Conselho Nacional de Desenvolvimento Científico e Tecnológico / The morphine addiction is a chronic disease that involves biological, cognitive and behavioral changes developed after repeated and compulsive drug use. Even after long periods of abstinence relapses occur to users, especially when faced with situations that resemble the use thereof. The protocol of conditioned place preference (CPP) has been one of the most widely used experimental models to measure the positive reinforcing effects (conditioned place preference) and negative (conditioned place aversion) of several drugs, including morphine. Studies show that antagonists of the N-methyl-D-aspartate (NMDA) block morphine-induced CPP, suggesting that this receptor is involved in the effects of morphine. Since polyamines act at the NMDA receptor, spermidine (SPD) positive allosteric modulating shape and arcaine acting as an antagonist of the polyamine site on this receiver, the purpose of this study the effect of polyamines on the preference induced conditioned place was to evaluate morphine. Adult male Swiss mice were pre-conditioned once a day for 15 minutes for two consecutive device in the CPP, the next day days were subjected twice daily for conditioning sessions with different drugs and protocols for four consecutive days. Twenty-four hours after the last conditioning session the animals were subjected to the test. The CPP score was calculated for the time spent in the compartment paired with the drug on test day, minus the time spent in the same compartment on the second day of the preconditioning. The results of this study showed that morphine (2.5-10 mg/kg, ip) induced CPP, but not aversion induced conditioned place aversion, the SPD (3-30 mg/kg, ip) and arcaine (0.3-3 mg/kg, ip) did not preferably nor induced conditioned place aversion. However, arcaine (3 mg/kg) administered 15 min before morphine (5 mg/kg) attenuated the pre-training acquisition of morphine-induced PCL. The arcaine (3 mg/kg) administered immediately after conditioning with morphine (5 mg/kg) blocked morphine induced PCL. Also, arcaine (3 mg/kg) administered 30 min pretest blocked morphine induced expression CPP. Furthermore, the effect of arcaine on attenuate the effect of morphine was prevented by the administration of SPD before conditioning, but was not reversed by postconditioning pre-test administration and SPD. These data indicate that arcaine blocks the rewarding effect of morphine and arcaine suggests that it could be a therapeutic target in the development of drugs to treat addiction to morphine. / A adicção a morfina consiste em uma doença crônica que envolve alterações biológicas, cognitivas e comportamentais desenvolvida após o uso repetido e compulsivo da droga. Mesmo após longos períodos de abstinência ocorrem recaídas aos usuários, principalmente quando se deparam com situações que lembram o uso da mesma. O protocolo de preferência condicionada por lugar (PCL) tem sido um dos modelos experimentais mais utilizados para mensurar os efeitos reforçadores positivos (preferência condicionada por lugar) e os negativos (aversão condicionada por lugar) de diversas drogas, incluindo a morfina. Estudos mostram que antagonistas do receptor N-Metil-D-Aspartato (NMDA) bloqueiam a PCL induzida por morfina, sugerindo que este receptor está envolvido nos efeitos da morfina. Uma vez que as poliaminas atuam no receptor NMDA, a espermidina (SPD) modulando de forma alostérica positiva e a arcaína agindo como antagonista do sítio das poliaminas neste receptor, o objetivo deste estudo foi avaliar o efeito das poliaminas sobre a preferência condicionada por lugar induzida por morfina. Camundongos Swiss machos foram pré-condicionados uma vez por dia, durante 15 minutos por dois dias consecutivos no aparelho de PCL, no dia seguinte, foram submetidos, duas vezes por dia às sessões de condicionamento, com diferentes drogas e protocolos durante quatro dias consecutivos. Vinte e quatro horas após a última sessão de condicionamento os animais foram submetidos ao teste. O escore de PCL foi calculado pelo tempo gasto no compartimento pareado com a droga no dia do teste, menos o tempo gasto no mesmo compartimento no segundo dia do pré-condicionamento. Os resultados deste estudo mostraram que a morfina (2,5-10 mg/kg, i.p.) induziu PCL, mas não aversão condicionada por lugar, a SPD (3-30 mg/kg, i.p.) e arcaína (0,3-3 mg/kg, i.p.) não induziram preferência e nem aversão condicionada por lugar. No entanto, a arcaína (3 mg/kg) administrada 15 minutos antes da morfina (5 mg/kg) no pré-treino atenuou a aquisição da PCL induzida por morfina. A arcaína (3 mg/kg) administrada imediatamente após o condicionamento com morfina (5 mg/kg) bloqueou PCL induzida por morfina. Ainda, arcaína (3 mg/kg) administrada 30 min pré-teste bloqueou a expressão PCL induzida por morfina. Além disso, o efeito da arcaína em atenuar o efeito da morfina foi prevenido pela administração de SPD antes do condicionamento, mas não foi revertido pela administração pós-condicionamento e pré-teste de SPD. Estes dados indicam que arcaína bloqueia o efeito de recompensa da morfina e sugere que a arcaína poderia ser um alvo terapêutico no desenvolvimento de drogas para tratar a adicção por morfina.

