Psychostimulant-induced Behavioral Sensitization Research Articles

The CaMKII-dependent phosphorylation of GABAB receptors in the nucleus accumbens was involved in cocaine-induced behavioral sensitization in rats.

Previous studies have established that the regulation of prolonged, distal neuronal inhibition by the GABAB heteroreceptor (GABAB R) is determined by its stability, and hence residence time, on the plasma membrane. Here, we show that GABAB R in the nucleus accumbens (NAc) of rats affects the development of cocaine-induced behavioral sensitization by mediating its perinucleus internalization and membrane expression. By immunofluorescent labeling, flow cytometry analysis, Co-immunoprecipitation and open field test, we measured the role of Ca2+ /calmodulin-dependent protein kinase II (CaMKII) to the control of GABAB R membrane anchoring and cocaine induced-behavioral sensitization. Repeated cocaine treatment in rats (15 mg/kg) significantly decreases membrane levels of GABAB1 R and GABAB2 R in the NAc after day 3, 5 and 7. The membrane fluorescence and protein levels of GABAB R was also decreased in NAc GAD67 + neurons post cocaine (1 μM) treatment after 5 min. Moreover, the majority of internalized GABAB1 Rs exhibited perinuclear localization, a decrease in GABAB1 R-pHluroin signals was observed in cocaine-treated NAc neurons. By contrast, membrane expression of phosphorylated CaMKII (pCaMKII) post cocaine treatment was significantly increased after day 1, 3, 5 and 7. Baclofen blocked the cocaine induced behavioral sensitization via inhibition of cocaine enhanced-pCaMKII-GABAB1 R interaction. These findings reveal a new mechanism by which pCaMKII-GABAB R signaling can promote psychostimulant-induced behavioral sensitization.

The cognitive and behavioral effects of D-amphetamine and nicotine sensitization in adult zebrafish

BackgroundZebrafish are growing in use as a model for understanding drug dependence and addiction. Sensitization paradigms have been a useful tool in identifying mechanisms involved in drug-induced behavioral and neurological changes, but in zebrafish have tended to focus on locomotor, rather than cognitive, endpoints.MethodsHere, we used a novel method, the FMP Y-maze, which measures continuous performance through a series of repeated binary choices (L vs R), to establish a model for assessing parameters associated with psychostimulant-induced behavioral and cognitive sensitization in adult zebrafish.ResultsRepeat, intermittent exposure to d-amphetamine (AMPH) for 14 days increased alternations (LRLR) in the maze, suggesting improved working memory, which was enhanced further following drug challenge after a short withdrawal period, suggesting behavioral sensitization. However, this cognitive enhancement coincided with a reduction in the use of other exploration strategies, hypolocomotion, and inhibition of cognitive flexibility. Like AMPH, exposure to nicotine (NIC) increased alternations following drug challenge after chronic treatment. Repeat NIC exposure appeared to induce both cognitive and psychomotor sensitization, as evidenced by increased working memory performance (alternations) and locomotor activity, without negatively impacting other search strategies or cognitive flexibility.ConclusionChronic treatment with AMPH or NIC boosts cognitive performance in adult zebrafish. Cognitive sensitization occurred with both drugs, resulting in enhanced working memory; however, repeat AMPH exposure, following a withdrawal period, resulted in inhibited cognitive flexibility, an effect not evident with repeat NIC exposure. Cognitive and behavioral sensitization paradigms in zebrafish could serve as a useful tool for assessing cognitive states which result in cognitive enhancing or impairing effects of drugs.

Effects of D2 or combined D1/D2 receptor antagonism on the methamphetamine-induced one-trial and multi-trial behavioral sensitization of preweanling rats.

