Methcathinone (MCAT) is the β-ketone analog of methamphetamine, and like its amphetamine analog, MCAT functions as a monoamine releaser that selectively promotes the release of dopamine (DA) and norepinephrine (NE) over serotonin (5-HT). MCAT produces amphetamine-like psychostimulant effects and is classified as a Schedule I drug of abuse by the United States Drug Enforcement Administration (DEA). Recently, synthetic MCAT analogs have emerged as designer drugs of abuse in Europe and the United States and have been marketed under deceptively benign names like “bath salts” in an attempt to evade legal restriction. These dangerous, recently emergent and novel drugs of abuse display varying selectivity to promote release of DA/NE vs. 5-HT, and selectivity for DA neurotransmission is believed to correlate with abuse liability. The goal of this dissertation was to conduct preclinical research to examine structural determinants of abuse-related behavioral and neurochemical effects produced by a series of synthetic MCAT analogs. Specifically, this project focused on one feature of the methcathinone scaffold: the para substituent of the benzene ring. A series of six novel MCAT analogs will be examined to evaluate how physicochemical parameters (steric, Es; electronic, σp; lipophilic, πp) of the para substituent influence in vitro monoamine transporter selectivity as well as in vivo neurochemical and behavioral effects. Results from this body of work implicate steric factors as being particularly important in determining a compound’s abuse-related neurochemical and behavioral effects. Thus, these data not only offer an improved understanding of the mechanism of abuse-related drug effects produced by synthetic MCAT analogs, but also help in the generation of homology models of the human DA and 5-HT transporters (DAT and SERT, respectively).

Though a host of analgesics have been developed to alleviate pain, especially acute pain, significant side effects and a lack of long-term efficacy have encouraged research attempts to pursue novel targets that may be associated with fewer side effects or a more sustained efficacy. Among these new targets are members of the nicotinic family of acetylcholine receptors (nAChRs). The non-selective nAChR agonists nicotine and epibatidine have been shown to function as potent antinociceptive drugs in many acute and chronic preclinical pain models, while nicotine has produced analgesic effects in humans. However, these non-selective nAChRs agonists also produce various side effects, including gastrointestinal and cardiovascular complications that limit clinical utility. To reduce these side effects, recent research has focused on evaluating the potential role of specific nAChR subtypes in the modulation of nociception. Traditionally, assays of pain-stimulated behaviors, or behaviors that increase in rate, frequency or intensity after presentation of a noxious stimulus, have been used to evaluate nAChR agonists and other classes of candidate analgesics pre-clinically. However, clinically relevant pain states are often associated with the depression of behavior; for example in humans, pain is often accompanied by impaired function in daily activities and depression of mood. To address these depressant manifestations of pain, novel preclinical assays have been developed to assess the expression and pharmacological modulation of pain-depressed behaviors, or behaviors that decrease in rate, frequency or intensity after presentation of a noxious stimulus. Additionally, the effects of nAChR agonists in preclinical assays of pain-depressed behavior are unknown. In assays of pain-stimulated behavior, agonism of α4β2* receptors appears to play a prominent role in antinociception produced by drugs that target nAChRs. Recent research suggests that α7 nAChR subtype might be an alternative target. Accordingly, the primary goal of this dissertation was to compare antinociceptive effects of the nAChR agonist nicotine and more selective nicotinic agonists in assays of pain-stimulated and pain-depressed behavior. Results from this body of work show that both nicotine and the more selective α4β2* agonist 5-I-A-85380 produced antinociception in both types of assays, whereas an α7 agonist did not. Taken together, these results suggest that α4β2* nAChR agonists may be especially effective to treat signs of pain-related behavioral depression; however nonselective behavioral effects of these compounds may contribute to apparent antinociception. Studies of nAChR agonist effects on pain-depressed behavior were conducted using an assay of intracranial self-stimulation (ICSS) as a baseline behavior that is depressed by noxious pain stimuli, and pain-related depression of ICSS can be selectively alleviated by clinically effective analgesics. As a prelude to studies of nAChR agonist effects on pain-related depression of ICSS, a preliminary study was conducted to assess effects of nicotine and 5-I-A-85380 on ICSS in the absence of a noxious stimulus. These studies indicated that selective α4β2* agonists may have higher abuse potential than nicotine. Additionally, cognitive function is one domain of behavior that may be impaired by pain, and nAChR agonists are used to treat cognitive impairment produced by other non-pain pathologies. Accordingly, a final goal of this project was to develop an assay of pain-related cognitive impairment in rats that could be used to evaluate effects of nAChR agonists. Although results of this study did provide evidence for pain-related impairment of cognition, the effects of the pain stimuli were sufficiently variable and transient to make this procedure impracticable for use in studies with nAChR agonists.

