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Background: The proliferation of novel psychoactive substances (NPS) in the drug market raises concerns about uncertainty on their pharmacological profile and the health hazard linked to their use. Within the category of synthetic stimulant NPS, the phenethylamine 2-Cl-4,5-methylenedioxymethamphetamine (2-Cl-4,5-MDMA) has been linked to severe intoxication requiring hospitalization. Thereby, the characterization of its pharmacological profile is urgently warranted., Methods: By in vivo brain microdialysis in adolescent and adult male rats we investigated the effects of 2-Cl-4,5-MDMA on dopamine (DA) and serotonin (5-HT) neurotransmission in two brain areas critical for the motivational and rewarding properties of drugs, the nucleus accumbens (NAc) shell and the medial prefrontal cortex (mPFC). Moreover, we evaluated the locomotor and stereotyped activity induced by 2-Cl-4,5-MDMA and the emission of 50-kHz ultrasonic vocalizations (USVs) to characterize its affective properties., Results: 2-Cl-4,5-MDMA increased dialysate DA and 5-HT in a dose-, brain area-, and age-dependent manner. Notably, 2-Cl-4,5-MDMA more markedly increased dialysate DA in the NAc shell and mPFC of adult than adolescent rats, while the opposite was observed on dialysate 5-HT in the NAc shell, with adolescent rats being more responsive. Furthermore, 2-Cl-4,5-MDMA stimulated locomotion and stereotyped activity in both adolescent and adult rats, although to a greater extent in adolescents. Finally, 2-Cl-4,5-MDMA did not stimulate the emission of 50-kHz USVs., Conclusions: This is the first pharmacological characterization of 2-Cl-4,5-MDMA demonstrating that its neurochemical and behavioral effects may differ between adolescence and adulthood. These preclinical data could help understanding the central effects of 2-Cl-4,5-MDMA by increasing awareness on possible health damage in users., (© The Author(s) 2024. Published by Oxford University Press on behalf of CINP.)

Energy drinks (EDs) are beverages similar to soft drinks, characterized by high caffeine concentrations with additional ingredients like taurine and vitamins, marketed for boosting energy, reducing tiredness, increasing concentration, and for their ergogenic effect. The majority of consumers are children, adolescents, and young athletes. Although EDs companies claim about the ergogenic and remineralizing properties of their products, there is a serious lack of evidence at preclinical as well as clinical level to validate their benefits. The regular intake and long-term consequences of these caffeinated drinks are not well documented, especially the possible negative effects in adolescents whose brain is still developing. EDs combined with alcohol are also gaining popularity among adolescents and different publications indicate that this combined consumption might increase the risk to develop an alcohol use disorder, as well as produce serious adverse cardiovascular effects. There is an increasing need to disseminate knowledge on EDs damage on health, so that adolescents can be aware about the potential harmful outcomes of consuming these drinks., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cadoni and Peana.)

Conceived and developed since 2001 at the Alba Center, Videodialysis (VD) was used initially to prevent dropout in prevalent PD patients by guiding them in performing dialysis (VD-Caregiver). Subsequently, its use was extended to the clinical follow-up of critical patients (VD-Clinical), problems relating to transport to the Center (VD-Transport), and since 2016 for training/retraining all patients (VD-Training). Since 2017 other Centers have employed VD using modalities analyzed in this paper. Methods: the paper reports the findings of an Audit (February 2021) of the Centers using VD on 31-12-2020. The Centers provided the following information: the characteristics of the patients using VD; the main and secondary reasons for using VD, considering nursing home (VD-NH) patients separately; VD outcomes: duration, drop-out, peritonitis, patient/caregiver satisfaction (minimum: 1 - maximum: 10). Results: VD, which began between 09-2017 and 12-2019, has been used in 6 Centers for 54 patients at 31-12-2020 (age:71.8±12.6 years - M:53.7% - CAPD:61.1% - Assisted PD:70.3%). The most frequent reason has been VD-Training (70.4%), followed by VD-Caregiver (16.7%), VD-NH (7.4%), VD-Clinical (3.7%), and VD-Transport (1.9%), with differences between Centers. VD-Training is used most with self-care patients (93.8% - p<0.05), while with patients on Assisted PD it is associated with secondary reasons (95.7% - p<0.02). VD-Training (duration: 1-4 weeks) has always been completed successfully. No peritonitis was reported; satisfaction was 8.4±1.4. Conclusion: videodialysis is a flexible, effective, safe, and valued tool that can be employed using various modalities depending on the choice of the Center and the complexity of the patient., (Copyright by Società Italiana di Nefrologia SIN, Rome,Italy.)

