Injection of the protein kinase C inhibitor Ro31-8220 into the nucleus accumbens attenuates the acute response to amphetamine: tissue and behavioral studies

The ability of amphetamine to produce heightened locomotor activity is thought to be due to its ability to enhance dopamine release from mesolimbic dopamine neurons. The mechanism by which amphetamine increases dopamine release is not well understood, but is thought to involve exchange diffusion with synaptosomal dopamine through the dopamine transporter. We recently reported that amphetamine-mediated dopamine release in the striatum is also dependent on protein kinase C activity. In the current study, we investigated the role of protein kinase C activity in the acute neurochemical and behavioral response to amphetamine in the nucleus accumbens. Consistent with previous results in the striatum, amphetamine-stimulated dopamine release from nucleus accumbens tissue was inhibited by the specific protein kinase C inhibitor Ro31-8220, but not by the relatively inactive analog bisindoylmaleimide V. In addition, the effects of protein kinase C activity on the acute behavioral response to amphetamine was examined by injecting Ro31-8220 into the nucleus accumbens 15 min prior to intra-accumbens amphetamine. Pretreatment with Ro31-8220 attenuated the motor-stimulant effects of intra-accumbens amphetamine relative to control subjects pretreated with vehicle. Bisindoylmaleimide V did not significantly inhibit the motor-stimulant effects of intra-accumbens amphetamine. These results suggest that the action of amphetamine in the nucleus accumbens in increasing dopamine release and locomotor activity is dependent on protein kinase C activity.     

Amphetamine-Induced time-dependent sensitization of dopamine neurotransmission in the dorsal and ventral striatum: A microdialysis study in behaving rats

The purpose of this study was to compare the effects of amphetamine exposure on subsequent amphetamine-induced changes in behavior and dopamine (DA) release in the dorsal and ventral striatum, as a function of time following the discontinuation of repeated amphetamine treatment. Rats were pretreated with either saline or an escalating-dose amphetamine regimen, and then received a 0.5 mg/kg amphetamine “challenge” after either 3, 7, or 28 days of withdrawal. Animals tested after 28 days of withdrawal were hypersensitive (sensitized) to the locomotor-activating effects of amphetamine, and relative to control animals showed a significant enhancement in amphetamine-stimulated DA release in both the dorsal and ventral striatum, as revealed by in vivo microdialysis. Animals tested after only 3 or 7 days of withdrawal showed neither behavioral sensitization nor enhanced amphetamine-stimulated DA release. These results establish that time-dependent changes in behavioral sensitization to amphetamine are associated with time-dependent changes in amphetamine-stimulated DA release, and support the hypothesis that persistent sensitization-related changes in striatal DA neurotransmission contribute to the expression of behavioral sensitization. © 1995 Wiley-Liss, Inc.     

Acute pharmacological blockade of corticosterone secretion reverses food restriction-induced sensitization of the locomotor response to cocaine

Several data indicate that a blockade of stress-induced corticosterone secretion prevents the development of the stress-induced sensitization of the behavioral effects of drugs of abuse. In this report we investigated if an acute blockade of corticosterone secretion could reverse stress-induced sensitization once it is already established. Food restriction (90% of initial body weight) was used as stressor. Corticosterone secretion was blocked by the corticosterone synthesis inhibitor metyrapone (100 mg/kg). After 8 days of food restriction, animals received an injection of metyrapone and 3 h later they were tested either for the locomotor response to cocaine or for the corticosterone secretion in response to stress (restraint, 30 min). Neither metyrapone nor food restriction had any effect on the locomotor response to a saline injection. In contrast, food-restricted animals, compared to ad libitum-fed controls, showed a higher locomotor response to cocaine and higher corticosterone levels. Treatment with metyrapone totally abolished these effects. Food-restricted animals, receiving a single injection of metyrapone, did not differ from ad libitum-fed controls for both locomotor response to cocaine and corticosterone secretion. Metyrapone treatment also similarly reduced the response to cocaine and corticosterone secretion in ad libitum-fed controls. In conclusion, this study provides further evidence that the enhancement in drug effects produced by stress depends on an increase in corticosterone levels. Since stress-induced sensitization is considered one of the conditions predisposing to drug abuse, the present results might have implications for the treatment of addiction.     

