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Abstract Nicotine addiction leads to in a huge burden on public health and the economy worldwide. Resveratrol (3,5,4'-tetrahydroxystilbene) is the most well-known polyphenolic stilbenoid. Resveratrol was shown to exhibit positive effects on numerous mechanisms that are important for drug and substance addiction. Thus, this study aimed to examine the effect of resveratrol on nicotine addiction. Intraperitoneal (i.p.) treatment with nicotine (0.5 mg/kg) significantly enhanced time spent in the nicotine-paired compartment. Resveratrol (50 and 75 mg/kg, i.p.) and varenicline (2 mg/kg, i.p.) co-administered with nicotine during the 3-day conditioning period effectively diminished the acquisition of nicotine-induced conditioned place preference (CPP). On the other hand, the administration of resveratrol (50 and 75 mg/kg, i.p.) and varenicline (2 mg/kg, i.p.) decreased the low dose (0.1 mg/kg, i.p.) nicotine-induced reinstatement. The results suggest that resveratrol and varenicline inhibit the acquisition and reinstatement of nicotine's reward properties. Resveratrol displayed similar results in the CPP phases as obtained with the reference drug varenicline. In conclusion, resveratrol could be beneficial as an adjuvant pharmacotherapy for nicotine addiction; however, more investigation is needed to completely explain this property.
Subject(s)
Animals , Male , Mice , Tobacco Use Disorder/diagnosis , Resveratrol/adverse effects , Varenicline/adverse effectsABSTRACT
Abstract Insulin receptors have distributed in all brain regions, including the nucleus Accumbens (NAc), and where is implicated in the reward properties of drugs. It is well known that insulin signaling can regulate dopamine release. Therefore, in the present study, we tried to examine the effect of insulin replacement on the acquisition and expression of morphine-induced conditioned place preference (CPP) in diabetic rats. Forty-eight male Wistar rats were divided into two non-diabetic (Naïve) and diabetic groups rendered by a single injection of streptozotocin (STZ). These groups separately received insulin (10U/kg) or saline (1 ml/kg) one hour prior to morphine administration (5mg/kg;s.c.) during conditioning days (acquisition phase) or post-conditioning day (expression phase) in the CPP paradigm. In this paradigm, conditioning score (CS) and locomotion activity were recorded by Ethovision. The STZ-induced diabetic rats displayed higher CS compared to naïve rats (P<0.05). This effect was abolished in all diabetic rats that received insulin during conditioning days but not the expression phase. This study has provided evidence that insulin plays a modulatory role in morphine-induced CPP, and insulin replacement during the acquisition phase could reduce the rewarding properties of morphine in diabetes conditions through a possible modulating effect on dopamine release in the NAc region
Subject(s)
Animals , Male , Rats , Diabetes Mellitus, Experimental/chemically induced , Insulin/adverse effects , Morphine/administration & dosage , Reward , Receptor, Insulin/agonistsABSTRACT
Drug-associated reward memories are conducive to intense craving and often trigger relapse. Simvastatin has been shown to regulate lipids that are involved in memory formation but its influence on other cognitive processes is elusive. Here, we used a mass spectrometry-based lipidomic method to evaluate the impact of simvastatin on the mouse brain in a cocaine-induced reinstatement paradigm. We found that simvastatin blocked the reinstatement of cocaine-induced conditioned place preference (CPP) without affecting CPP acquisition. Specifically, only simvastatin administered during extinction prevented cocaine-primed reinstatement. Global lipidome analysis showed that the nucleus accumbens was the region with the greatest degree of change caused by simvastatin. The metabolism of fatty-acids, phospholipids, and triacylglycerol was profoundly affected. Simvastatin reversed most of the effects on phospholipids induced by cocaine. The correlation matrix showed that cocaine and simvastatin significantly reshaped the lipid metabolic pathways in specific brain regions. Furthermore, simvastatin almost reversed all changes in the fatty acyl profile and unsaturation caused by cocaine. In summary, pre-extinction treatment with simvastatin facilitates cocaine extinction and prevents cocaine relapse with brain lipidome remodeling.