Genetic background and age at first exposure have been identified as critical variables that contribute to individual vulnerability to drug addiction. Evidence shows that genetic factors may account for 40-70% of the variance in liability to addiction. Alcohol consumption by young people, especially in the form of binge-drinking, is becoming an alarming phenomenon predictive of future problems with drinking. Thus, the literature indicates the need to better understand the influence of age and genetic background on the development of alcohol dependence. To this aim, the inbred rat strains Lewis (LEW, addiction prone) and Fischer 344 (F344, addiction resistant) were used as a model of genetic vulnerability to addiction and compared with the outbred strain Sprague-Dawley (SD) in a two-bottle choice paradigm as a model of alcohol abuse. During a 9-week period, adolescent and adult male rats of the three strains were intermittently exposed to ethanol (20%) and water during three 24-h sessions/week. Adult and adolescent SD and LEW rats escalated their alcohol intake over time reaching at stable levels, while F344 rats did not escalate their intake, regardless of age at drinking onset. Among adolescents, only F344 rats consumed a higher total amount of ethanol than adults, although only SD and LEW rats escalated their intake. Adult LEW rats, albeit having a lower ethanol consumption as compared to SD rats but greater than F344, showed a more compulsive intake, consuming higher amounts of ethanol during the first hour of exposure, reaching a higher degree of ethanol preference when start drinking as adolescents. Behavioral analysis during the first hour of ethanol consumption revealed significant strain differences, among which noticeable the lack of sedative effect in the LEW strain, at variance with F344 and SD strains, and highest indices of withdrawal (most notable jumping) in LEW rats during the first hour of abstinence days. The present results underscore the importance of individual genetic background and early onset of alcohol use in the progression toward abuse and development of alcohol addiction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Corongiu, Dessì, Espa, Pisanu, Pinna, Lecca, Fenu and Cadoni.)

Smoking during adolescence may increase the likelihood to develop nicotine dependence and to abuse other drugs such as cocaine. Despite great efforts to understand underlying neurobiological mechanisms of this progression, less attention has been paid to the role of genetic factors. Here, we investigated the influence of both genetic background and age at first nicotine exposure in the long-lasting effects on mesolimbic dopamine transmission including the increased cocaine-rewarding effect. Mid-adolescent and adult rats of inbred strains Lewis (addiction prone) and Fischer 344 (addiction resistant) were administered nicotine (0.4 mg/kg) or vehicle once daily for 5 days. Changes in dopamine transmission were investigated by in vivo microdialysis and electrophysiology after 30 days of withdrawal, whereas changes in cocaine-rewarding effect were assessed via conditioned place preference paradigm. Nicotine pre-exposure differentially changed mesolimbic dopamine transmission depending on strain and age of pre-exposure. A potentiation of dopamine response to nicotine was observed in nucleus accumbens (NAc) core of both strains and age groups, whereas dopamine response in NAc shell was enhanced exclusively in Lewis rats exposed to nicotine during adolescence. A similar response was observed following cocaine challenge at adulthood. Changes in VTA dopamine cell population and activity were observed only in adolescent nicotine-pretreated Lewis rats, which also showed an increased cocaine-rewarding effect at adulthood. These results highlight the influence of genetic background in the long-lasting effects of nicotine exposure and suggest that exposure during adolescence might increase nicotine and cocaine-rewarding properties in genetically vulnerable individuals, thereby facilitating progression toward dependence., (© 2019 Society for the Study of Addiction.)