A dependência de drogas é um transtorno multifatorial complexo que se desenvolve em uma minoria de indivíduos que fazem uso dessas substâncias. Memórias associativas entre a droga e o contexto funcionam como gatilho para disparar comportamentos não adaptativos de busca e consumo, além de recaídas após períodos de abstinência. Subjacentes a essas mudanças comportamentais, existem modificações nas subunidades de receptores glutamatérgicos do tipo AMPA em estruturas envolvidas com memória (Hipocampo) e recompensa (Núcleo Accumbens). Por isso, estratégias que enfraqueçam a associação do contexto com a droga e que aprofundem o conhecimento dos circuitos envolvidos nesses comportamentos são de extrema relevância terapêutica. A memória quando evocada pode passar por dois processos pós-evocação: a extinção, em que uma nova memória é formada inibindo uma prévia associação, e a reconsolidação, em que a memória original entra em um estado lábil e suscetível a modificações, em que é possível enfraquecê-la através da inibição de sua reconsolidação. A reconsolidação da memória mostra-se uma estratégica mais eficaz e duradoura em relação à extinção, já que a memória original é modificada. Como modelo animal para o estudo da memória na dependência de drogas, o condicionamento de preferência por local (CPL) é bastante utilizado e sabe-se que é possível enfraquecer a preferência através do bloqueio da reconsolidação. Porém, são escassos os estudos que investigaram a existência da reconsolidação no modelo de sensibilização locomotora, que parece ocorrer, na maioria dos casos, em condição dependente do contexto de aquisição do comportamento, embora existam exemplos que demonstrem sua independência. As questões a serem respondidas neste trabalho são (a) se é possível reverter conjuntamente a preferência por local e a sensibilização locomotora à morfina (5 mg/kg) em ratos Wistar adultos machos, inibindo-se a síntese proteica com cicloheximida (CHX) i.p. logo após uma sessão de reativação contextual da memória no CPL, (b) se a reversão dos comportamentos reflete alterações (já descritas por outros autores) em GluA1, GluA1p (Ser845) e GluA2, no Hipocampo dorsal (HPCd) e no Núcleo Accumbens (NAc), e (c) se o mesmo tratamento em ambas estruturas reverte os dois parâmetros avaliados – comportamental e neuroquímico – de forma diferente ou igual. Nossos resultados mostraram ser possível reverter a preferência por local e a sensibilização locomotora por inibição sistêmica de síntese proteica, e que o condicionamento com exposição à morfina induz alterações nas subunidades analisadas de AMPA, conforme verificado no HPCd e NAc, embora a CHX não tenha produzido um efeito tão bem definido. Os animais que receberam infusões centrais no HPCd e NAc (central) não exibiram preferência por local, nem sensibilização. Em conjunto, nossos resultados mostraram, pela primeira vez em um mesmo desenho experimental, que é possível reverter diferentes aspectos da memória de recompensa (preferência e sensibilização) por meio do bloqueio da reconsolidação. / Drug addiction is a complex and multifactorial disorder that develops in a few people who use these substances. Associative memories between the drug and context of use act as a trigger for maladaptive behavior such as drug seeking and drug use, in addition to relapse after an extended period of withdrawal. Underlying these behavioral changes are modifications in glutamatergic reception (AMPA) in structures involved with memory (Hippocampus) and reward (Nucleus Accumbens). Therefore, strategies that weaken the drug and context association and deepen knowledge of circuits involved in these behaviors are extremely relevant therapeutically. When retrieved, a memory can undergo two distinct processes post-retrieval: extinction, in which a new memory inhibiting a previous association is generated, and reconsolidation, in which the