There is suggestive evidence that the neural mechanisms mediating one-trial and multi-trial behavioral sensitization differ, especially when the effects of various classes of dopamine (DA) agonists are examined. The purpose of the present study was to determine the role of the D2 receptor for the induction of one-trial and multi-trial methamphetamine sensitization in preweanling rats. In a series of experiments, rats were injected with saline or raclopride (a selective D2 receptor antagonist), either alone or in combination with SCH23390 (a selective D1 receptor antagonist), 15min prior to treatment with the indirect DA agonist methamphetamine. Acute control groups were given two injections of saline. This pretreatment regimen occurred on either postnatal days (PD) 13-16 (multi-trial) or PD 16 (one-trial). On PD 17, rats were challenged with methamphetamine and locomotor sensitization was determined. Blockade of D2 or D1/D2 receptors reduced or prevented, respectively, the induction of multi-trial methamphetamine sensitization in young rats, while the same manipulations had minimal effects on one-trial behavioral sensitization. DA antagonist treatment differentially affected the methamphetamine-induced sensitized responding of preweanling rats depending on whether a one-trial or multi-trial procedure was used. The basis for this effect is uncertain, but there was some evidence that repeated DA antagonist treatment caused nonspecific changes that produced a weakened sensitized response. Importantly, DA antagonist treatment did not prevent the one-trial behavioral sensitization of preweanling rats. The latter result brings into question whether DA receptor stimulation is necessary for the induction of psychostimulant-induced behavioral sensitization during early ontogeny.

Effects of gender on locomotor sensitivity to amphetamine, body weight, and fat mass in regulator of G protein signaling 9 (RGS9) knockout mice

Regulator of G-protein signaling (RGS) protein 9-2 is enriched in the striatum where it modulates dopamine and opioid receptor-mediated signaling. RGS9 knockout (KO) mice show increased psychostimulant-induced behavioral sensitization, as well as exhibit higher body weights and greater fat accumulation compared to wild-type (WT) littermates. In the present study, we found gender influences on each of these phenotypic characteristics. Female RGS9 KO mice exhibited greater locomotor sensitization to amphetamine (1.0mg/kg) treatment as compared to male RGS9 KO mice. Male RGS9 KO mice showed increased body weights as compared to male WT littermates, while no such differences were detected in female mice. Quantitative magnetic resonance showed that male RGS9 KO mice accumulated greater fat mass vs. WT littermates at 5months of age. Such observations could not be explained by increased caloric consumption since male and female RGS9 KO mice demonstrated equivalent daily food intake as compared to their respective WT littermates. Although indirect calorimetry methods found decreased oxygen consumption and carbon dioxide production during the 12-hour dark phase in male RGS9 KO vs. WT mice which are indicative of less energy expenditure, male RGS9 KO mice exhibited lower levels of locomotor activity during this period. Genotype had no effect on metabolic activities when KO and WT groups were compared under fasting vs. feeding treatments. In summary, these results highlight the importance of factoring gender into the experimental design since many studies conducted in RGS9 KO mice utilize locomotor activity as a measured outcome.

Age-dependent differences in the strength and persistence of psychostimulant-induced conditioned activity in rats: effects of a single environment-cocaine pairing.

The aim of the present study was to determine the strength and persistence of cocaine-induced conditioned activity in young and adult rats. A one-trial protocol has proven useful for studying the ontogeny of psychostimulant-induced behavioral sensitization; therefore, a similar procedure was used to examine conditioned activity. On postnatal day (PD) 19 or PD 80, rats were injected with saline or cocaine in either a novel test chamber or the home cage. After various drug abstinence intervals (1-21 days), rats were injected with saline and returned to the test chamber, where conditioned activity was assessed. In a separate experiment, we examined whether cocaine-induced conditioned activity was a consequence of Pavlovian conditioning or a failure to habituate to the test environment. The results indicated that adult rats showed strong one-trial conditioned activity that persisted for at least 21 days, whereas young rats did not show a conditioned locomotor response. The conditioned activity shown by adult rats did not result from a failure to habituate to the cocaine-paired environment. These results indicate that cocaine-paired contextual stimuli differentially affect behavior depending on the age of the animal. The data obtained from adult rats have potential translational relevance for humans because a single environment-drug pairing caused long-term alterations in behavior.