On the basis of epidemiological studies it has been proposed that cannabis use plays a causal role in the abuse of highly addictive drugs (Gateway Hypothesis). However, epidemiological studies are intrinsically unable to provide evidence of causality. Experimental studies can provide this evidence but they are feasible only in animal models and to date such evidence is lacking. In view of the importance of genetic factors in drug abuse, we investigated the influence of adolescent cannabis exposure on adult heroin reinforcement in two inbred rat strains differentially vulnerable to drugs of abuse, addiction prone Lewis (LEW) and addiction resistant Fischer 344 (F344) strains. Male LEW and F344 rats aged six weeks were exposed to increasing Δ 9 -tetrahydrocannabinol (THC) doses, twice a day for 3 days (2, 4, 8 mg/kg, i.p.). At adulthood they were allowed to self-administer heroin (0.025 mg/kg) under both Fixed- (FR) and Progressive- (PR) ratio schedules of responding. Following extinction, responding was reinstated by drug-cues and/or by heroin priming. THC pre-exposure increased responding for heroin and heroin intake under FR-3 and FR-5 as well as PR protocols and increased breaking point in PR schedules in LEW but not F344 rats. Drug cues and heroin priming reinstated responding in LEW and F344, but THC pre-exposure increased reinstatement by priming in LEW rats and by cues in F344 rats. These observations show that in genetically predisposed individuals, adolescent cannabis exposure increases heroin reinforcing properties, thus providing a mechanism for a causal role of adolescent cannabis use in heroin abuse., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Epidemiological studies have shown that people who begin experimenting drugs of abuse during adolescence are more likely to develop substance use disorders, and the earliest is the beginning of their use, the greatest is the likelihood to become dependent. Understanding the neurobiological changes increasing adolescent vulnerability to drug use is becoming imperative. Although all neurotransmitter systems undergo relevant developmental changes, dopamine system is of particular interest, given its role in a variety of functions related to reward, motivation, and decision making. Thus, in the present study, we investigated differences in mesolimbic and nigrostriatal dopamine transmission between adolescent (5, 6, 7 weeks of age) and adult rats (10-12 weeks of age), in basal conditions and following drug challenge, by using in vivo brain microdialysis. Although no significant difference between adolescents and adults was observed in dopamine basal levels in the nucleus accumbens (NAc)shell and core, reduced DA levels were found in the dorsolateral striatum (DLS) of early and mid-adolescent rats. Adolescent rats showed greater increase of dopamine in the NAc shell following nicotine (0.4 mg/kg), THC (1.0 mg/kg), and morphine (1.0 mg/kg), in the NAc core following nicotine and morphine, and in the DLS following THC, morphine, and cocaine (10 mg/kg). These results, while adding new insight in the development and functionality of the dopamine system during different stages of adolescence, might provide a neurochemical basis for the greater vulnerability of adolescents to drugs of abuse and for the postulated gateway effect of nicotine and THC toward abuse of other illicit substances., (© 2019 Society for the Study of Addiction.)