original memory can enter a labile state and is susceptible to modifications, when it can be weakened by inhibition of its reconsolidation. Reconsolidation of memory has been shown to be a more effective and long lasting strategy in relation to extinction, since the original memory is modified. An animal model for studying drug addiction, conditioned place preference (CPP) is largely used and it is well known that it is possible to weaken preference by disrupting reconsolidation. However, there are few studies that investigate the existence of reconsolidation in a locomotor sensitization paradigm, which seems to occur in a condition dependent on context of acquisition, although some works report its independence. The questions answered in this work were (a) if it is possible to reverse both, context preference and locomotor sensitization to morphine (5mg/kg) by protein synthesis inhibition (CHX) after a contextual memory reactivation session in CPP, (b) if the disruption of behaviors reflects a reversal of changes of GluA1, GluA1p (Ser845) e GluA2 in dorsal Hippocampus (dHPC) and Nucleus Accumbens (NAc) and (c) if the same treatment in these structures differentially reverts the two parameters assessed. Our results indicate that it is possible to revert context preference and locomotor sensitization via systemic disruption of protein synthesis and that morphine conditioning induces changes in AMPA subunits in dHPC and NAc, although CHX did not have an evident effect on molecular reversal. Animals cannulated in dHPC and NAc core did not induce preference or sensitization. Taken together, our results demonstrated, for the first time, using the same experimental design that is possible to revert different aspects of reward memory (preference and sensitization) by disrupting the reconsolidation process.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The abusive use of psychostimulant drugs is a common social problem in countries of different cultures, whose incidence is increasing and alarming dimensions taken. Experimentally, some studies have shown the influence of early exposure to stress on changes in patterns of abuse, which may play an important role on the vulnerability to excessive use of psychostimulant drugs in adulthood. On the other hand, procedures such as neonatal tactile stimulation (TS) and neonatal isolation (NI), has been described by interfering with behavioral and neurophysiological parameters, which may persist into adulthood. This study aimed to investigate the conditioned place preference (CPP) and the psychostimulant drugs on anxiety-like symptoms related to abstinence in young rats exposed to TS and NI. In the first experiment, male pups of Wistar rats were subjected daily to TS or NI10 for 10 minutes, or NI60 for 1 hour, from postnatal day 1 (PND1) to PND21. The unhandled (UH) animals remained in the nest without any manipulation. At PND41, animals were subjected to CPP protocol induced by cocaine (20mg/kg, i.p.), for 10 days. At PND53, animals were tested for preference, and at PND55 symptoms of anxiety were evaluated on the elevated plus-maze task (EPM). TS and NI10 groups did not show preference on CPP, however UH and NI60 preferred the chamber associated with drug. In relation to anxiety-like symptoms observed during drug withdrawal, TS and NI10 groups presented higher time spent in the open arms of EPM, showing less anxiety-like behavior. Following the first study, a 2nd experiment was conducted to verify the influence of TS and NI on the CPP induced by amphetamine (AMPH), following the same neonatal handling protocol described in the previous experiment until the PND40, when animals were submitted to a CPP paradigm associated with administration of AMPH (4mg/kg, i.p.) for 8 days. At PND50, following behavioral assessment was observed that NI group had preference for the compartment associated with