Extending therapeutic use of psychostimulants: Focus on serotonin-1A receptor

Despite a number of medicinally important pharmacological effects, the therapeutic use of psychostimulants is limited because of abuse potential and psychosis following long term use. Development of pharmacological agents for improving and extending therapeutic use of psychostimulants in narcolepsy, attention deficit hyperactivity disorder, Parkinson's disease, obesity and as cognitive enhancer is an important research imperative. In this regard, one potential target system is the 5-hydroxytryptamine (5-HT; serotonin) neurotransmitter system. The focus of the present article is to evaluate a potential role of 5-HT-1A receptor in the alleviation of abuse potential and psychosis-induced by prescription psychostimulants amphetamines and apomorphine. Synaptic contacts between dopamine systems and 5-HT-1A receptors are traced. Studies on serotonin-1A influences on the modulation of dopamine neurotransmission and psychostimulant-induced behavioral sensitization are accumulated. Inhibition of amphetamine and apomorphine-induced behavioral sensitization by co administration of 5-HT-1A agonists cannot be explained in terms of direct activation of 5-HT-1A receptors, because activation of pre- as well as postsynaptic 5-HT-1A receptors tends to increase dopamine neurotransmission. Long term use of amphetamine and apomorphine produces adaptive changes in 5-HT-1A receptor mediated functions, which are prevented by the co-use of 5-HT-1A agonists. In view of extending medicinal use of psychostimulants, it is important to evaluate the effects of co-use of 5-HT-1A agonists on potential therapeutic profile of amphetamine and apomorphine in preclinical research. It is also important to evaluate the functional significance of 5-HT-1A receptors on psychostimulant-induced behaviors in other addiction models such as drug self-administration and reinstatement of drug seeking behavior.

Neuropharmacologic Studies on the Brain Serotonin<sub>1A</sub> Receptor Using the Selective Agonist Osemozotan

Alterations in serotonin (5-HT) neurochemistry have been implicated in the etiology of major neuropsychiatric disorders such as anxiety-spectrum disorders, depression, and schizophrenia. The neuromodulatory effects of 5-HT are mediated through 14 receptor subtypes, and those receptors, including the 5-HT1A receptor, are considered to be potential targets for the treatment of psychiatric disorders. We developed the novel 5-HT1A receptor agonist MKC-242 (called osemozotan) and characterized its neurochemical and pharmacological profiles. 5-HT1A receptor agonists modulate the release of amine neurotransmitters through the activation of presynaptic or postsynaptic 5-HT1A receptors in the brain. The agonist has antianxiety and antidepressant effects and improves abnormal behaviors such as aggressive behavior and deficits of prepulse inhibition in isolation-reared mice. We also demonstrated that spinal 5-HT1A receptor activation is involved in isolation rearing-induced hypoalgesia. Concerning the mechanism for induction of isolation-induced abnormal behaviors, we have recently found that the raphe-prefrontal 5-HT system plays a key role in encounter stimulation-induced hyperactivity in isolation-reared mice. Furthermore, we showed that osemozotan attenuates psychostimulant-induced behavioral sensitization and that prefrontal dopamine release is enhanced by functional interaction between the 5-HT1A receptor and other receptors. This review summarizes the neuropharmacology of the 5-HT1A receptor, focusing on our studies using osemozotan, and suggests that the 5-HT1A receptor may be a target molecule for the treatment of psychiatric disorders, pain, and drug dependence.

Aripiprazole attenuates established behavioral sensitization induced by methamphetamine

Psychostimulant-induced behavioral sensitization is an experimental model of the stimulant psychosis and the vulnerability to relapse in schizophrenia. This study investigated the effects of aripiprazole, an antipsychotic drug that has dopamine D2 receptor partial agonist activity, on established sensitization induced by methamphetamine (MAP) in mice. Repeated treatment with MAP (1.0 mg/kg, s.c.) for 10 days progressively increased the ability of MAP to increase locomotor activity. The enhanced locomotion induced by a challenge dose of MAP (0.24 mg/kg, s.c.) also occurred after withdrawal from MAP pretreatment. Repeated treatment with aripiprazole from days 10 to 14 during withdrawal from MAP administration attenuated the effect of MAP pretreatment, enhancing the motor response to a challenge dose of stimulant 3 days after the aripiprazole preparation. In contrast, sulpiride, a dopamine D2 receptor specific antagonist, and risperidone, a serotonin 5-HT2 and dopamine D2 receptor antagonist, did not show effects similar to aripiprazole. The attenuation effect of aripiprazole was blocked by pretreatment with the specific serotonin 5-HT1A antagonist WAY100635. These results of aripiprazole suggest that the attenuation effect of aripiprazole was mediated by 5-HT1A receptors and imply that aripiprazole may have therapeutic value in treating drug-induced psychosis and schizophrenia.