The Chapman psychosis-proneness scales-also known as Wisconsin schizotypy scales (WSS)-are among the most used tools to measure schizotypy. The factor structure of the short-form WSS was investigated in a mixed sample of patients with chronic mental disorders and of healthy subjects from the general population. One hundred patients with a chronic mental disorder were enrolled over a 6-month period. For each patient, two controls of same sex and similar age (±5 years) were enrolled; 131 accepted to take part in the study. The unidimensional, the correlated four-factor, the second-order two-factor models, and the bifactor model with two or four orthogonally independent factors of the short-form WSS were tested with confirmatory factor analysis. Good reliability of the short-form WSS was confirmed, as its capacity of differentiating people with and without schizotypy. The bifactor models were superior to other models. However, in both bifactor models the explained common variance (ECV) attributable to the general factor and the percentage of uncontaminated correlations (PUC) were too low to use a general summary score as a measure of a single latent schizotypy variable. Symptoms scores derived from the short-form WSS can be better appreciated within a multidimensional model of schizotypy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Although MDMA (3,4-methylendioxymethamphetamine, ecstasy) neurotoxicity in serotonin neurons is largely recognized in a wide variety of species including man, neurotoxicity in dopamine (DA) neurons is thought to be species-specific. MDMA is mainly consumed by adolescents, often in conjunction with caffeine (Energy Drinks) and this association has been reported to exacerbate MDMA toxic effects. In order to model these aspects of MDMA use, vis-à-vis their impact on DA neurons, we investigated the effects of adolescent exposure to low doses of MDMA (5 mg/kg for 10 days), alone or in combination with caffeine (10 mg/kg) on neuronal and functional DA indices and on recognition memory in adult rats. MDMA reduced density of tyrosine hydroxylase (TH) positive neurons in the ventral tegmental area and in the substantia nigra pars compacta, and immunoreactivity of TH and DA transporter in the nucleus accumbens (NAc) shell and core, and caudate-putamen. This same treatment caused a reduction of basal dialysate DA in the NAc core. MDMA-pretreated rats also showed behavioral sensitization to a MDMA challenge at adulthood and potentiation of MDMA-induced increase of dialysate DA in the NAc core, but not in the NAc shell. In addition, MDMA-treated rats displayed a deficit in recognition memory. Caffeine co-administration did not affect the above outcomes. Our results show that adolescent exposure of rats to low doses of MDMA induces long-lasting and widespread reduction of DA neurons indicative of a neurotoxic effect on DA neurons and suggestive of a degeneration of the same neurons., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Substance use, including cannabis, has been documented amongst women both in the pre-conception period and during pregnancy, particularly during the 1st trimester, which is clearly the most critical period in the organogenesis. The recent emergence on the drug market of synthetic cannabimimetics/SC ('spice') may represent a new challenge for clinicians., Objective: A literature overview on the teratogenicity profile of both cannabis and synthetic cannabimimetics was here carried out., Method: The PubMed database was searched in order to collect all relevant cases and data regarding the possible evidence of teratogenicity issues associated with cannabis and SC intake., Results: The use of cannabis in pregnant women has been associated with a plethora of both obstetrical/ gestational complications and neurobehavioral/neurological effects on newborns. Conversely, only few and conflicting data are related to SC misuse issues., Conclusion: Although cannabis use may be considered a risk factor for the occurrence of pregnancyrelated morbidity issues, many studies relied on self-reports and showed inconsistent results when controlling for potential confounders, including tobacco use. Given the role of the endocannabinoid system in both pregnancy and delivery, SC potency at interacting with the endocannabinoid system may be a reason of concern. Clinicians should carefully assess each woman planning a pregnancy, or who is pregnant already, and who is at risk of persisting in her current cannabis and/or SC intake. A nonjudgmental approach, aiming at collecting both a history of drug/alcohol use and at providing information regarding the risks associated with cannabis/SC intake during pregnancy is here advised., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Cannabis is the illicit drug with both the largest current levels of consumption and the highest reported lifetime prevalence levels in the world. Across different countries, the prevalence of cannabis use varies according to the individual income, with the highest use being reported in North America, Australia and Europe. Despite its 'soft drug' reputation, cannabis misuse may be associated with several acute and chronic adverse effects., Objective: The present article aims at reviewing several papers on epidemiological, neurobiological and psychopathological aspects of the use of cannabis. The PubMed database was here examined in order to collect and discuss a range of identified papers., Discussion: Cannabis intake usually starts during late adolescence/early adulthood (15-24 years) and drastically decreases in adulthood with the acquisition of working, familiar and social responsibilities. Clinical evidence supports the current socio-epidemiological alarm concerning the increased consumption among youngsters and the risks related to the onset of psychotic disorders. The mechanism of action of cannabis presents some analogies with other abused drugs, e.g. opiates. Furthermore, it has been well demonstrated that cannabis intake in adolescence may facilitate the transition to the use and/or abuse of other psychotropic drugs, hence properly being considered a 'gateway drug'. Some considerations on synthetic cannabimimetics are provided here as well., Conclusion: In conclusion, the highest prevalence of cannabis use and the social perception of a relatively low associated risk are in contrast with current knowledge based on biological and clinical evidence. Indeed, there are concerns relating to cannabis intake association with detrimental effects on both cognitive impairment and mental health., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Today it is well acknowledged that both nature and nurture play important roles in the genesis of psychopathologies, including drug addiction. Increasing evidence suggests that genetic factors contribute for at least 40-60% of the variation in liability to drug dependence. Human genetic studies suggest that multiple genes of small effect, rather than single genes, contribute to the genesis of behavioral psychopathologies. Therefore, the use of inbred rat strains might provide a valuable tool to identify differences, linked to genotype, important in liability to addiction and related disorders. In this regard, Lewis and Fischer 344 inbred rats have been proposed as a model of genetic vulnerability to drug addiction, given their innate differences in sensitivity to the reinforcing and rewarding effects of drugs of abuse, as well their different responsiveness to stressful stimuli. This review will provide evidence in support of this model for the study of the genetic influence on addiction vulnerability, with particular emphasis on differences in mesolimbic dopamine (DA) transmission, rewarding and emotional function. It will be highlighted that Lewis and Fischer 344 rats differ not only in several indices of DA transmission and adaptive changes following repeated drug exposure, but also in hypothalamic-pituitary-adrenal (HPA) axis responsiveness, influencing not only the ability of the individual to cope with stressful events, but also interfering with rewarding and motivational processes, given the influence of corticosteroids on dopamine neuron functionality. Further differences between the two strains, as impulsivity or anxiousness, might contribute to their different proneness to addiction, and likely these features might be linked to their different DA neurotransmission plasticity. Although differences in other neurotransmitter systems might deserve further investigation, results from the reviewed studies might open new vistas in understanding aberrant deviations in reward and motivational functions.

