.v.), with a synthetic cannabinoid agonist WIN55212-2 (75 and 150 microg/kg i.v.) or with morphine (0.5 mg/kg i.v.), through a catheter inserted into the left femoral vein 24 h before, and the behaviour recorded. RESULTS: Rats previously administered with Delta(9)-THC showed a greater behavioural activation compared to controls in response to challenge with Delta(9)-THC (150 microg/kg i.v.) and to challenge with morphine (0.5 mg/kg i.v.). Similar to that observed after repeated opiates, this behavioural sensitization was characterized by stereotyped activity. Animals administered with a schedule of morphine that induces behavioural sensitization to morphine also showed a behavioural sensitization to challenge with cannabinoids (Delta(9)-HC and WIN55212-2, 75 and 150 microg/kg i.v.). The effect of the challenge with Delta(9)-THC was prevented by the administration of the CB1 antagonist SR141716A (1 mg/kg i.p.), 40 min beforehand. CONCLUSIONS: The results of the present study demonstrate that repeated exposure to Delta(9)-THC induces behavioural sensitization not only to cannabinoids but also to opiates. This cross-sensitization was symmetrical since rats behaviourally sensitized to morphine were also sensitized to cannabinoids. These observations further support the evidence of an interaction between the opioid and the cannabinoid system and might provide a neurobiological basis for a relationship between cannabis use and opiate abuse.

Analgesics, Non-Narcotic↗
PubMed2001

Role of dopamine D1 receptors in the control of striatal acetylcholine release by endogenous dopamine.

In order to determine the role of dopamine (DA) D1 receptors in the control of striatal acetylcholine (ACh) transmission, we studied the effects of SCH 39166 (D1 receptor antagonist), alone or in combination with quinpirole (D2/D3 agonist) or PD 128,907 (D3 agonist) on ACh and DA release. Quinpirole reduced DA and ACh release; PD 128,907 decreased DA but not ACh release. SCH 39166 stimulated DA and decreased ACh release. Pretreatment with quinpirole reduced or prevented (depending on the dose) the stimulation of DA release while potentiating the decrease of ACh release elicited by SCH 39166. Similarly, SCH 39166 administered following PD 128,907 did not stimulate DA release, further decreasing ACh release. These results indicate that quinpirole or PD 128,907 affect the actions of SCH 39166 on DA and ACh release in opposite manner, counteracting the increase of DA release and potentiating the reduction of ACh release. These data support the tenet that endogenous DA exerts a stimulatory input on striatal ACh neurotransmission mediated by D1 receptors.

Acetylcholine↗
PubMed2001

Role of striatal acetylcholine on dopamine D1 receptor agonist-induced turning behavior in 6-hydroxydopamine lesioned rats: a microdialysis-behavioral study.

The effects of MK-801, a non-competitive N-methyl D-aspartate (NMDA) receptor antagonist, of quinpirole, a dopamine (DA) D2 receptor agonist, and of SCH 58261, an A2A adenosine antagonist, were studied on acetylcholine (ACh) release in the striatum of 6-hydroxydopamine (60HDA) lesioned rats and on turning behavior induced by the administration of the DA D1 agonist CY 208-243. Administration of CY 208-243 to 6OHDA lesioned rats induced turning behavior and dose-dependently stimulated ACh release. At the dose of 50 microg/kg, MK-801 failed to affect basal ACh, while at 100 microg/kg MK-801 reduced it; however, MK-801 (50 and 100 microg/kg) potentiated the turning behavior elicited by CY 208-243, but failed to affect the CY 208-243-induced increase of striatal ACh release. The administration of quinpirole induced low-intensity turning behavior and decreased basal ACh release; on the other hand, quinpirole potentiated the turning behavior induced by CY 208-243, but failed to affect the CY 208-243-elicited increase of ACh release. Finally, intravenous administration of SCH 58261 stimulated basal ACh release but not turning behavior; SCH 58261, however, potentiated turning behavior induced by CY 208-243, while failing to affect the D1-elicited increase of ACh release. These results indicate that potentiation of D1-dependent turning behavior by MK-801, quinpirole and SCH 58261 is not mediated by a reduced ability of D1-agonists to stimulate ACh release from the denervated striatum.

Acetylcholine↗
PubMed2000

Stimulation of in vivo dopamine transmission in the bed nucleus of stria terminalis by reinforcing drugs.

Drugs of abuse preferentially increase dopamine transmission in the shell of the nucleus accumbens. This area is considered as a transition between the striatum and the extended amygdala a complex neural system that includes the central amygdala and the bed nucleus of stria terminalis, areas that, like the nucleus accumbens shell, are heavily innervated by mesolimbic dopamine neurons originating in the ventral tegmental area. Given the anatomical and neurochemical relationships and similarities with the nucleus accumbens shell it was of interest to investigate whether the dopamine transmission of the bed nucleus of stria terminalis shares with the accumbens shell the peculiar responsiveness to drugs of abuse. To this end we studied by microdialysis with concentric probes, the effect of drugs of abuse on extracellular dopamine in the bed nucleus of stria terminalis. We report that morphine, nicotine, cocaine, ethanol, and the selective dopamine uptake inhibitor GBR 12909 increase effectively and dose dependently extracellular dopamine in the bed nucleus of stria terminalis. These results indicate that the bed nucleus of stria terminalis shares with the nucleus accumbens shell a peculiar sensitivity to the dopamine stimulant actions of drugs of abuse.