Methamphetamine- and 3,4-Methylenedioxymethamphetamine–Induced Behavioral Changes in Histamine H3–Receptor Knockout Mice

Histamine H3 receptors inhibit the release of not only histamine itself, but also other neurotransmitters including dopamine. Previous papers have reported that histaminergic neurons inhibit psychostimulant-induced behavioral changes. To examine whether deficiency in histamine H3 receptors influences psychostimulant-induced behavioral sensitization and reward, we examined locomotor activity, conditioned place preference (CPP), and c-Fos expression in histamine H3 receptor–gene knockout mice (H3KO) and their wild-type (WT) counterparts before and after treatment with methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA). The increase in locomotion induced by treatment with METH or MDMA was lower in histamine H3KO mice than in WT mice, while the locomotor sensitization was developed by METH or MDMA in both strains. However, no significant difference in METH- and MDMA-induced preference scores of CPP between histamine H3KO mice and WT mice was observed. Following treatment with METH, the number of c-Fos–positive neurons in the the caudate-putamen of histamine H3KO mice was lower than that in the caudate-putamen of WT mice. In contrast, there was no significant difference in the number of the psychostimulant-induced c-Fos–positive cells in the nucleus accumbens between the two strains of mice. These findings suggest that deficiency in histamine H3 receptors may have inhibitory effects on psychostimulant-induced increase in locomotion, but insignificant effects on the reward.

Cocaine-induced behavioral sensitization in adolescent rats endures until adulthood: Lack of association with GluR1 and NR1 glutamate receptor subunits and tyrosine hydroxylase

Exposure to repeated cocaine induces enduring behavioral sensitization, which has been implicated in the psychostimulant-induced craving and psychosis. Adaptations in dopamine and glutamate neurotransmission in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) seem to mediate psychostimulant-induced behavioral sensitization. The abuse of drugs often begins during adolescence; however few studies have been devoted to study the effects of drugs of abuse at this age. The aim of our study was to examine whether repeated cocaine during adolescence could induce behavioral sensitization that endures into adulthood. Moreover, the protein levels of Tyrosine Hydroxylase (TH) and the glutamate receptor subunits GluR1 and NR1 in the NAc and mPFC were measured following the behavioral tests. Adolescent rats were treated with cocaine from postnatal day (PND) 30 to PND34 and behavioral sensitization was verified recording locomotor activity after cocaine challenge injection to adolescent (PND37) or adult (PND64 or 94) rats in separate groups at each time point. TH, GluR1, and NR1 protein levels were measured by Western blotting. Rats exposed to cocaine during adolescence expressed behavioral sensitization when tested on PND37 and PND64. In cocaine sensitized rats GluR1 protein was increased in the mPFC on PND37 but not in other ages. Thus, cocaine-induced behavioral sensitization during adolescence endures into early adulthood. However, cocaine pretreatment during adolescence induced a transient increase of GluR1 in the mPFC only when animals were challenged in the same age.

Augmented behavioral response and enhanced synaptosomal calcium transport induced by repeated cocaine administration are decreased by calcium channel blockers

Recent studies suggest that calcium influx via L-type calcium channels is necessary for psychostimulant-induced behavioral sensitization. In addition, chronic amphetamine upregulates subtype Cav1.2-containing L-type calcium channels. In the present studies, we assessed the effect of calcium channel blockers (CCBs) on cocaine-induced behavioral sensitization and determined whether the functional activity of L-type calcium channels is altered after repeated cocaine administration. Rats were administered daily intraperitoneal injections of either flunarizine (40 mg/kg), diltiazem (40 mg/kg) or cocaine (20 mg/kg) and the combination of the CCBs and cocaine for 30 days. Motor activities were monitored on Day 1, and every 6th day during the 30-day treatment period. Daily cocaine administration produced increased locomotor activity. Maximal augmentation of behavioral response to repeated cocaine administration was observed on Day 18. Flunarizine pretreatment abolished the augmented behavioral response to repeated cocaine administration while diltiazem was less effective. Measurement of tissue monoamine levels on Day 18 revealed cocaine-induced increases in DA and 5-HT in the nucleus accumbens. By contrast to behavioral response, diltiazem was more effective in attenuating increases in monoamine levels than flunarizine. Cocaine administration for 18 days produced increases in calcium uptake in synaptosomes prepared from the nucleus accumbens and frontal cortex. Increases in calcium uptake were abolished by flunarizine and diltiazem pretreatment. Taken together, the augmented cocaine-induced behavioral response on Day 18 may be due to increased calcium uptake in the nucleus accumbens leading to increased dopamine (DA) and serotonin (5-HT) release. Flunarizine and diltiazem attenuated the behavioral response by decreasing calcium uptake and decreasing neurochemical release.