Microdialysis during i.v. drug self-administration (SA) have implicated nucleus accumbens (NAc) shell DA in cocaine and heroin reinforcement. However, this correlative evidence has not been yet substantiated by experimental evidence obtained by studying the effect of selective manipulation of NAc shell DA transmission on cocaine and heroin SA. In order to investigate this issue, DA D1a receptor (D1aR) expression was impaired in the NAc shell and core by locally infusing lentiviral vectors (LV) expressing specific D1aR-siRNAs (LV-siRNAs). Control rats were infused in the same areas with LV expressing GFP. Fifteen days later, rats were trained to acquire i.v. cocaine or heroin self-administration (SA). At the end of behavioral experiments, in order to evaluate the effect of LV-siRNA on D1aR expression, rats were challenged with amphetamine and the brains were processed for immunohistochemical detection of c-Fos and D1aR. Control rats acquired i.v. cocaine and heroin SA. Infusion of LV-siRNAs in the medial NAc shell reduced D1aR density and the number of c-Fos positive nuclei in the NAc shell, while sparing the core, and prevented the acquisition of cocaine, but not heroin SA. In turn, LV-siRNAs infusion in the core reduced D1aR density and the number of c-Fos positive nuclei in the same area, while sparing the shell, and failed to affect acquisition of cocaine. The differential effect of LV impairment of NAc shell D1aR on cocaine and heroin SA indicates that NAc shell DA acting on D1aR specifically mediates cocaine reinforcement.