No description available.

Inhalants are a loosely defined diverse group of volatile substances which people abuse. Despite widespread misuse of inhalants, there are limited preclinical methods available to study the reinforcement-like properties of inhalants. One procedure which has demonstrated substantial promise as a tool to investigate inhalant pharmacology is the intracranial self-stimulation (ICSS) procedure. ICSS utilizes pulses of electrical stimulation to the mesolimbic reward pathway to serve as a temporally defined and controlled operant reinforcer with a highly adjustable efficacy. The first aim of the project was to characterize the effects of commonly abused inhalants: including toluene, trichloroethane, nitrous oxide, isoflurane and R134a in ICSS. The second aim was to attenuate inhalant-facilitated ICSS by utilization of compounds which would attenuate the pharmacological actions of toluene on GABAA receptors. The low efficacy benzodiazepine negative modulator Ro15-4513 significantly attenuated the ability of toluene to facilitate ICSS without itself significantly altering baseline ICSS responding. Pretreatment with Ro15-4513 also attenuated methamphetamine ICSS even though there is no evidence of methamphetamine interacting with GABAA receptors. Given these unexpected results, I employed a microdialysis procedure to examine the effect of Ro15-4513 on methamphetamine stimulated dopamine release in the nucleus accumbens. Pretreatment with Ro15-4513 significantly attenuated methamphetamine stimulated dopamine release while having a negligible effect on dopamine release when administered alone. These results suggest that a modest level of benzodiazepine-site negative modulation can reduce the reinforcement enhancing effects of abused drugs regardless of their primary mechanism of action through allosteric modulation of GABAergic neurons within the mesolimbic pathway. Further, these results may have implications for expanding the examination of GABAA negative modulator medications beyond those trials currently being conducted with alcohol. Finally, the effects of chronic intermittent toluene exposure on ICSS and nesting behaviors were examined. Subjects were systemically exposed to air, chronic intermittent toluene (CIT), or escalating chronic intermittent (ECIT) toluene for 15 min at 3300 PPM toluene vapor per exposure. The results show that ECIT resulted in decreased overall responding in ICSS relative to air control and showed a tolerance-like effect to facilitatory effects of 3300 ppm toluene during ICSS compared to CIT group. These results indicate that escalating use of toluene produces reductions in its reward-like effects and may contribute to escalation to other drugs of abuse.