The potential role of sigma-1 receptors in lipid transport and lipid raft reconstitution in the brain: Implication for drug abuse

The brain is highly enriched in lipids. However, the molecular biological roles of lipids in the brain have been largely unexplored. Although, in 1990s, several studies have demonstrated the roles of lipids in a variety of neuronal functions and certain neurological diseases, the involvement of lipids in drug dependence, if any, is almost totally unknown. Sigma-1 receptors are brain-enriched proteins that interact with psychostimulants such as cocaine and methamphetamine. Sigma-1 receptors possess a putative sterol-binding pocket and are predominantly expressed on the endoplasmic reticulum (ER) where most lipids and their precursors are synthesized. Sigma-1 receptors are involved in drug-seeking behaviors and in psychostimulant-induced behavioral sensitization. Recent studies demonstrated that sigma-1 receptors target the lipid-storing subcompartments of the ER and are colocalized with cholesterol and neutral lipids. Sigma-1 receptors form detergent-insoluble lipid microdomains (lipid rafts) on the ER subcompartments and can translocate on the ER when stimulated. Upregulation of sigma-1 receptors affect the levels of plasma membrane lipid rafts by changing the lipid components therein. The membrane reconstitution thus induced by sigma-1 receptors in turn affects functions of proteins residing in plasma membrane lipid rafts including tropic factor receptors and tyrosine kinases. Specifically, we recently found that sigma-1 receptors modulate MAP kinase activation induced by tropic factors, neuritegenesis and oligodendrocyte differentiation—all related to lipid raft reconstitution. Sigma-1 receptors may thus play a role in psychostimulant-induced long-lasting morphological changes in the brain via the capacity of sigma-1 receptors in regulating ER lipid transport and the resultant plasma membrane lipid raft reconstitution.

Ibotenic acid lesions of the medial prefrontal cortex block the development and expression of 3,4-methylenedioxymethamphetamine-induced behavioral sensitization in rats

There is ample evidence that plastic changes in the nervous system require the excitatory amino acid transmission. This appears to be also the case for psychostimulant-induced behavioral sensitization. More specifically the glutamatergic input from the medial prefrontal cortex (mPFC) to the VTA and the NAc appears to be involved in behavioral sensitization processes. However, dissociations regarding the role of the mPFC with respect to the development and expression of sensitization, as well as with respect to the psychostimulant being studied (amphetamine versus cocaine) appear to exist. The present study examined the role of the dorsal mPFC in the development and expression of 3,4-methylenedioxymethamphetamine (MDMA)-induced sensitization. Bilateral ibotenic acid or sham lesions of the dorsal mPFC were performed 7 days prior to or 4 days after a context-dependent sensitization-inducing regimen of MDMA (15 mg/kg i.p.) or saline. Rats were then challenged with MDMA (5 mg/kg i.p.) after 12 days of withdrawal. Ibotenic acid lesions did not affect the activating effects of MDMA, but prevented the development and expression of MDMA sensitization. Thus, the distance traveled during the development phase of sensitization increased in sham-lesioned rats but not in ibotenic-lesioned animals. Similarly, sham-lesioned rats showed a sensitized response when challenged with MDMA after the withdrawal period, an effect not observed in ibotenic-lesioned animals. These data reinforce the view that the dorsal mPFC is involved in psychostimulant sensitization and more specifically they indicate that the dorsal mPFC plays a key role in the development and expression of MDMA-induced behavioral sensitization.