The dorsomedial shell of the nucleus accumbens facilitates cocaine-induced locomotor activity during the induction of behavioral sensitization

The mesolimbic dopamine system has been intensely studied as the neural circuit mediating the locomotor response to psychostimulants and behavioral sensitization. In particular, the dopaminergic innervation of the nucleus accumbens has been implicated as a site responsible for the manifestations of behavioral sensitization. Previous studies have demonstrated an augmented release of dopamine in the nucleus accumbens upon a systemic injection of a psychostimulant. In addition, alterations in the dopaminergic innervation patterns in this brain region have been demonstrated in animals that received repeated injections of cocaine. Furthermore, lesions of projection sites that have terminations in the nucleus accumbens have demonstrated alterations in psychostimulant induced locomotion, both acutely, as well as in sensitization paradigms. Since dopamine in the nucleus accumbens is believed to regulate several excitatory amino acid inputs, the present study examined the effects of a localized electrolytic lesion in the dorsomedial shell of the nucleus accumbens in order to better understand the functional role this brain region has in behavioral sensitization. All animals received bi-daily injections of 15 mg/kg i.p. cocaine. Only those demonstrating behavioral sensitization after a subsequent challenge dose were included in the analysis. Following acute exposure to cocaine, lesioned animals did not show any difference in their locomotor response when compared with sham controls. However, after repeated exposure to cocaine, sensitized animals demonstrated a significant attenuation in locomotor behavior when compared with sensitized sham controls. This decrease in horizontal locomotion persisted 2 days into withdrawal, yet dissipated in the sensitized animals that were challenged 2 weeks following their last injection. The data presented here demonstrate that the dorsomedial shell of the nucleus accumbens plays an important role in the initial stages of behavioral sensitization to cocaine.     

Chronic corticosterone administration enhances behavioral sensitization to amphetamine in mice

The role of corticosterone (CCS) in regulating sensitization to ampetamine's locomotor activating effects was measured in female DBA/2 mice that had been sham-operated or adrenalectomized and implanted with CCS-containing or cholesterol pellets. Three days following surgery, the mice were injected with saline and circular open field locomotor activity was measured for a 5-min time period starting 15 min after injection. Over the next 4 days, amphetamine (1.0–10.0 mg/kg) was injected and locomotor response measured. Control animals (sham-operated, cholesterol pellet) showed increased locomotor activity following their first injection of 5.0 mg/kg and 10.0 mg/kg amphetamine, while ADX animals showed increased activity only after treatment with the 10 mg/kg dose. Chronic CCS treatment did not significantly alter initial responsiveness to amphetamine in either sham-operated or ADX animals, but it did alter the dose-dependent sensitization to amphetamine. Both sham-operated and ADX animals implanted with cholesterol pellets showed increased locomotor respponse to amphetamine (sensitation) following injection with 2.5, 5.0 and 10.0 mg/kg doses of amphetamine. However, the enhancement of locomotor activity was greater in the sham-operated control animals. CCS-treated sham-operated animals exhibited sensitization to the locomotor-activating effects of amphetamine at the lowest dose used (1.0 mg/kg) and increased stereotypy following treatment with the higher doses. ADX/CCS animals developed sensitization to the locomotor-activating effects of amphetamine following chronic injection with the 2.5 mg/kg dose, and showed sensitization to amphetamine-induced stereotypy at higher doses. These data demonstrate that adrenocortical status modulates the effects of chronic and acute amphetamine administration and suggest that CCS may be an important component of stress-induced alterations in amphetamine sensitivity.     