Adolescent Cannabis exposure has been hypothesized to act as a gateway to opiate abuse. In order to investigate the role of genetic background in cannabinoid-opiate interactions, we studied the effect of Δ(9) -tetrahydrocannabinol (THC) exposure of adolescent Lewis and Fischer 344 rats on the responsiveness of accumbens shell and core dopamine (DA), as monitored by microdialysis, to THC and heroin at adulthood. Heroin reward and reinstatement by heroin priming were studied by conditioned place preference (CPP) and cognitive and emotional functions by object recognition, Y maze and elevated plus maze paradigms. THC stimulated shell DA in Lewis but not in Fischer 344 rats. Adolescent THC exposure potentiated DA stimulant effects of heroin in the shell and core of Lewis and only in the core of Fischer 344 rats. Control Lewis rats developed stronger CPP to heroin and resistance to extinction compared with Fischer 344 strain. In Lewis rats, THC exposure did not affect heroin CPP but potentiated the effect of heroin priming. In Fischer 344 rats, THC exposure increased heroin CPP and made it resistant to extinction. Lewis rats showed seeking reactions during extinction and hedonic reactions in response to heroin priming. Moreover, adolescent THC exposure affected emotional function only in Lewis rats. These observations suggest that long-term effects of Cannabis exposure on heroin addictive liability and emotionality are dependent on individual genetic background., (© 2013 Society for the Study of Addiction.)

Rationale: Sensitization of the incentive and dopamine (DA) stimulant properties of drug-conditioned stimuli (CSs) by repeated exposure to drugs of abuse has been assigned an important role in the genesis of drug addiction., Objective: To test in rats if morphine-induced sensitization potentiates incentive and DA-releasing properties in the nucleus accumbens (NAc) shell and core elicited by presentation of a morphine-conditioned stimulus(CS) and if this property generalizes to a non-drug-(palatable food, Fonzies)-CS., Methods: Controls and rats previously sensitized by morphine were trained via three daily sessions consisting of a 10-min presentation of CS (Fonzies filled box, FB) followed by s.c. saline and morphine (1 mg/kg) or by standard food and Fonzies. Rats were implanted with microdialysis probes and the next-day incentive reactions and NAc shell and core DA were monitored during CS presentation and subsequent morphine (1 mg/kg) administration or Fonzies feeding., Results: Morphine sensitization increased incentive and NAc shell and core DA responses to morphine-CS. Morphine conditioning per se increased incentive reactions and NAc shell but not core DA responses to FB presentation. Morphine sensitization potentiated incentive responses but did not affect NAc shell and core DA responses to Fonzies-CS. Fonzies conditioning increased incentive reactions and NAc core but not shell DA responses to FB presentation., Conclusions: These observations confirm the prediction of the incentive sensitization theory in the case of drug-CS but not of non-drug-CS. NAc DA might be differentially involved in the expression of incentive sensitization of drug- and non-drug-CSs, thus providing a clue for the abnormal incentive properties of drug CSs.

Saccharin avoidance conditioned by drugs of abuse (CSA) has been interpreted as an expression of the appetitive, dopamine-dependent, properties of the drug. Repeated exposure to these drugs induces an increase (sensitization) of their motor stimulant properties associated with differential changes in DA transmission in the NAc shell and core. The present study investigated the changes in drug CSA induced by schedules of repeated drug exposure that induce behavioral sensitization. CSA was performed in a two-bottle choice paradigm with two saccharin-drug associations in rats previously sensitized to morphine, cocaine, amphetamine and nicotine. In control rats morphine (1 and 5mg/kg s.c.), cocaine (5 and 10mg/kg i.p.), amphetamine (0.25 and 0.5mg/kg s.c.) and nicotine (0.4 mg/kg s.c.) induced dose-dependent CSA. Sensitization to morphine, cocaine and nicotine, which is known to reduce the responsiveness of NAc shell DA to the same drugs, also reduced CSA. In contrast, sensitization to amphetamine, that does not affect the responsiveness of NAc shell DA to the drug, failed to affect CSA. The results are consistent with the hypothesis that NAc shell DA is a substrate of the appetitive properties of drugs of abuse., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Genetic factors are known to affect the reinforcing properties of nicotine. Thus, inbred Lewis rats have been reported to be more sensitive to nicotine compared to Fischer 344 rats in self-administration, conditioned place preference and drug discrimination paradigms. In order to clarify the mechanisms of these differences we investigated, by means of dual probe microdialysis, the effect of different doses of nicotine (0.05, 0.1, 0.2, 0.4 mg/kg s.c.) on dopamine transmission in the shell and in the core of nucleus accumbens. Behavior was monitored during microdialysis. While no differences were observed between strains in dopamine basal values, Lewis rats, compared to Fischer 344 ones, showed in general a larger increase of DA transmission following nicotine both in the shell and in the core of the nucleus accumbens. In regard to behavioral stimulation no differences were observed between strains at higher doses while at the lowest doses Lewis rats appeared more sensitive than Fischer 344 rats to the locomotor stimulating effects of nicotine. These results suggest that strain-related differences in the sensitivity of mesolimbic dopamine transmission to nicotine might be involved in the reported differences in the reinforcing effect of nicotine in Lewis and Fischer 344 rats.