Adenosine A2a receptor/dopamine D2 receptor hetero-oligomerization: a hypothesis that may explain behavioral sensitization to psychostimulants and schizophrenia

The mechanisms underlying psychostimulant-induced behavioral sensitization and schizophrenia are yet to be fully elucidated. Evidence suggests that the dopamine D2 receptor (DRD2) as well as other neurotransmitter system receptors may be involved in the two conditions, and previous reports have hypothesized that oligomerization of dopamine receptors and analogs from other neurotransmitter systems may underlie the mechanism responsible. This paper describes findings which show co-localization of DRD2 and the adenosine A2a receptor (A2aAR) in the striatum, interaction between the two receptors and A2aAR/DRD2 hetero-oligomerization in the neuronal cell. The possibility that A2aAR/DRD2 hetero-oligomerization may be involved in the development of psychostimulant-induced behavioral sensitization or the pathogenesis of schizophrenia is explored. A2aAR/DRD2 hetero-oligomerization can enhance dopaminergic function, resulting in an increased behavioral response to psychostimulants or the development of psychotic symptoms. Receptor oligomerization can affect receptor degradation, which may affect the persistence of behavioral sensitization or psychotic symptoms. The proposed A2aAR/DRD2 hetero-oligomerization model may suggest new directions in the understanding and treatment of schizophrenia.

Morphine-induced c-fos mRNA expression in striatofugal circuits: modulation by dose, environmental context, and drug history.

Opiates and psychostimulants produce many shared behavioral and neurobiological adaptations, such as behavioral sensitization and the induction of immediate early genes in the caudate-putamen (CPu). Previous studies indicate that factors such as dose, the environmental context surrounding drug administration and drug history can influence both morphine- and psychostimulant-induced behavioral sensitization. In addition, these factors can modulate the ability of psychostimulants to engage striatofugal circuits in the CPu. The present study, therefore, sought to examine whether these factors have similar influences over the ability of morphine to engage cortico-striatofugal circuits. We report that, when given in the home cage, morphine produced a small, but significant increase in the number of c-fos+ striatonigral cells and c-fos+ cells in cingulate cortex, but had no effect on the number of c-fos+ striatopallidal cells. When given in a novel test environment, however, morphine dramatically increased the number of c-fos+ striatonigral cells in a dose-dependent fashion, and this effect was maintained following repeated treatment. Unexpectedly, morphine treatment in a novel environment produced a dose-dependent reduction in the number of c-fos+ striatopallidal cells and c-fos+ cells in cingulate cortex, relative to exposure to novelty alone-effects that were reversed by repeated morphine treatment. We suggest that alterations in c-fos expression patterns in striatofugal circuits following morphine administration may be involved in drug-experience-dependent plasticity.

Changes in PKA activity and Gs alpha and Golf alpha levels after amphetamine- and cocaine-induced behavioral sensitization.

Neuroadaptations in the cAMP signal transduction system have been proposed to play a critical role in psychostimulant-induced behavioral sensitization. Studies relevant to this hypothesis have provided conflicting evidence, however, because repeated cocaine and amphetamine treatment has been alternately reported to either increase or decrease protein kinase A (PKA) activity in the nucleus accumbens and dorsal striatum. In an attempt to reconcile these disparate findings, PKA activity and the stimulatory G-protein subunits, G(salpha) and G(olfalpha), were measured after rats had received a sensitization-inducing regimen of amphetamine or cocaine. Results showed that seven consecutive daily injections of amphetamine or cocaine produced locomotor sensitization and caused a reduction in accumbal PKA activity. A challenge injection of amphetamine on the test day also reduced dorsal striatal PKA activity. G(salpha) levels were unaffected by psychostimulant exposure, while G(olfalpha) levels in the nucleus accumbens declined significantly after amphetamine or cocaine pretreatment. Because repeated amphetamine and cocaine treatment both induced behavioral sensitization and decreased accumbal PKA activity, it appears that psychostimulant-induced increases in PKA activity are not necessary for the ultimate expression of behavioral sensitization.