ABSTRACT
Drug-associated reward memories are conducive to intense craving and often trigger relapse. Simvastatin has been shown to regulate lipids that are involved in memory formation but its influence on other cognitive processes is elusive. Here, we used a mass spectrometry-based lipidomic method to evaluate the impact of simvastatin on the mouse brain in a cocaine-induced reinstatement paradigm. We found that simvastatin blocked the reinstatement of cocaine-induced conditioned place preference (CPP) without affecting CPP acquisition. Specifically, only simvastatin administered during extinction prevented cocaine-primed reinstatement. Global lipidome analysis showed that the nucleus accumbens was the region with the greatest degree of change caused by simvastatin. The metabolism of fatty-acids, phospholipids, and triacylglycerol was profoundly affected. Simvastatin reversed most of the effects on phospholipids induced by cocaine. The correlation matrix showed that cocaine and simvastatin significantly reshaped the lipid metabolic pathways in specific brain regions. Furthermore, simvastatin almost reversed all changes in the fatty acyl profile and unsaturation caused by cocaine. In summary, pre-extinction treatment with simvastatin facilitates cocaine extinction and prevents cocaine relapse with brain lipidome remodeling.
Subject(s)
Animals , Male , Mice , Brain , Cocaine , Conditioning, Operant , Extinction, Psychological , Lipidomics , Simvastatin/therapeutic useABSTRACT
Aim To study the effect of ginsenoside Rbl on methamphetamine-induced CPP in rats and to explore the role of NR2B/CREB in it. Methods METH(2mg·kg-1, i.p) was administered to establish METH-induced CPP model in rats. 0 ∼3 d was the adaptation stage and 4 ∼ 13 d was the experimental stage. METH (2 mg · kg-1, i. p) or saline (10 mg · kg-1, i. p) was injected every other day. Rb1 (10 mg · kg-1, i.p) or saline was pre-injected lh before injection of METH or saline. After perfusion, the hippocampus was isolated from brain on ice, and the expression levels of NR2B, CREB and p-CREB were detected by Western blot. Results The animal model of METH-induced CPP was successfully established. The rats were pretreated with Rbl (10 mg · kg-1) for 1 h, and the time that the rats stayed in drug-paired was significantly reduced compared with METH group. Western blot results showed that NR2B, p-CREB and p-CREB/CREB significantly increased in METH group and without altering CREB expression levels compared with control group. However, after pre-treated with Rbl, the expression levels of NR2B, p-CREB and p-CREB/CREB decreased compared with METH group. Conclusions METH can significantly induce CPP in rats. Rbl may inhibit METH-induced CPP in rats by regulating NR2B and p-CREB.
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Objective To examine the effect of NK1 receptor ( NK1R) antagonist L-703,606 on ethanol-induced conditioned place preference (CPP) and levels of NK1R protein in different brain regions in juvenile mice. Methods Four-week-old male C57BL/6 mice were divided into high anxiety group and low anxiety group according to the percentage of time spent in open arms of elevated plus maze(EPM). Then the mice in the two groups were divided into control group and experimental group according to random number table,which were high anxiety control group,high anxiety experimental group,low anxiety control group and low anxiety experimental group,with 11 in each group. L-703,606 was injected intraperitoneally 40 minutes before CPP training in the high and low anxiety experimental group,while the control group received solvent treatment. After CPP test,the anxiety level of four groups of mice was detected by EPM again. The expres-sion of NK1R protein in hippocampus,prefrontal lobe and amygdala of mice was detected by Western blot. Results Compared with the high anxiety control group, the CPP value of the high anxiety experimental group was lower,and the difference was statistically significant ((77. 7 ± 9. 3) s vs (13. 6 ± 13. 0) s,P=0. 002). Compared with the low anxiety control group,the CPP value of the low anxiety experimental group was lower,and the difference was statistically significant ((113. 2±10. 3)s vs (28. 0±9. 6)s,P<0. 01). Af-ter L-703,606 treatment,there was no significant difference in the percentage of open arm time between the control group and experimental group either in high anxiety group or in low anxiety group (both P>0. 05) . Compared with the high anxiety control group,the expression of NK1R increased in hippocampus,prefrontal lobe and amygdala of mice in high anxiety experimental group (all P<0. 05). And the expression of NK1R in the above three brain regions had the same result between the low anxiety control group and the low anxiety experimental group (all P<0. 05). Conclusions L-703,606 can attenuate ethanol-induced CPP but has no effect on anxiety-like behaviors,suggesting the direct effect of NK1R in alcohol reward in juvenile mice.