Initial increases in extracellular dopamine in the ventral tegmental area provide a mechanism for the development of desipramine-induced sensitization within the midbrain dopamine system

In an attempt to understand the basis of the changes in the mesolimbic dopamine system that occur in response to chronic treatment with the antidepressant drug, desipramine HCI (DMI), we monitored changes in extracellular dopamine in ventral tegmental area (VTA) and nucleus accumbens septi (NAS) using in vivo microdialysis in freely moving animals. Early in treatment at a time before changes in the responsiveness of the dopamine system are observed, basal levels of dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were found to be increased in the VTA of rats treated with 5.0 mg/kg DMI twice daily for 6 days compared to those of saline-treated animals. After 12 days of treatment, and in a second group of animals after 18 days of treatment, basal levels of dopamine, DOPAC, HVA and 5HIAA, and levels in response to challenge with 1.5 mg/kg d-amphetamine sulphate were measured in the NAS. No differences in these measures taken in NAS were found between DMI-and saline-pretreated animals after 12 days of treatment. In DMI-treated animals tested after 18 days, the dopamine response to amphetamine was elevated compared to that of saline-treated animals. Furthermore, although there were no differences in basal levels of dopamine, basal levels of DOPAC and HVA were increased in DMI-treated animals. These findings lend support to the view that the time-dependent sensitization of dopaminergic function brought about by the tricyclic antidepressants may share processes in common with the development of sensitization to the indirect dopamine receptor agonist, amphetamine. © 1996 Wiley-Liss, Inc.     

Cortical cholinergic deficiency enhances amphetamine-induced dopamine release in the accumbens but not striatum

Cholinergic dysfunction has been implicated as a putative contributing factor in the pathogenesis of schizophrenia. Recently, we showed that cholinergic denervation of the neocortex in adult rats leads to a marked increase in the behavioral response to amphetamine. The main objective of this study was to investigate if the enhanced locomotor response to amphetamine seen after cortical cholinergic denervation was paralleled by an increased amphetamine-induced release of dopamine in the nucleus accumbens and/or striatum. The corticopetal cholinergic projections were lesioned by intraparenchymal infusion of 192 IgG-saporin into the nucleus basalis magnocellularis of adult rats. Amphetamine-induced dopamine release in the nucleus accumbens or striatum was monitored by in vivo microdialysis 2 to 3 weeks after lesioning. We found that cholinergic denervation of the rat neocortex leads to a significantly increased amphetamine-induced dopamine release in the nucleus accumbens. Interestingly, the cholinergic lesion did not affect amphetamine-induced release of dopamine in the striatum. The enhanced amphetamine-induced dopamine release in the nucleus accumbens in the cholinergically denervated rats could be reversed by administration of the muscarinic agonist oxotremorine, but not nicotine, prior to the amphetamine challenge, suggesting that loss of muscarinic receptor stimulation is likely to have caused the observed effect. The results suggest that abnormal responsiveness of dopamine neurons can be secondary to cortical cholinergic deficiency. This, in turn, might be of relevance for the pathophysiology of schizophrenia and provides a possible link between cholinergic disturbances and alteration of dopamine transmission.     

The orphan GPCR,GPR88, modulates function of the striatal dopamine system: A possible therapeutic target for psychiatric disorders?

In rodents, the orphan G protein-coupled receptor, Gpr88, is highly expressed in brain regions implicated in the pathophysiology of and is modulated by treatments for schizophrenia. We compared striatal function of Gpr88 knockout mice (Gpr88KOs) to wild-type mice using molecular, neurochemical and behavioral tests. Gpr88KOs lacked expression of Gpr88 in striatum, nucleus accumbens and layer IV of cortex. Gpr88KOs had normal striatal dopamine D2 receptor density and affinity and DARPP-32 expression but Gpr88KOs had higher basal striatal phosphorylated DARPP-32 Thr-34. In vivo microdialysis detected lower basal dopamine in Gpr88KOs while amphetamine-induced dopamine release was normal. Behaviorally, Gpr88KOs demonstrated disrupted prepulse inhibition of startle (PPI) and increased sensitivity to apomorphine-induced climbing and stereotypy (AICS) and amphetamine-stimulated locomotor activity. Antipsychotic administration to Gpr88KOs normalized the PPI deficit and blocked AICS. The modulatory role of Gpr88 in striatal dopamine function suggests it may be a new target for treatments for psychiatric disorders.     