Dopamine receptor hetero-oligomerization: a hypothesis for behavioral sensitization to psychostimulants

Repeated psychostimulant pretreatment can induce behavioral sensitization. Many previous studies have demonstrated that receptors of the dopamine and other neurotransmitter systems are involved in the sensitization process, however, the precise mechanism of this interaction is still unknown. We propose the hypothesis that oligomerization of the dopamine receptors and analogs from other neurotransmitter systems may contribute, at least in part, to psychostimulant-induced behavioral sensitization. Psychostimulant exposure can enhance central dopamine release, which can increase oligomerization of the dopamine receptors with their analogs. Receptor oligomerization can enhance the functional properties of the receptors and affect receptor degradation, which may be related to the behavioral augmentation which characterizes the sensitized state and produces the persistence of behavioral sensitization. The proposed receptor hetero-oligomerization model may provide a new direction in the exploration of the functionally critical sensitization phenomenon.

The roles of calcium/calmodulin-dependent and Ras/mitogen-activated protein kinases in the development of psychostimulant-induced behavioral sensitization.

Although the development of behavioral sensitization to psychostimulants such as cocaine and amphetamine is confined mainly to one nucleus in the brain, the ventral tegmental area (VTA), this process is nonetheless complex, involving a complicated interplay between neurotransmitters, neuropeptides and trophic factors. In the present review we present the hypothesis that calcium-stimulated second messengers, including the calcium/calmodulin-dependent protein kinases and the Ras/mitogen-activated protein kinases, represent the major biochemical pathways whereby converging extracellular signals are integrated and amplified, resulting in the biochemical and molecular changes in dopaminergic neurons in the VTA that represent the critical neuronal correlates of the development of behavioral sensitization to psychostimulants. Moreover, given the important role of calcium-stimulated second messengers in the expression of behavioral sensitization, these signal transduction systems may represent the biochemical substrate through which the transient neurochemical changes associated with the development of behavioral sensitization are translated into the persistent neurochemical, biochemical and molecular alterations in neuronal function that underlie the long-term expression of psychostimulant-induced behavioral sensitization.

Inactivation of adenosine A2A receptors selectively attenuates amphetamine-induced behavioral sensitization.

Repeated treatment with the psychostimulant amphetamine produces behavioral sensitization that may represent the neural adaptations underlying some features of psychosis and addiction in humans. In the present study we investigated the role of adenosine A(2A) receptors in psychostimulant-induced locomotor sensitization using an A(2A) receptor knockout (A(2A) KO) model. Daily treatment with amphetamine for 1 week resulted in an enhanced motor response on day 8 (by two-fold compared to that on day 1), and remained enhanced at day 24 upon rechallenge with amphetamine. By contrast, locomotor sensitization to daily amphetamine did not develop in A(2A) KO mice on day 8 or 24, and this absence was not the result of a nonspecific threshold effect. The absence of behavioral sensitization was selective for amphetamine since daily treatment with the D(1) agonist SKF81297 (2.5 mg/kg) or the D(2) agonist quinpirole (1.0 mg/kg) produced similar behavioral sensitization in both WT and A(2A) KO mice. Furthermore, coinjection of SKF81297 and quinpirole also resulted in indistinguishable locomotor sensitization in A(2A) KO and WT mice, suggesting normal D(1) and D(2) receptor responsiveness. Finally, at the cellular level A(2A) receptor inactivation abolished the increase in striatal dynorphin mRNA induced by repeated amphetamine administration. The selective absence of amphetamine-induced behavioral sensitization in A(2A) KO mice suggests a critical role of the A(2A) receptor in the development of psychostimulant-induced behavioral sensitization, and supports the pharmacological potential of A(2A) adenosinergic agents to modulate adaptive responses to repeated psychostimulant exposure.

Stimulant-induced psychosis and schizophrenia: the role of sensitization.

Three different conditions, psychostimulant-induced behavioral sensitization in rodents, psychostimulant-induced psychoses in human, and chronic schizophrenia show similar longitudinal alternations, progressively enhanced susceptibility to abnormal behaviors, psychotic state, and relapse. Sensitization phenomena to the drugs or endogenous dopamine should be involved in the mechanisms underlying the development of such susceptibility. Recently, an enhanced dopamine release in vivo by amphetamine administration in the striatum has been shown in schizophrenics, which is a replication of that previously proven in the behavioral sensitization in rats. Accordingly, common molecular mechanisms of sensitization phenomena must develop in these three conditions, and are overviewed in this review