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Objective To examine the effect of adolescent intermittent ethanol exposure (AIE) on ethanol-induced conditioned place preference (CPP) and anxiety-like behavior in adolescent mice. Methods In experiment 1, adolescent male C57BL/6 mice at 4 weeks of age were randomly divided into AIE group and NS group (n=10 for each group). The binge drinking model was established by AIE (3 g/kg, 25%). The alcohol reward was evaluated using the ethanol-induced CPP paradigm (2 g/kg, 20%). In experiment 2, the anxiety-like behavior of adolescent male C57BL/6 mice were assessed using the elevated plus maze (EPM) test, and the animals were then allocated into high-anxiety mouse (HAM) and low-anxiety mouse (LAM) groups based on the percentage of open arm time (OT%). HAM and LAM were randomly divided into AIE group and NS group (n=8～10 for each group) with random number method, respectively. Then, anxiety-like behavior in four groups was measured again using the EPM test. Results In experiment 1. Ethanol preference (116.1± 12.9)s vs. (70.8±14.8)s, P=0.035) was significantly higher in AIE group relative to NS group. However, In experiment 2. The alteration in anxiety-like behaviors was not significant in either HAM-AIE or LAM-AIE groups (all P＞0.05). Conclusions AIE reinforces ethanol-induced CPP but does not affect the anxiety-like behavior in adolescent mice, suggesting that AIE may not play a role in anxiety-like behavior.
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Objective To explore the impact of exercise on the learning and memory of rats undergoing nicotine withdrawal and its underlying mechanism.Methods Forty four-week-old male SpragueDawley rats were subjected to nicotine conditioned place preference(CPP) training before being randomly separated into a high-,moderate-,low-intensity exercise and control(no exercise) group.Rats in exercise groups underwent the treadmill running at low,moderate or high intensity 30 minutes per day for 10 days consecutively.The nicotine-associated context memory was evaluated using the CPP preference score.Morris water maze (MWM) tasks were used to examine the spatial learning and memory.The protein level of α7 acetylcholine receptors(nAChRs) in the prefrontal cortex and hippocampus was visualized by Western blotting.Results Rats undergoing exercises at a high or moderate intensity had a significantly lower CPP score than the control group (P＜0.01 and P＜0.05 respectively).However,there was no significant difference in the CPP score between the low-intensity exercise and control groups.Only rats doing moderate-intensity exercise presented a significantly shorter escape latency than controls in the MWM place navigation test(P＜0.01).Significant increase in time spent and distance swam in the target quadrant was observed in the moderate-and high-intensity exercise group,but without significant differences between the two groups.Moreover,a significant increase in the number of crossing target quadrant was only observed in rats that exercised at a moderate intensity (P＜ 0.05).The protein level of α7 nAChRs was significantly elevated in the prefrontal cortex(P＜0.01),but not in the hippocampus of rats doing moderate intensity exercise.Conclusion Ten-day treadmill running at a moderate intensity may improve learning and memory performance,and facilitate the extinction of nicotine reward memory of nicotine-treated rats via increasing α7 nAChR-mediated signaling in the frontal cortex.
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Aim To analyze the expression of phosphatidylethanolamine-binding protein(PEBP) and ERK in critical brain regions of psychological dependence rats.Methods Morphine-induced rats conditioned place preference(CPP) model was established to mimic different stages of morphine psychological dependence, during which PEBP expression and ERK activity were assayed in different brain regions.Results PEBP expression in hippocampus, prefrontal cortex, striatum and nucleus accumbens showed no change at three stages of psychological dependence.However, ERK activity increased notably in prefrontal cortex on CPP formation, and decreased remarkably in hippocampus on CPP reinstatement.Conclusions The formation and retrieval of associated memory between morphine effects and environment involve different neural circuits, in which ERK activity is critical, and PEBP might not be involved in such a memory-related ERK regulation.
ABSTRACT
The anterior cingulate cortex (ACC) is known for its role in perception of nociceptive signals and the associated emotional responses. Recent optogenetic studies, involving modulation of neuronal activity in the ACC, show that the ACC can modulate mechanical hyperalgesia. In the present study, we used optogenetic techniques to selectively modulate excitatory pyramidal neurons and inhibitory interneurons in the ACC in a model of chronic inflammatory pain to assess their motivational effect in the conditioned place preference (CPP) test. Selective inhibition of pyramidal neurons induced preference during the CPP test, while activation of parvalbumin (PV)-specific neurons did not. Moreover, chemogenetic inhibition of the excitatory pyramidal neurons alleviated mechanical hyperalgesia, consistent with our previous result. Our results provide evidence for the analgesic effect of inhibition of ACC excitatory pyramidal neurons and a prospective treatment for chronic pain.