Socially isolated rats exhibit changes in dopamine homeostasis pertinent to schizophrenia

Post-weaning social isolation of rats produces an array of behavioral and neurochemical changes indicative of altered dopamine function. It has therefore been suggested that post-weaning social isolation mimics some aspects of schizophrenia. Here we replicate and extent these findings to include an investigation of prefrontal cortical dopamine dynamics using in vivo microdialysis.Social isolation for 12 weeks after weaning caused increased locomotor activity in response to novelty and amphetamine challenge. In vivo microdialysis experiments revealed that while social isolation did not change basal dopamine levels in the nucleus accumbens, it did cause a significant reduction of basal dopamine release in the prefrontal cortex. In addition, social isolation lead to a significantly larger dopamine response to an amphetamine challenge, in both the nucleus accumbens and the prefrontal cortex compared to group housed controls. Taken together, these results indicate that post-weaning social isolation alters dopaminergic function with changes resembling subcortical hyperdopaminergia and prefrontal hypodopaminergia similar to what has been observed in schizophrenic patients.     

Mechanisms of cocaine-induced sensitization

Sorg, Barbara A. and Jeffery D. Steketee: Mechanisms of Cocaine-Induced Sensitization. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1992, 16(6): 1003–1012.

1. 1. Rats pretreated with repeated footshock demonstrated an augmentation in cocaineinduced locomotor activity and extracellular dopamine concentrations in the nucleus accumbens.

2. 2. Pertussis toxin injections into the A10 region also led to cocaine- induced enhancement in extracellular dopamine levels in the nucleus accumbens and a strong trend towards elevated locomotor activity.

3. 3. Repeated treatment with cocaine led to a blockade of the footshock-induced increase in extracellular dopamine in the medial prefrontal cortex.

4. 4. Prior treatment with pertussis toxin microinjection into the A10 region resulted in enhanced levels of tissue dopamine metabolites in the medial prefrontal cortex following footshock stress.

5. 5. The pertussis toxin- and daily stress-induced behavioral and neurochemical sensitization suggest that behavioral sensitization to these stimuli involves a loss of inhibitory tone on A10 dopamine cells.

The role of the nucleus accumbens in sensitization to drugs of abuse.

1. Male rats received cannula implants above the nucleus accumbens for monitoring extracellular concentrations of dopamine via in vivo microdialysis. 2. Daily injections with cocaine led to an augmentation in both the behavioral response and the neurochemical response (i.e. cocaine-induced increase in extracellular dopamine within the nucleus accumbens) to this drug. 3. Pertussis toxin injections into the A10 region led to sensitized behavioral and neurochemical responses to an acute injection of cocaine. 4. Prior exposure to footshock stress augmented the cocaine-induced increase of motor activity and of extracellular dopamine within the nucleus accumbens. 5. These data suggest that treatments which lead to behavioral sensitization also lead to sensitization within the mesolimbic dopamine system as measured by an augmented dopamine release in the nucleus accumbens.     