L’habenula, un noyau épithalamique, est située au centre de la voie dorsale diencéphalique. Cette voie relie les structures limbiques et les ganglions de la base aux cellules monoaminergiques du mésencéphale. En particulier, l’habenula latérale (HbL) projette directement aux cellules dopaminergiques et GABAergiques de l’aire tegmentale ventrale (ATV). L’ATV est le site d’origine de la voie mésolimbique dopaminergique, une voie impliquée de façon cruciale dans la manifestation des comportements dirigés. L’importance de cette projection habenulaire pour le comportement demeure encore méconnue. Ainsi, l’objectif de cette étude est d’approfondir notre compréhension du rôle de régulation de l’HbL sur les comportements dépendants de la neurotransmission dopaminergique. MATÉRIEL ET MÉTHODES: Des rats adultes mâles Sprague-Dawley ont été anesthésiés avec de l’isofluorane et installés sur un appareil stéréotaxique. L’acide iboténique, une neurotoxine agoniste des récepteurs glutamatergiques, était infusée bilatéralement dans l’HbL (0,25 μg/0,25 μl/côté). Les rats du groupe contrôle recevaient des infusions NaCl 0,9%. Les rats de l’expérience d’autostimulation intracérébrale (ASIC) étaient aussi implantés d’une électrode monopolaire dans le mésencéphale postérieur. Un groupe de rats était testé pour leur réponse de locomotion à l’amphétamine (0; 0,5 ou 1 mg/kg, intrapéritonéal), dix jours suivant la lésion de l’HbL. La locomotion était mesurée dans des chambres d’activité, chacune équipée de deux faisceaux parallèles infrarouges. Le jour du test, les rats étaient pesés et placés dans la chambre d’activité puis leur activité locomotrice de base était mesurée pendant une heure. Les rats recevaient ensuite une dose d’amphétamine ou le véhicule (NaCl 0,9%) par voie intrapéritonéale et l’activité locomotrice était mesurée pendant deux heures supplémentaires. Un groupe de rats distinct a été utilisé dans l’expérience d’ASIC. Commençant sept jours suivant la lésion, les rats étaient entraînés à appuyer sur un levier afin de s’autoadministrer des stimulations électriques, au cours de sessions quotidiennes. Nous avons ensuite mesuré chacun des taux de réponses d’une série de stimulations aux fréquences décroissantes. À partir d’une courbe réponses-fréquences, le seuil de récompense était inféré par la fréquence de la stimulation nécessaire pour produire une réponse semi-maximale. Les seuils de récompense étaient stabilisés à un niveau similaire pour l’ensemble des rats. Enfin, l’effet sur la récompense de l’amphétamine était testé aux mêmes doses employées pour l’expérience de locomotion. RÉSULTATS: Une lésion neurotoxique de l’HbL n’a pas altéré les niveaux de base de l’activité locomotrice dans chaque groupe. Cependant, une telle lésion a potentialisé l’effet de locomotion de l’amphétamine (1 mg/kg) pendant la première heure suivant son administration, et une tendance similaire était observable pendant la seconde heure. À l’inverse, nous n’avons observé aucune interaction entre une lésion à l’HbL et l’effet amplificateur sur la récompense de l’amphétamine. CONCLUSION: Nos résultats révèlent une importante contribution fonctionnelle de l’HbL à la locomotion induite par l’activation de la voie mésolimbique dopaminergique avec une dose de 1 mg/kg d’amphétamine. À l’opposé, aucun effet sur la récompense n’a été observé. Ces résultats suggèrent que l’activation psychomotrice et l’amplifiation de la récompense produite par l’amphétamine dépendent de substrats dissociables, chacun étant différentiellement sensible à la modulation provenant de l’HbL. / The habenula, an epithalamic nucleus, is centrally located within the dorsal diencephalic conduction system. This dorsal pathway connects the limbic forebrain and basal ganglia to midbrain monoaminergic cell groups intricately involved in the control of behavior. In particular, the lateral habenula (LHb) projects to, among other sites, the ventral tegmental area (VTA). Indeed, recent work has revealed direct LHb innervation of VTA dopamine as well as GABA cells. Little is known, however, about the behavioral relevance of this innervation but this knowledge is of potential importance, since the VTA gives rise to the mesolimbic dopamine pathway, a system critically involved in goal-directed behavior. Our aim here was to begin to understand the contribution of the LHb to dopamine-dependent behaviors. To do this, we produced neurotoxic lesions of the LHb and measured amphetamine-enhanced locomotion and intracranial self-stimulation (ICSS), two behaviors highly sensitive to mesolimbic dopamine neurotransmission. METRIALS AND METHODS: Adult male Sprague-Dawley rats were anesthetised with isoflurane and mounted onto a stereotaxic apparatus. Ibotenic acid, an excitatory neurotoxin at glutamatergic receptors, was infused bilaterally into the LHb (0.25 μg/0.25 μl/side). Sham-lesioned rats received infusions of 0.9% sterile saline. Rats in the ICSS experiment were additionally implanted with a monopolar stimulation electrode in the posterior mesencephalon. One group of rats was