AMPH, and at PND53 during withdrawal of drug, TS group showed lower preference to compartment associated with drug. The exploratory activity in open field was higher in TS group at PND50, while NI group showed anxiety-like symptoms at PND53. Similarly, animals exposed to TS showed lesser degree of anxiety-like behavior in many different parameters evaluated at EPM and at staircase test, where the exploratory activity also was higher than other handlings. Taken together, these studies showed for the first time that beneficial effects of TS can modify the behavior on CPP paradigm, and influence the anxiety-like symptoms related to withdrawal from cocaine and AMPH. Continuity of studies related to the benefits of TS on reward pathways, neurotransmitter systems and signaling pathways, should be completed in the near future. / O uso abusivo de drogas psicoestimulantes é um problema social comum em países de diferentes culturas, cuja incidência tem tomado dimensões crescentes e alarmantes. Experimentalmente, alguns estudos tem mostrado a influência da exposição precoce ao estresse sobre alterações nos padrões de abuso, a qual pode cumprir um importante papel sobre a vulnerabilidade para o uso excessivo de drogas psicoestimulantes na idade adulta. Por outro lado, procedimentos como estimulação tátil (ET) neonatal e o isolamento neonatal (IN), têm sido descritos por interferir em parâmetros comportamentais e neurofisiológicos, que podem persistir durante a vida adulta. Assim, este estudo objetivou investigar a preferência condicionada de lugar (PCL) a drogas psicoestimulantes e sobre sintomas de ansiedade relacionados à abstinência, em ratos jovens expostos à ET e ao IN. No 1º experimento, filhotes machos de ratos Wistar foram submetidos diariamente à ET ou IN10, por 10 minutos, ou a IN60, por 1 hora, desde o dia pós-natal 1 (DPN1) até o DPN21. Os animais não manuseados (NM) permaneceram no ninho sem qualquer tipo de manipulação. No DPN40, os animais foram submetidos ao protocolo de PCL, induzido por cocaína (20mg/Kg, i.p.), durante 10 dias. No DPN52, os animais foram testados quanto à preferência e no DPN55 foram avaliados sintomas de ansiedade no teste do labirinto em cruz elevado (LCE). Os grupos ET e IN10 não apresentaram PCL, entretanto NM e IN60 preferiram o compartimento associado à droga. Em relação aos sintomas de ansiedade observados durante a abstinência da droga, os grupos ET e IN10, apresentaram maior tempo de permanência nos braços abertos do LCE, mostrando menor grau de ansiedade. Na sequencia do estudo, um 2º experimento foi conduzido, a fim de verificar a influência da ET e do IN sobre a PCL induzida por anfetamina (ANF), seguindo o mesmo protocolo de manuseio descrito no experimento anterior até o DPN40, quando os animais foram submetidos ao protocolo de PCL associado à administração de ANF (4mg/Kg, i.p.), durante 8 dias. No DPN50, após avaliação comportamental, observou-se que o grupo IN apresentou preferência pelo compartimento associado à ANF e no DPN53, durante abstinência da droga, o grupo ET apresentou menor preferência ao compartimento associado à droga. A atividade exploratória em campo aberto foi maior para o grupo ET no DPN50, enquanto o grupo IN apresentou sintomas de ansiedade no DPN53. De forma semelhante, animais expostos à ET mostraram menor grau de ansiedade em diversos parâmetros avaliados no LCE e no teste da escada, onde a atividade exploratória também foi maior do que para outros manuseios. Tomados em conjunto, estes estudos mostraram pela primeira vez que os efeitos benéficos da ET, podem modificar o comportamento frente à PCL, bem como influenciar os sintomas de ansiedade relacionados à abstinência de cocaína e ANF. A continuidade dos estudos relacionados aos benefícios da ET sobre vias de recompensa, sistemas de neurotransmissores e vias de sinalização celular, deverá ser realizada em um futuro breve.