Subject(s)
Animals , Mice , Chronic Pain , Gyrus Cinguli , Hyperalgesia , Interneurons , Neurons , Optogenetics , Prospective Studies , Pyramidal CellsABSTRACT
A diversity of synthetic cathinones has flooded the recreational drug marketplace worldwide. This variety is often a response to legal control actions for one specific compound (e.g. methcathinone) which has resulted in the emergence of closely related replacement. Based on recent trends, the nitrogen atom is one of the sites in the cathinone molecule being explored by designer type modifications. In this study, we designed and synthesized two new synthetic cathinones, (1) α-piperidinopropiophenone (PIPP) and (2) α-piperidinopentiothiophenone (PIVT), which have piperidine ring substituent on their nitrogen atom. Thereafter, we evaluated whether these two compounds have an abuse potential through the conditioned place preference (CPP) in mice and self-administration (SA) in rats. We also investigated whether the substances can induce locomotor sensitization in mice following 7 days daily injection and challenge. qRT-PCR analyses were conducted to determine their effects on dopamine-related genes in the striatum. PIPP (10 and 30 mg/kg) induced CPP in mice, but not PIVT. However, both synthetic cathinones were not self-administered by the rats and did not induce locomotor sensitization in mice. qRT-PCR analyses showed that PIPP, but not PIVT, reduced dopamine transporter gene expression in the striatum. These data indicate that PIPP, but not PIVT, has rewarding effects, which may be attributed to its ability to affect dopamine transporter gene expression. Altogether, this study suggests that PIPP may have abuse potential. Careful monitoring of this type of cathinone and related drugs are advocated.
Subject(s)
Animals , Mice , Rats , Dopamine Plasma Membrane Transport Proteins , Gene Expression , Nitrogen , RewardABSTRACT
Recently, there has been a rise in the number of amphetamine derivatives that serve as substitutes for controlled substances (e.g. amphetamine and methamphetamine) on the global illegal drug market. These substances are capable of producing rewarding effects similar to their parent drug. In anticipation of the future rise of new and similar psychoactive substances, we designed and synthesized four novel amphetamine derivatives with N-benzyl, N-benzylamphetamine HCl (NBNA) substituent on the amine region, 1,4-dioxane ring, ethylenedioxy-amphetamine HCl (EDA), methyl, para-methylamphetamine HCl (PMEA), and naphthalene, 2-(aminopropyl) naphthalene HCl (2-APN) substituents on the phenyl site. Then, we evaluated their abuse potential in the conditioned place preference (CPP) test in mice and self-administration (SA) test in rats. We also investigated the psychostimulant properties of the novel drugs using the locomotor sensitization test in mice. Moreover, we performed qRT-PCR analyses to explore the effects of the novel drugs on the expression of D1 and D2 dopamine receptor genes in the striatum. NBNA, but not EDA, PMEA, and 2-APN, induced CPP and SA in rodents. None of the test drugs have produced locomotor sensitization. qRT-PCR analyses demonstrated that NBNA increased the expression of striatal D1 dopamine receptor genes. These data indicate that NBNA yields rewarding effects, suggesting potential for abuse. Continual observation for the rise of related substances is thus strongly encouraged.
Subject(s)
Animals , Humans , Mice , Rats , Amphetamine , Controlled Substances , Parents , Receptors, Dopamine , Reward , RodentiaABSTRACT
Although lisdexamfetamine is used as a recreational drug, little research exists regarding its potential for dependence or its precise mechanisms of action. This study aims to evaluate the psychoactivity and dependence profile of lisdexamfetamine using conditioned place preference and self-administration paradigms in rodents. Additionally, biochemical techniques are used to assess alterations in the dopamine levels in striatal synaptosomes following administration of lisdexamfetamine. Lisdexamfetamine increased both conditioned place preference and self-administration. Moreover, after administration of the lisdexamfetamine, dopamine levels in the striatal synaptosomes were significantly increased. Although some modifications should be made to the analytical methods, performing high performance liquid chromatography studies on synaptosomes can aid in predicting dependence liability when studying new psychoactive substances in the future. Collectively, lisdexamfetamine has potential for dependence possible via dopaminergic pathway.