tested for their locomotor response to amphetamine (0, 0.5 or 1 mg/kg, i.p.), ten days after LHb lesion. Locomotion was measured in rectangular activity chambers, each equipped with two parallel infrared photobeams. On test day, rats were weighed, placed in the activity chamber and baseline locomotor activity was measured for 1 hour. Rats then received amphetamine or vehicle (0.9% saline) and locomotor activity was measured for 2 more hours. A separate group of rats was used in the ICSS experiment. Beginning seven days post-lesion, rats were trained to press a lever in order to self-administer trains of stimulation pulses. We then measured response rates at each of a series of pulse frequencies during daily sessions. From these response-frequency curves, we obtained estimates of reward thresholds, defined as the pulse frequency necessary for half-maximal responding. Baseline reward thresholds were matched across all rats and once stable, we tested the reward-enhancing effect of amphetamine, at the same doses tested in the locomotion experiment. RESULTS: Neurotoxic lesions of the LHb did not alter baseline locomotor activity in either group. Amphetamine enhanced locomotor activity throughout the entire 2 hour test. Importantly, the locomotor stimulant effect of amphetamine (1 mg/kg) was significantly greater in lesioned rats during the first hour, and a similar tendency was observed during the second hour. On the other hand, we did not observe any difference in amphetamine-induced enhancement of reward between lesioned and sham rats, at any dose or any time post-injection. CONCLUSION: Our findings reveal an important functional contribution of the LHb to dopamine-mediated locomotion. On the other hand, the clear dissociation between the locomotor-stimulant and rewarding effects of amphetamine suggests that the neural substrates mediating these two are dissociable and differentially sensitive to LHb modulation.

La contribution de la neurotransmission dopaminergique dans le noyau accumbens à l’effet de récompense induit par la stimulation électrique du cerveau a été l’objet de plusieurs années de recherche. Cependant, d’autres sites recevant des terminaisons dopaminergiques pourraient contribuer à moduler la récompense dans d’autres régions cérébrales. Parmi elles, on retrouve l’habenula qui reçoit des projections dopaminergiques de l’aire tegmentale ventrale. La contribution de cette voie au phénomène de récompense en général et à l’effet de recompense induit par l’autostimulation intracrânienne est peu connue. Le but de cette recherche était d’étudier la contribution de la dopamine mésohabenulaire à l’effet de recompense induit par la stimulation électrique du raphé dorsal. Des rats ont été implantés d’une bicanule dans l’Hb et d’une électrode dans le raphé dorsal. Le paradigme du déplacement de la courbe a été utilisé pour évaluer les changements dans l’effet de récompense à la suite de l’injection intra-habenulaire d’amphétamine (10-40 μg). À titre de contrôles positifs, des rats ont reçu l’amphétamine dans le core et dans le shell (1-20 μg) du noyau accumbens. Les injections d’amphétamine dans l’habenula n’ont pas changé l’effet de récompense induit par la stimulation électrique. Dans le noyau accumbens, les injections dans le shell et le core provoquent des augmentations dans l’effet de récompense comme il a déjà été démontré. Nos résultats suggèrent que la neurotransmission dopaminergique dans l’habenula latérale ne contribue pas significativement au circuit soutenant l’effet renforçant de la stimulation électrique du cerveau. / The contribution of nucleus accumbens dopamine neurotransmission to reward and reinforcement has been the focus of many years of study. Other terminal sites have received comparatively less research attention, but may be potentially important. One of these sites is the lateral habenula, which receives dopaminergic innervation from cells arising from the ventral tegmental area. Very little is known about the contribution of this pathway to reward in general and to the rewarding effect of electrical brain stimulation in particular. The goal of this study was to study the contribution of mesohabenular dopamine to reward induced by electrical stimulation of the dorsal raphe. Male Sprague-Dawley rats were implanted with bilateral cannulae in the lateral habenula and a stimulation electrode aimed at the dorsal raphe nucleus. Using the curveshift paradigm, we measured the rewarding effect of intra-habenular infusions of amphetamine (10-40 μg). Control rats received amphetamine infusions into nucleus accumbens core or shell subregions (1-20 μg). Our findings show that regardless of concentration, intra-habenular amphetamine did not alter brain stimulation reward. Infusions into the nucleus accumbens enhanced the rewarding effectiveness of the stimulation, as previously shown. Our findings suggest that dopaminergic neurotransmission within the lateral habenula does not contribute significantly to the circuitry that mediates the rewarding effect of electrical brain stimulation.