Schizophrenia is a severe neuropsychiatric disorder of largely unknown etiology that is often accompanied by high rates of cigarette smoking, reduced quit success, and high relapse rates. Dysregulated dopamine signaling and aberrant synaptic plasticity in the mesocorticolimbic pathway are implicated in the pathophysiology of schizophrenia and conferred substance abuse disorder and relapse vulnerability. Genetic factors are presumed to play a significant role in the development of schizophrenia, with a 40-50% concordance rate for monozygotic twins, although genetic markers are inconsistent. As such, epigenetic factors have instead been implicated. Specifically, there is strong evidence to suggest DNA methylation at several candidate genes contributes significantly to the pathophysiology of schizophrenia. To investigate this heritable component, our laboratory has developed a novel heritable model of drug abuse vulnerability in psychosis. This model is the first to show heritable increases in dopamine D2 receptor sensitivity via several behavioral and neurobiological markers, including enhanced behavioral responding to nicotine and changes in D2 signaling cascades in brain regions associated with psychosis and comorbid drug abuse. Increased D2 receptor sensitivity is the most consistent biomarker of psychosis found in preclinical animal models and postmortem brain tissue of individuals diagnosed with schizophrenia, lending considerable strength to the validity of the model. This study aimed to further validate the model as a useful and valuable tool for better understanding the pathophysiology of comorbid nicotine use and relapse in psychosis, and to explore more effective therapeutic targets than current antipsychotic medications. Results reveal DNA methylation as an epigenetic mechanism conferring heritability of the psychosis-like phenotype in the model. We additionally demonstrate altered relapse-like behavior, clinically consistent with reduced quit success and elevated relapse vulnerability. Interestingly, changes in relapse-like behavior were correlated to elevated protein levels of brain derived neurotrophic factor (BDNF), a marker of activity-dependent plasticity, in brain areas associated with drug reward. Further, modulation of the metabotropic glutamate type 5 (mGlu5) receptor alleviates the enhanced nicotine conditioned place preference observed in the model. Mechanistically, mGlu5 modulation restores normal dopamine D2 signaling and mitigates aberrant plasticity responses that are thought to drive the behavior in a region-specific manner.

Rationale: Peak initiation of smoking occurs during adolescence and early onset of smoking is associated with a reduced probability of quitting and greater risk of relapse compared to later onset. Considering the epidemiological evidence, adolescents may exhibit a unique biological susceptibility to nicotine taking, in addition to the behavioural and psychosocial factors known to influence adolescent smoking. Objectives: The current series of experiments, using a rat model of adolescent nicotine taking, was designed to investigate age differences in the processes involved in the acquisition and maintenance of nicotine taking that might account for the elevated initiation rates of smoking during adolescence. Methods: We first investigated age differences in the neural response to acute nicotine administration using c-fos mRNA expression. We then examined age differences in the rewarding and aversive effects of nicotine in the conditioned place preference (CPP) and conditioned taste avoidance (CTA) paradigms, respectively. The direct reinforcing effects of nicotine were tested in adolescent and adult rats under a variety of reinforcement schedules in the operant intravenous self-administration paradigm; extinction and nicotine priming-induced reinstatement were also examined. Finally, age differences in nicotine withdrawal precipitated by mecamylamine were assessed. Results: Nicotine had greater activational effects on c-fos mRNA expression in reward-related neural substrates of adolescent compared to adult brain. Adolescent rats were also more sensitive to the rewarding effects of nicotine (CPP) yet less sensitive to its aversive effects (CTA) compared to adult rats. Nicotine was equally reinforcing in adolescents and adults self-administering under simple reinforcement schedules, but adults were more motivated to obtain nicotine under higher reinforcement schedules. Adults were more resistant to extinction, yet both age groups demonstrated similar priming-induced reinstatement of nicotine seeking. Under spontaneous acquisition conditions, adults were more sensitive to the reinforcing effects of a low nicotine infusion dose. The aversive effects of nicotine withdrawal were also more prominent in adults compared to adolescents. Conclusions: These findings have important implications since they demonstrate a unique susceptibility to the conditioned rewarding effects of nicotine that would promote acquisition of smoking behaviour during adolescence, whereas adults may be more vulnerable to processes involved in its maintenance.