Although cannabinoid-induced behavioral sensitization and cross-sensitization with opiates has been recently demonstrated, no information is available on the associated state and responsiveness of dopamine (DA) transmission in the nucleus accumbens (NAc) shell and core. In this study we investigate by means of dual probe microdialysis, the effect of exposure to a sensitizing regimen of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and morphine on the extracellular concentrations of DA under basal conditions and after challenge with Delta(9)-THC and morphine in the NAc shell and core. Different groups of male Sprague-Dawley rats were administered twice daily for 3 days with increasing doses of Delta(9)-THC (2, 4, and 8 mg/kg i.p.), morphine (10, 20, and 40 mg/kg s.c.), and vehicle. After 14-20 days from the last injection, the animals were implanted with two microdialysis probes, one aimed at the NAc shell and the other at the core. The following day animals pre-treated with Delta(9)-THC and vehicle controls were challenged with 150 microg/kg i.v. of Delta(9)-THC or 0.5 mg/kg i.v. of morphine. Animals pre-treated with morphine and their vehicle controls were administered with 150 microg/kg i.v. of Delta(9)-THC. Rats pre-exposed to Delta(9)-THC showed behavioral sensitization associated with a reduced stimulation of DA transmission in the NAc shell and an increased stimulation in the NAc core in response to Delta(9)-THC challenge. Pre-exposure to Delta(9)-THC induced behavioral sensitization to morphine also, but only a reduced stimulation of DA transmission in the NAc shell was observed. Animals pre-treated with morphine showed behavioral sensitization and differential changes of DA in the NAc shell and core in response to Delta(9)-THC challenge with a decreased response in the shell and an increased response in the core. The results show that Delta(9)-THC-induced behavioral sensitization is associated with changes in the responsiveness of DA transmission in the NAc subdivisions that are similar to those observed in the sensitization induced by other drugs of abuse.

Repeated administration of addictive drugs and prolonged exposure to stressful stimuli induce sensitization to their behavioural stimulant properties. In this study, male Sprague-Dawley rats were repeatedly exposed to morphine [twice a day for 3 days at increasing doses, 10, 20, 40 mg/kg subcutaneously (s.c)], amphetamine (1 mg/kg s.c., once a day for 10 days), nicotine (0.4 mg/kg s.c., once a day for 5 days) and stress (food restriction for 7 days). After an interval of 3-30 days, depending on the pretreatment, rats were challenged with vehicle, with the same drug received as pretreatment (5 mg/kg of morphine, 0.5 mg/kg of amphetamine or 0.4 mg/kg of nicotine, respectively) or, in the case of food-restricted rats, with 0.5 mg/kg of amphetamine. Thereafter, changes in the expression of glutamic acid decarboxylase (GAD)67 mRNA were estimated by in situ hybridization in the central nucleus of the amygdala (CeA), basolateral amygdala (BLA), dorsolateral striatum (dLStr), nucleus accumbens shell (AcS) and core (AcC). All sensitizing pretreatments increased GAD67 mRNA in the CeA. Drug challenge did not further affect GAD67 mRNA in the CeA of saline, drug and stress pre-exposed rats. As to the other areas, no differences were observed in drug pre-exposed compared with saline pre-exposed and fed ad libitum rats, except for amphetamine. Amphetamine pre-exposure decreased GAD67 mRNA levels in the dLStr and the AcC and AcS, and this effect was reversed by amphetamine challenge. The results show that different drugs and stress models of behavioural sensitization have in common an increase of GA67 in the CeA but not in the BLA, and suggest the changes of GAD67 in the CeA are a substrate of the sensitized response to drug challenge.