Nicotine-induced behavioral sensitization is associated with extracellular dopamine release and expression of c-Fos in the striatum and nucleus accumbens of the rat

It is well known that repeated injections of nicotine produce progressively larger increases in locomotor activity, an effect referred to as behavioral sensitization. This study was carried out to investigate the neural mechanisms underlying nicotine-induced behavioral sensitization using in vivo microdialysis and Fos-like immunohistochemistry (FLI). Rats were given repeated injections of saline or nicotine (0.4 mg/kg s.c., twice daily for 7 days) followed by one challenge injection on the 4th day after the last daily injection. Systemic challenge with nicotine produced a much larger increase in locomotor activity in nicotine-pretreated rats (659.1+/-94.9 counts/2 h) than in saline-pretreated rats (218.1+/-61 counts/2 h). A direct local challenge of nicotine (1 or 5 mM) via a microdialysis probe in the nucleus accumbens or striatum induced a much greater dose-dependent increase of dopamine (DA) output in nicotine-pretreated rats than in saline-pretreated rats. Furthermore, in parallel with the behavioral and biochemical data, systemic challenge with nicotine produced marked Fos-like immunohistochemistry in the nucleus accumbens and the striatum in the nicotine-pretreated rats. Taken together, this study demonstrates that behavioral sensitization is clearly associated with an increase in DA release and activation of Fos-like immunoreactive cells in the striatum and the nucleus accumbens produced by repeated nicotine treatment. Our results strongly suggest that the striatum and the nucleus accumbens may play a major role in nicotine-induced behavioral sensitization. The present results are discussed in terms of the development and expression of nicotine-induced behavioral sensitization.     

The AT₁ angiotensin II receptor blockade attenuates the development of amphetamine-induced behavioral sensitization in a two-injection protocol

It has been shown that a single exposure to amphetamine is sufficient to induce long‐term behavioral, neurochemical, and neuroendocrine sensitization in rats. Dopaminergic neurotransmission in the nucleus accumbens and the caudate‐putamen plays a critical role in the addictive properties of drugs of abuse. Angiotensin (Ang) II receptors are found on the soma and terminals of mesolimbic dopaminergic neurons and it has been shown that Ang II acting through its AT₁ receptors facilitates dopamine release. The hypothesis was tested that Ang II AT₁ receptors are involved in the neuroadaptative changes induced by a single exposure to amphetamine and that such changes are related to the development of behavioral and neurochemical sensitization. For this purpose, the study examined the expression of amphetamine‐enhanced (0.5 mg kg⁻¹ i.p.) locomotor activity in animals pretreated with candesartan, an AT₁ blocker, (3 mg kg⁻¹ p.o × 5 days), 3 weeks after an amphetamine injection (5 mg kg⁻¹ i.p.). Dopaminergic hyperreactivity was tested by measuring the 3H‐DA release in vitro from caudate‐putamen and nucleus accumbens slices, induced by K⁺ stimulus. It was confirmed the behavioral sensitization in the two‐injection protocol and candesartan pretreatment attenuate this response. It was also found that AT₁ blockade pretreatment did not affect the locomotor response to dopamine agonists. In respect to the neurochemical sensitization tested using ex vivo 3H‐DA release experiments it was found that AT₁ receptor pretreatment blunted the enhanced response induced by K⁺ stimulus. The results support the idea that the development of neuroadaptive changes induced by amphetamine involves brain AT₁ Ang II receptor activation. Synapse, 2011. © 2010 Wiley‐Liss, Inc.     

Individual differences in stress-induced dopamine release in the nucleus accumbens are influenced by corticosterone

Stressful experiences, glucocorticoids hormones and dopaminergic neurons seems to interact in determining a higher propensity to develop drug abuse. In this report, we studied the acute interaction between these three factors. For this purpose, we compared stress-induced dopamine release in intact rats and in rats in which stress-induced corticosterone secretion was experimentally blocked. Ten-minute tail-pinch was used as a stressor and dopamine release estimated in the nucleus accumbens by using the microdialysis technique. Individual differences were also taken into account by comparing rats identified as either predisposed (HRs) or resistant (LRs) to develop self-administration of drugs of abuse, on the basis of their locomotor response to novelty. It was found that suppression of stress-induced corticosterone secretion significantly decreased stress-induced dopamine release. However, such an effect greatly differed between HR and LR rats. When corticosterone secretion was intact HR animals had a higher and longer dopamine release in response to stress than LRs. The blockade of stress-induced corticosterone secretion selectively reduced the dopaminergic response of HRs that did not differ from LRs anymore. These findings strength the idea that glucocorticoids could be involved in determining propensity to develop drug self-administration. In particular, these hormones could play a role in determining the higher dopaminergic activity that characterizes drug proned individuals.     