Pain is a significant health problem. Mu opioid receptor agonists are used clinically as analgesics, but their use is constrained by high abuse liability. Intracranial self-stimulation (ICSS) is a preclinical behavioral procedure that has been used to assess abuse potential of opioids, and drug-induced facilitation of ICSS is interpreted as an abuse-related effect. ICSS can also be used as a behavioral baseline to detect affective dimensions of pain. Specifically, pain-related depression of ICSS can model pain-related depression of behavior and mood, and drug-induced blockade of pain-related ICSS depression can serve as a measure of affective analgesia. This dissertation used mu agonists that vary in efficacy at the mu receptor (methadone> fentanyl> morphine> hydrocodone> buprenorphine> nalbuphine) and compared their effects on ICSS in the absence (phase one) or presence (phase 2) of pain. Adult male Sprague-Dawley rats were equipped with intracranial electrodes targeting the medial forebrain bundle and trained to lever press for brain stimulation. Different frequencies of stimulation maintained a frequency-dependent increase in ICSS rates, and permitted detection of both rate-increasing and rate-decreasing treatment effects. During phase 1, medium- and high-efficacy mu agonists produced initial rate-decreasing effects, followed by abuse-related rate-increasing effects at later time points. Repeated morphine administration produced tolerance to its own rate-decreasing effects, cross-tolerance to rate-decreasing effects of other mu agonists, and enhanced expression of rate-increasing effects. Low efficacy mu agonists only produced rate-increasing effects, which were enhanced after repeated morphine. These results suggest that previous opioid exposure increases expression of abuse-related facilitation of ICSS by mu agonists regardless of efficacy. During phase 2, intraperitoneal administration of lactic acid (1.8%) served as a noxious stimulus to depress ICSS. All mu agonists blocked acid-induced depression of ICSS at doses similar to those that facilitated ICSS in the absence of pain. A higher intensity noxious stimulus (5.6 % acid) produced further depression of ICSS and reduced the antinociceptive potency of both methadone and nalbuphine. Morphine antinociception was resistant to tolerance in the assay of acid-depressed ICSS. Overall, these results provide a basis for comparing determinants of abuse-related opioid effects in the absence of pain with their affective analgesic effects in the presence of pain.