制約場地偏好行為為研究藥物成癮的常用模式之一，對於其行為表現及再復發的神經機制，多巴胺系統佔有舉足輕重的地位。而大腦神經滋養因子(BDNF)與多巴胺系統密切相關，影響其神經元可塑性。故本研究以BDNF來作為目標分子，進行一系列的實驗探討制約場地偏好的神經機制。實驗一A以不同劑量安非他命建立制約場地偏好行為，並分析其BDNF mRNA的表現量。實驗結果顯示1 mg/kg安非他命能夠引發制約場地偏好行為，但是對於內側前額葉、紋狀體、依核、背側海馬迴、杏仁核等五個區塊的BDNF mRNA無顯著的影響效果。實驗一B再次確認實驗一A的結果，顯示俱有安非他命引發制約場地偏好行為的受試，其大腦五個區塊BDNF mRNA沒有顯著的變化。實驗二探測制約場地偏好行為再復發對於相同的五個區塊BDNF mRNA變化。結果發現0.75 mg/kg安非他命能誘發制約場地偏好再復發行為，並且能引發內側前額葉中BDNF mRNA的增加，但對其餘四個區塊則無明顯的影響效果。實驗三以單次注射安非他命探討對於BDNF mRNA是否有立即性的影響，結果顯示五個區塊皆無明顯的變化。實驗四以安非他命引發的行為致敏化反應為行為模式，偵測BDNF mRNA的表現情形。結果發現藥物制約配對組與單次注射安非他命組在活動量上無顯著的差異，顯示出無行為致敏化反應的發生。檢驗五個區塊BDNF mRNA的表現，亦沒有發現明顯的改變。綜合以上的實驗結果，本研究得到安非他命制約場地偏好再復發行為，會伴隨內側前額葉BDNF mRNA的增加。而單獨的安非他命引發制約場地偏好行為，並不會改變BDNF mRNA。這些結果顯示BDNF參與在較複雜的制約學習行為歷程，而不是在單獨的藥物注射或與環境配對的制約過程。 / Conditioned place preference (CPP) is widely used as an experimental behavioral model in the study of drug addiction and reward learning. Brain dopamine systems play an important role to drive the CPP performance and its relapse. Brain-derived neurotrophic factor (BDNF) is closely related to dopamine system that can promote neuron plasticity involved in certain types of behavior. Taking BDNF as the target molecule, this project conducted a series of experiments to delve into the neural mechanism of CPP. Different doses of amphetamine on the CPP behavior were assessed in Experiment 1A, and BDNF mRNA was tested after CPP test. The results show that 1 mg/kg amphetamine significantly induced CPP, but no significant effect on BDNF mRNA in any of five brain areas tested, including medial prefrontal cortex, striatum, nucleus accumbens, dorsal hippocampus and amygdala. The results of Experiment 1A was further confirmed by Experiment 1B, indicating no significant change on BDNF mRNA in five brain areas of rats with significant amphetamine-induced CPP. Experiment 2 examined the effects of CPP relapse and tested BDNF mRNA in the aforementioned five brain areas. The results show that 0.75 mg/kg amphetamine significantly induced CPP relapse and also increased BDNF mRNA level in medial prefrontal cortex. Such an increase of BDNF mRNA was not observed in any other four areas. Single acute injection of amphetamine was administered in Experiment 3 to delve into the possible immediate drug effect on BDNF mRNA. Its results show no significant change on five brain areas following this acute drug treatment. Experiment 4 used amphetamine-induced behavioral sensitization as a behavioral mode to determine the expression of BDNF mRNA. The results show no significant difference both for amphetamine-paired group and acute amphetamine group on locomotion, that indicated no behavioral sensitization formed in this test. There was no significant difference in the expression of BDNF mRNA in five brain areas. These results indicate that amphetamine-induced CPP relapse, but not CPP performance itself, is accompanied by the increase of BDNF mRNA level in medial prefrontal cortex. These findings indicate that BDNF is involved in place conditioning formed by psychostimulant drug when it is reinstated after extinction, rather than by a solitary drug injection or a relatively simple conditioning process by pairing drug with the environmental context.