Concomitant characterization of behavioral and striatal neurotransmitter response to amphetamine using in vivo microdialysis

The temporal and dose-related behavioral and striatal monoamine response to amphetamine (AMPH) was examined using in vivo microdialysis in freely moving rats. Extracellular dopamine (DA), serotonin (5-HT), and their metabolites were monitored concomitant with detailed characterization of the locomotor and stereotypy profiles. Consistent with previous results, AMPH (0.5-5.0 mg/kg) induced a rapid dose-dependent increase in DA concentration and decrease in the concentrations of the DA metabolites, DOPAC and HVA. DA and its metabolites exhibited contrasting temporal and dose-related patterns, suggesting that the decline in DA metabolites is functionally dissociated from the AMPH-enhanced DA release. In addition, AMPH at doses of 2.0 mg/kg and greater significantly increased extracellular concentrations of 5-HT, which, in contrast to the changes in dopamine, persisted for only 20-40 min. Comparisons of concentrations of DA and 5-HT for individual animals revealed significant correlations both during baseline and drug response, suggesting a possible functional interdependence between dopaminergic and serotonergic activity in striatum. Dose-response comparisons revealed a significant relationship between AMPH-induced increases in behavioral perseveration and the magnitude and duration of the DA release. However, the temporal patterns of the neurotransmitter response and individual components of stereotypy were not parallel, suggesting that the presence of stereotypies is not associated simply with quantitative differences in striatal DA release. By contrast, some features of the behavioral response were significantly correlated with AMPH-induced changes in striatal 5-HT concentrations. Our results suggest that the behavioral response to AMPH may be influenced by the interaction between levels of DA and 5-HT release, as well as by the state of their respective receptors.     

Blockade of neurotensin receptors during amphetamine discontinuation indicates individual variability

Psychostimulant-induced locomotor sensitization has been related to changes within the mesolimbic dopamine system and has been suggested to be useful to study mechanisms underlying drug craving. Neurotensin is a neuropeptide co-localized with dopamine in the mesolimbic system. The response to novelty has been suggested to be a predictor of enhanced vulnerability to behavioral sensitization. The effects of repeated treatment with the neurotensin antagonist SR48692 after amphetamine discontinuation were investigated in mice previously classified as high responders (HRs) or low responders (LRs) to novelty. Mice were repeatedly treated with 2.0mg/kg amphetamine, every other day for 11 days. During the first 7 days after amphetamine discontinuation, the animals received a daily injection of saline or 0.3mg/kg SR48692. On the eighth day after amphetamine discontinuation all subjects received a 2.0mg/kg amphetamine challenge injection. Then, mice were tested for an open field behavior and after 90min, were sacrificed for Fos expression quantification in the nucleus accumbens. Both HRs and LRs expressed amphetamine-induced sensitized locomotor activation and increased expression of Fos protein. Treatment with SR48692 prevented behavioral sensitization and Fos protein expression enhancement in LRs but not in HRs mice. These data suggest that neurotensin plays a role in individual variability to amphetamine-induced sensitization.     