Analysis of Variance↗
PubMed2000

Cannabinoid CB(1) receptor agonists increase rat cortical and hippocampal acetylcholine release in vivo.

Intravenous administration of the cannabinoid CB(1) receptor agonists (R-(+)-[2, 3-Dihydro-5-methyl-3[morpholinyl)methyl]-pyrrolo[1,2,3-de]-1, 4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate), WIN 55,212-2 (10, 37.5, 75 and 150 microg/kg), and ((6aR)-trans-3-(1, 1-Dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6, 6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol), HU 210 (1 and 4 microg/kg) dose-dependently increased acetylcholine release in dialysates from the prefrontal cortex and the hippocampus of freely moving rats. Administration of the cannabinoid receptor antagonist [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3 carboxamide]HCl, SR 141716A, at a dose that per se did not affect basal acetylcholine release (2. 5 microg/kg), prevented the increase of acetylcholine release by WIN 55,212-2 (150 microg/kg i.v.) or by HU 210 (4 microg/kg i.v.) in both areas. These data demonstrate that, at low i.v. doses, the synthetic cannabinoid CB(1) receptor agonists, WIN 55,212-2 and HU 210 stimulate cortical and hippocampal acetylcholine release.

Acetylcholine↗
PubMed2000

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 nicotine's 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.

Behavior, Addictive↗
PubMed2000

Dissociation of physical abstinence signs from changes in extracellular dopamine in the nucleus accumbens and in the prefrontal cortex of nicotine dependent rats.

The aim of the present study was to investigate the relationship between physical abstinence and changes in dopamine release in the nucleus accumbens and in the medial prefrontal cortex induced by mecamylamine and naloxone in rats chronically exposed to nicotine. The rats were implanted with osmotic minipumps (Alzet) delivering nicotine tartrate at a rate of 9 mg/kg/day (3.16 mg of free base) and 8 days later with a dialysis probe in the nucleus accumbens or in the medial prefrontal cortex. Steady-state dopamine output from the nucleus accumbens of the rats implanted with nicotine minipumps was higher than that of sham implanted rats; no differences were observed in the prefrontal cortex. In nicotine but not in sham implanted rats mecamylamine (1 mg/kg s.c.) precipitated a physical abstinence syndrome and brought dopamine output back to control values in the nucleus accumbens. In contrast mecamylamine (1 mg/kg s.c.) increased dopamine output in the medial prefrontal cortex of nicotine but not sham-implanted rats. Naloxone (2 mg/kg) precipitated a physical abstinence syndrome qualitatively similar to that produced by mecamylamine but failed to modify extracellular dopamine in the nucleus accumbens or in the prefrontal cortex of nicotine-implanted and sham-implanted rats. The results indicate that the mesolimbic and mesocortical dopamine system undergo opposite changes during mecamylamine-precipitated abstinence in rats chronically exposed to nicotine and that physical abstinence signs can be dissociated from changes in dopamine transmission.

Analysis of Variance↗
PubMed2000

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.

Amphetamine↗
PubMed2000

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.

Animals↗
PubMed2000

Increase of dialysate dopamine in the bed nucleus of stria terminalis by clozapine and related neuroleptics.

Neuroleptics are known to stimulate dopamine release in neostriatal terminal areas. In the present study, we have investigated by brain microdialysis in freely moving rats the effect of typical and atypical neuroleptics on dopamine transmission in the bed nucleus of stria terminalis, a dopamine terminal area belonging to the limbic system and recently assigned the so-called extended amygdala. Mean basal dialysate dopamine values were 14.3 f moles/20 microliters sample. Dopamine output in dialysates was increased dose-dependently by clozapine (max + 158%, 298%, and 461% of basal at 5, 10, and 20 mg/kg i.p., respectively), risperidone (max + 115% and 221% of basal at 1 and 3 mg/kg i.p., respectively), olanzapine (max + 138% and 235% of basal at 3 and 6 mg/kg i.p., respectively), BIMG 80 (max + 64% and 164% of basal at 3 and 5 mg/kg i.p., respectively), amperozide (max + 110% and 194% of basal at 3 and 6 mg/kg i.p., respectively). The selective dopamine D4 antagonist L-745,870 increased dialysate dopamine but at rather high doses and not as effectively as clozapine (max + 32%, 89%, and 130% of basal at 2.7, 5.4, and 10.8 mg/kg i.p., respectively). The typical neuroleptic haloperidol (0.1 and 0.5 mg/kg s.c.) and the selective D2 antagonist raclopride (0.14, 0.56, and 2.1 mg/kg s.c.), the serotonergic 5-HT2 antagonist ritanserin (0.5 and 1.5 mg/kg i.p.), and the adrenergic alpha 1 antagonist prazosin (0.91 and 2.73 mg/kg i.p.) did not affect dialysate dopamine in the bed nucleus of stria terminalis. Saline (1 ml/kg s.c. or 3 ml/kg i.p.) did not modify dialysate dopamine. Therefore, atypical neuroleptics share the ability of stimulating dopamine transmission in the bed nucleus of stria terminalis, but this property is not mimicked by any of the drug tested that selectively act on individual receptors among those that are affected by atypical neuroleptics. These observations raise the possibility that the property of increasing dopamine transmission in the bed nucleus of stria terminalis is the result of combined blockade of dopamine, serotonin, and noradrenaline receptors and that might be predictive of an atypical neuroleptic profile.

Animals↗
PubMed1999

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.

Animals↗