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

It is known that most of drugs abused by humans preferentially stimulate dopamine transmission in the shell subdivision of the nucleus accumbens as compared to the core. The aim of the present study was to evaluate whether this applies also to intravenous 3,4-methylendioxymethamphetamine (MDMA, "ecstasy") administered at doses that sustain self-administration behavior in rats. The effect of 0.32, 0.64, 1.0, 2.0 and 3.2 mg/kg i.v. of MDMA on dopamine transmission in the nucleus accumbens shell and core was studied in freely moving rats by means of dual probe microdialysis. MDMA dose-dependently stimulated dopamine transmission both in the shell and in the core but the increase in the shell was more pronounced compared to the core at doses of 0.64, 1.0 and 2.0 mg/kg. The increase of dialysate dopamine obtained after 0.32 mg/kg and after 3.2 mg/kg was not significantly different in the shell compared to the core of nucleus accumbens. This study extends to MDMA the property of other drugs of abuse to increase preferentially nucleus accumbens shell dopamine.

Microdialysis studies in animals have shown that addictive drugs preferentially increase extracellular dopamine (DA) in the n. accumbens (NAc). Brain imaging studies, while extending these finding to humans, have shown a correlation between psychostimulant-induced increase of extracellular DA in the striatum and self-reported measures of liking and 'high' (euphoria). Although a correlate of drug reward independent from associative learning and performance is difficult to obtain in animals, conditioned taste avoidance (CTA) might meet these requirements. Addictive drugs induce CTA to saccharin most likely as a result of anticipatory contrast of saccharin over drug reward. Consistently with a role of DA in drug reward, D2 or combined D1/D2 receptor blockade abolishes cocaine, amphetamine and nicotine CTA. Intracranial self-administration studies with mixtures of D1 and D2 receptor agonists point to the NAc shell as the critical site of DA reward. NAc shell DA acting on D1 receptors is also involved in Pavlovian learning through pre-trial and post-trial consolidation mechanisms and in the utilization of spatial short-term memory for goal-directed behavior. Stimulation of NAc shell DA transmission by addictive drugs is shared by a natural reward like food but lacks its adaptive properties (habituation and inhibition by predictive stimuli). These peculiarities of drug-induced stimulation of DA transmission in the NAc shell result in striking differences in the impact of drug-conditioned stimuli on DA transmission. It is speculated that drug addiction results from the impact exerted on behavior by the abnormal DA stimulant properties acquired by drug-conditioned stimuli as a result of their association with addictive drugs.

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.

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.

In normal striata, pre-treatment with the D-1 antagonist SCH 23390 (250 and 25 micrograms kg-1, s.c.) completely and lastingly prevented the D-2 antagonist remoxipride (REM) from increasing acetylcholine (ACh) release; post-treatment did not affect REM action. In alpha-methyl-p-tyrosine (alpha-MpT) dopamine (DA)-depleted striata, however, pretreatment with SCH 23390 resulted in a transient impairment of REM induced stimulation of ACh release but post-treatment still had no effect. Two different mechanisms therefore seem to be involved in D-2 antagonist-induced stimulation of ACh release; the antagonists indirectly activate a D-1 receptor-mediated facilitatory mechanism regulating cholinergic function, and directly block a D-2 receptor-mediated inhibitory one. In normal rats, in an early phase after D-2 antagonist administration, only the first mechanism is operative; in a later phase, both mechanisms cooperate in the stimulation of ACh release. When DA release is impaired by alpha-MpT, the D-2 inhibitory receptor mechanism becomes more important than the D-1 facilitatory one in controlling ACh release.