Argon blocks the expression of locomotor sensitization to amphetamine through antagonism at the vesicular monoamine transporter-2 and mu-opioid receptor in the nucleus accumbens

We investigated the effects of the noble gas argon on the expression of locomotor sensitization to amphetamine and amphetamine-induced changes in dopamine release and mu-opioid neurotransmission in the nucleus accumbens. We found (1) argon blocked the increase in carrier-mediated dopamine release induced by amphetamine in brain slices, but, in contrast, potentiated the decrease in KCl-evoked dopamine release induced by amphetamine, thereby suggesting that argon inhibited the vesicular monoamine transporter-2; (2) argon blocked the expression of locomotor and mu-opioid neurotransmission sensitization induced by repeated amphetamine administration in a short-term model of sensitization in rats; (3) argon decreased the maximal number of binding sites and increased the dissociation constant of mu-receptors in membrane preparations, thereby indicating that argon is a mu-receptor antagonist; (4) argon blocked the expression of locomotor sensitization and context-dependent locomotor activity induced by repeated administration of amphetamine in a long-term model of sensitization. Taken together, these data indicate that argon could be of potential interest for treating drug addiction and dependence.     

A single exposure to morphine induces long-lasting behavioural and neurochemical sensitization in rats

Repeated exposure to drugs of abuse causes persistent behavioural sensitization and associated adaptations in striatal neurotransmission, which is thought to play an important role in certain aspects of drug addiction. Remarkably, even a single exposure to psychostimulant drugs such as amphetamine or cocaine can be sufficient to elicit long-lasting sensitization. The present study was designed to evaluate whether long-lasting behavioural and neurochemical sensitization can also be evoked by a single exposure to morphine, an opiate drug of abuse. Rats were pretreated once with morphine (2, 10 or 30 mg/kg). Three weeks later, the locomotor effects of morphine and amphetamine, as well as the electrically evoked release of [3H]dopamine and [14C]acetylcholine from slices of nucleus accumbens and caudate-putamen, was assessed. In morphine-pretreated rats, the psychomotor effects of morphine and amphetamine were sensitized. In addition, the electrically evoked release of [3H]dopamine and [14C]acetylcholine was augmented in slices of nucleus accumbens and caudate-putamen from morphine-pretreated animals. Although the sensitization of the locomotor effect of morphine was less profound than previously observed after repeated intermittent morphine treatment, the enduring behavioural and neurochemical consequences of a single and repeated intermittent morphine treatment appear to be highly comparable. We therefore conclude that a single exposure to morphine induces long-lasting behavioural sensitization and associated neuroadaptations.     

Robust sensitization to amphetamine following intra-VTA cholera toxin administration

Studies were conducted regarding the hypothesis that enhanced cAMP formation in the ventral tegmental area (VTA) affects the magnitude of the behavioral responses elicited by psychostimulant drugs. In the first paradigm, spontaneous and amphetamine-elicited locomotor activity was measured at various times following injection of cholera toxin (CTX), a known activator of adenylate cyclase, into the VTA. Adult male rats showed enhanced amphetamine-stimulated locomotor activity when tested 1 or 3 days after treatment with 0.5 μg CTX into the VTA. Spontaneous activity was markedly increased 1 and 3 days following treatment with the higher dose of 1.0 μg CTX into the VTA, and amphetamine was still capable of eliciting an increased level of locomotor activity above this high baseline. Using a paradigm in which repeated amphetamine injections were given on an intermittent schedule following injection of CTX into the VTA, it was observed that a single low dose of amphetamine (0.5 mg/kg) given 1 day after CTX (0.5 μg) injection into the VTA led to a markedly potentiated locomotor activity response to subsequent treatment with amphetamine. Evaluation of this protocol (initial amphetamine dose 24 h after CTX injection, and challenge treatment of amphetamine at various times thereafter) showed that the sensitization was long-lasting and could be observed after an initial dose of amphetamine as low as 0.1 mg/kg. A sensitized response was also expressed when the challenge dose was given directly into the nucleus accumbens. These data suggest that injection of CTX into the VTA enhances the induction of locomotor sensitization to amphetamine. Synapse 25:335–344, 1997. © 1997 Wiley-Liss, Inc.     

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.