Subject(s)
Chromatography, Liquid , Dopamine , In Vitro Techniques , Lisdexamfetamine Dimesylate , Rodentia , SynaptosomesABSTRACT
Although lisdexamfetamine is used as a recreational drug, little research exists regarding its potential for dependence or its precise mechanisms of action. This study aims to evaluate the psychoactivity and dependence profile of lisdexamfetamine using conditioned place preference and self-administration paradigms in rodents. Additionally, biochemical techniques are used to assess alterations in the dopamine levels in striatal synaptosomes following administration of lisdexamfetamine. Lisdexamfetamine increased both conditioned place preference and self-administration. Moreover, after administration of the lisdexamfetamine, dopamine levels in the striatal synaptosomes were significantly increased. Although some modifications should be made to the analytical methods, performing high performance liquid chromatography studies on synaptosomes can aid in predicting dependence liability when studying new psychoactive substances in the future. Collectively, lisdexamfetamine has potential for dependence possible via dopaminergic pathway.
Subject(s)
Chromatography, Liquid , Dopamine , In Vitro Techniques , Lisdexamfetamine Dimesylate , Rodentia , SynaptosomesABSTRACT
OBJECTIVE: The noradrenaline system is involved in the reward effects of various kinds of abused drugs. Betaxolol (BTX) is a highly selective β1-antagonist. In the present study, we evaluated the effect of BTX on methamphetamine (MAP)-induced conditioned place preference (CPP) and hyperactivity in mice. METHODS: The mice (n=72) were treated with MAP or saline every other day for a total of 6 days (from day 3 to day 8; 3-times MAP and 3-times saline). Each mouse was given saline (1 mL/kg) or MAP (1 mg/kg, s.c.) or BTX (5 mg/kg, i.p.) or MAP with BTX (5 mg/kg, i.p.) 30 min prior to the administration of MAP (1 mg/kg, s.c.) every other day and paired with for 1 h (three-drug and three-saline sessions). We then compared the CPP score between the two groups. After the extinction of CPP, the mice were given BTX (5 mg/kg, i.p.) or saline (1 mL/kg) 24 h prior to a priming injection of MAP, and were then immediately tested to see whether the place preference was reinstated. RESULTS: The repeated administration of BTX 30 min prior to the exposure to MAP significantly reduced the development of MAP-induced CPP. When BTX was administered 24 h prior to the CPP-testing session on day 9, it also significantly attenuated the CPP, but did not result in any change of locomotor activity. In the drug-priming reinstatement study, the extinguished CPP was reinstated by a MAP (0.125 mg/kg, s.c.) injection and this was significantly attenuated by BTX. CONCLUSION: These findings suggest that BTX has a therapeutic and preventive effect on the development, expression, and drug-priming reinstatement of MAP-induced CPP.
Subject(s)
Animals , Mice , Betaxolol , Methamphetamine , Motor Activity , Norepinephrine , RewardABSTRACT
The emergence and use of synthetic cannabinoids have greatly increased in recent years. These substances are easily dispensed over the internet and on the streets. Some synthetic cannabinoids were shown to have abuse liability and were subsequently regulated by authorities. However, there are compounds that are still not regulated probably due to the lack of abuse liability studies. In the present study, we assessed the abuse liability of three synthetic cannabinoids, namely JWH-030, JWH-175, and JWH-176. The abuse liability of these drugs was evaluated in two of the most widely used animal models for assessing the abuse potential of drugs, the conditioned place preference (CPP) and self-administration (SA) test. In addition, the open-field test was utilized to assess the effects of repeated (7 days) treatment and abrupt cessation of these drugs on the psychomotor activity of animals. Results showed that JWH-175 (0.5 mg/kg), but not JWH-030 or JWH-176 at any dose, significantly decreased the locomotor activity of mice. This alteration in locomotor activity was only evident during acute exposure to the drug and was not observed during repeated treatment and abstinence. Similarly, only JWH-175 (0.1 mg/kg) produced significant CPP in rats. On the other hand, none of the drugs tested was self-administered by rats. Taken together, the present results indicate that JWH-175, but not JWH-030 and JWH-176, may have abuse potential. More importantly, our findings indicate the complex psychopharmacological effects of synthetic cannabinoids and the need to closely monitor the production, dispensation, and use of these substances.
Subject(s)
Animals , Mice , Rats , Cannabinoid Receptor Agonists , Cannabinoids , Cannabis , Hand , Internet , Models, Animal , Motor ActivityABSTRACT
Objective To compare the effect of extinction using different methods and the subsequent reinstatement of morphine-primed on morphine-induced conditioned place preference (CPP).