Rationale: Peak initiation of smoking occurs during adolescence and early onset of smoking is associated with a reduced probability of quitting and greater risk of relapse compared to later onset. Considering the epidemiological evidence, adolescents may exhibit a unique biological susceptibility to nicotine taking, in addition to the behavioural and psychosocial factors known to influence adolescent smoking. Objectives: The current series of experiments, using a rat model of adolescent nicotine taking, was designed to investigate age differences in the processes involved in the acquisition and maintenance of nicotine taking that might account for the elevated initiation rates of smoking during adolescence. Methods: We first investigated age differences in the neural response to acute nicotine administration using c-fos mRNA expression. We then examined age differences in the rewarding and aversive effects of nicotine in the conditioned place preference (CPP) and conditioned taste avoidance (CTA) paradigms, respectively. The direct reinforcing effects of nicotine were tested in adolescent and adult rats under a variety of reinforcement schedules in the operant intravenous self-administration paradigm; extinction and nicotine priming-induced reinstatement were also examined. Finally, age differences in nicotine withdrawal precipitated by mecamylamine were assessed. Results: Nicotine had greater activational effects on c-fos mRNA expression in reward-related neural substrates of adolescent compared to adult brain. Adolescent rats were also more sensitive to the rewarding effects of nicotine (CPP) yet less sensitive to its aversive effects (CTA) compared to adult rats. Nicotine was equally reinforcing in adolescents and adults self-administering under simple reinforcement schedules, but adults were more motivated to obtain nicotine under higher reinforcement schedules. Adults were more resistant to extinction, yet both age groups demonstrated similar priming-induced reinstatement of nicotine seeking. Under spontaneous acquisition conditions, adults were more sensitive to the reinforcing effects of a low nicotine infusion dose. The aversive effects of nicotine withdrawal were also more prominent in adults compared to adolescents. Conclusions: These findings have important implications since they demonstrate a unique susceptibility to the conditioned rewarding effects of nicotine that would promote acquisition of smoking behaviour during adolescence, whereas adults may be more vulnerable to processes involved in its maintenance.

No description available.

Pharmacological treatment of neuropathic pain is still insufficient. Methylphenidate, a psychostimulant that increases the dopamine and noradrenaline levels, is commonly used for treating ADHD. There have been reports of changes in patients pain thresholds by ADHD patients treated with methylphenidate. The aim of the study is to examine if methylphenidate can affect peripheral neuropathic pain. Neuropathic pain has been modelled on laboratory rats by chronic constriction of the ischiatic nerve. The effect of methylphenidate on the evoked pain component was evaluated on control animals and on animals with neuropathic pain using reflex (plantar test, vonFrey test) and operanting test (thermal place preference). The effect of methylphenidate on the spontaneous components of pain was evaluated using the methods of conditioned place preference. This study has proven that methylphenidate in an applicable dose of 1 mg/kg has an antialodynic effect but does not act antinociceptively. This study further confirms that methylphenidate in low doses does not act as attractant and has no effect on spontaneous pain. The last part of the study compares the different methods for pain measurement and comes to the conclusion that the plantar test is not an adequate method for evaluating the effect of analgesics...

This study investigated nicotine conditioned place preference (CPP) in two different ages of adolescence using a rodent model of schizophrenia. Both 2- and 3-chambered CPP apparatuses were used to test whether the CPP was due to an aversion to the white chamber. Animals were neontally treated with the dopamine D2/D3 agonist, quinpirole, or saline and raised to either early postweanling age (P 22) or adolescence (P 29). Rats were conditioned to prefer the white chamber using nicotine. Results showed that nicotine induced CPP and appeared to alleviate an increased stress response in D2 primed animals, which appeared to diminish over time. Additionally, adult D2 and non-D2 primed rats were tested on the elevated T-maze. Results revealed that D2 primed rats demonstrated a significant increase in unconditioned fear. This study showed that nicotine induced CPP in D2 and non-D2 primed rats regardless of age, and D2 primed rats appear to demonstrate an increase in stress levels that was alleviated by nicotine.