ABSTRACT
Objective To observe the effect of mPFC neuron synaptic plasticity changes in the formation of morphine related reward memory.Methods 40 SD rats were administered morphine (10 mg/kg,ip) or saline (2 ml/kg,ip)and sacrificed 0,2,4 and 8 h after the treatment.The temporal profile of activity-regulated cytoskeleton-associated protein (Arc/Arg 3.1) expression in medial prefrontal cortex (mPFC) was analyzed.Another 40 rats receiving a single injection of morphine at different doses (0,5,10 or 20 mg/kg),and rats were sacrificed by decapitation 2 h later.In mPFC,changes of Arc/Arg 3.1 protein was analyzed by Western Blot,Arc/Arg 3.1 positive cells was detected by immunohistochemistry (IHC),and number of spines were analyzed by Golgi-cox method.In the second experiment,CPP model was established by 5 mg/kg morphine for 8 days.Arc/Arg 3.1 antisense oligodeoxynucleotide (AS) or the control (CS) was microinjected into mPFC 15 minutes before each morphine injection,then CPP score was evaluated.Results Compared with saline groups,Arc/Arg 3.1 protein,Arc/Arg 3.1 positive cells,number of spines ((1.01±0.04) vs (1.58±0.18),P＜0.01 ; (42.80±7.63) vs (74.47±8.02),P＜0.01 ;(17.27±5.64) vs (39.47±7.56),P＜0.01) were significantly increased 2 hours after morphine administration.All three doses of morphine (5,10 and 20 mg/kg) increased Arc/Arg 3.1 protein expression in the mPFC,and there were no dose-dependent effects.In CPP experiments,compared with microinjection of Arc/Arg 3.1 CS (0.74±0.02),Arc/Arg 3.1 AS microinjection significantly decreased the CPP score (0.51±0.01) in morphine group (P＜0.01).Conclusion It is enough to increase Arc/Arg 3.1 protein content and synaptic plasticity in mPFC by 10 mg/kg,and the changes implied in formation of morphine relative reward memory.
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Objective To compare the effect of extinction using different methods and the subsequent reinstatement of morphine-primed on morphine-induced conditioned place preference (CPP). Methods Mouse received morphine(10 mg/kg, sc) or saline (10 mg/kg, sc) injections alternately for 8 days to establish CPP. Different methods were used for extinction. Program 1, withdrawal group. Extinction sessions were conducted 21 days after the CPP test at 7 days interval; Program 2, extinction test group. Extinction sessions were carried out once a day from the second day after the CPP test; Program 3, extinction training group. Extinction sessions began one day after the CPP test. Mice were treated alternately two trials daily, in compartments where they received saline instead of morphine. A test for reinstatement was performed on the 2nd or 7th day after all groups completed extinction by 5 mg/kg morphine-primed. Results Morphine injections induce strong CPP. In withdrawal group, CPP extinguished on the 35th day and maintained for at least 28 days. Six trials extinction tests and 4 trials extinction training caused morphine induced CPP extinction. The three programs mentioned above were all primed by 5mg/kg morphine. Conclusion Morphine induced mouse CPP model can maintain at least 28 days, both extinction test and training can accelerate the extinction of CPP, and reinstatement by 5 mg/kg morphine.
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Nicotine addiction is a worldwide problem. However, previous studies characterizing the rewarding and reinforcing effects of nicotine in animal models have reported inconsistent findings. It was observed that the addictive effects are variable on different factors (e.g. route, dose, and age). Here, we evaluated the rewarding and reinforcing effects of nicotine in different routes of administration, across a wide dose range, and in different age groups. Two of the most widely used animal models of drug addiction were employed: the conditioned place preference (CPP) and self-administration (SA) tests. Nicotine CPP was evaluated in different routes [intraperitoneal (i.p.) and subcutaneous (s.c.)], doses (0.05 to 1.0 mg/kg) and age [adolescent and adult rats]. Similarly, intravenous nicotine SA was assessed in different doses (0.01 to 0.06 mg/kg/infusion) and age (adolescent and adult rats). In the CPP test, s.c. nicotine produced greater response than i.p. The 0.2 mg/kg dose produced highest CPP response in adolescent, while 0.6 mg/kg in adult rats; which were also confirmed in 7 days pretreated rats. In the SA test, adolescent rats readily self-administer 0.03 mg/kg/infusion of nicotine. Doses that produced nicotine CPP and SA induced blood nicotine levels that corresponded well with human smokers. In conclusion, we have demonstrated that nicotine produces reliable CPP [0.2 mg/kg dose (s.c.)] in adolescents and [0.6 mg/kg dose (s.c.)] in adults, and SA [0.03 mg/kg/infusion] in adolescent rats. Both tests indicate that adolescent rats are more sensitive to the rewarding and reinforcing effects of nicotine.