La voie dopaminergique mésolimbique qui prend son origine dans le mésencéphale ventral et qui projette vers des régions rostrales du système limbique fait partie du substrat nerveux qui contrôle la récompense et les comportements motivés. Il a été suggéré qu’un signal de récompense est produit lorsque le patron de décharge des neurones dopaminergiques passe d’un mode tonique à un mode phasique, une transition qui est initiée par l’action du glutamate aux récepteurs N-Méthyl-D-aspartate (NMDA). Étant donné qu’une altération du système de récompense est souvent associée à des anomalies cliniques telles que l’addiction compulsive et à des troubles émotionnels tels que l’anhédonie, nous avons étudié le rôle des récepteurs NMDA dans la récompense induite par la stimulation électrique intracérébrale. Puisque les récepteurs NMDA sont composés de sous-unités distinctes, GluN1, GluN2 et GluN3, nous avons étudié le rôle de deux sous-unités qui sont présentes dans le mésencéphale ventral : GluN2A et GluN2B. Les résultats montrent que des injections mésencéphaliques de R-CPP et de PPPA, des antagonistes préférentiels aux sous-unités GluN2A/B, ont produit une augmentation dose-dépendante de l’effet de récompense, un effet qui était, à certains temps après les injections, accompagné d’une augmentation du nombre de réponses maximales. Ces effets n’ont pas été observés après l’injection d’une large gamme de doses de Ro04-5595, un antagoniste des sous-unités GluN2B. Ces résultats suggèrent que le glutamate mésencéphalique exerce une modulation négative sur le circuit de récompense, un effet dû à son action au niveau des récepteurs NMDA composés des sous-unités GluN2A. / The mesolimbic dopaminergic pathway, originating from the ventral midbrain and projecting to rostral limbic structures, is part of a neural substrate that controls reward and incentive behaviors. It has been suggested that the rewarding effect is produced by a tonic to phasic shift in dopamine cell firing and a transduction process initiated by the action of glutamate at the N-Methyl-D-aspartate (NMDA) receptors. Given that an alteration in reward signaling is often associated with clinical symptoms of compulsive addictive behaviors and emotional disturbances such as anhedonia, we investigated the role of NMDA receptors in reward induced by intracranial electrical stimulation. Since NMDA receptors are composed of distinct subunits, GluN1, GluN2 and GluN3, we investigated the role of the main GluN2 subunits that are expressed in the ventral midbrain, GluN2A and GluN2B. Results show that ventral midbrain injections of R-CPP or PPPA, preferential GluN2A/2B antagonists, produce a dose-orderly enhancement of reward, an effect that was, at some time after the injection, accompanied by an increase in maximum response rates. These effects were not observed following ventral midbrain injections of a wide range of doses of the selective GluN2B antagonist, Ro-04-5595. These findings suggest that ventral midbrain glutamate exerts a negative modulation on reward induced by electrical stimulation of the posterior mesencephalon, an effect most likely mediated by NMDA receptors composed of GluN2A subunits.

L’habenula, un noyau épithalamique, est située au centre de la voie dorsale diencéphalique. Cette voie relie les structures limbiques et les ganglions de la base aux cellules monoaminergiques du mésencéphale. En particulier, l’habenula latérale (HbL) projette directement aux cellules dopaminergiques et GABAergiques de l’aire tegmentale ventrale (ATV). L’ATV est le site d’origine de la voie mésolimbique dopaminergique, une voie impliquée de façon cruciale dans la manifestation des comportements dirigés. L’importance de cette projection habenulaire pour le comportement demeure encore méconnue. Ainsi, l’objectif de cette étude est d’approfondir notre compréhension du rôle de régulation de l’HbL sur les comportements dépendants de la neurotransmission dopaminergique. MATÉRIEL ET MÉTHODES: Des rats adultes mâles Sprague-Dawley ont été anesthésiés avec de l’isofluorane et installés sur un appareil stéréotaxique. L’acide iboténique, une neurotoxine agoniste des récepteurs glutamatergiques, était infusée bilatéralement dans l’HbL (0,25 μg/0,25 μl/côté). Les rats du groupe contrôle recevaient des infusions NaCl 0,9%. Les rats de l’expérience d’autostimulation intracérébrale (ASIC) étaient aussi implantés d’une électrode monopolaire dans le mésencéphale postérieur. Un groupe de rats était testé pour leur réponse de locomotion à l’amphétamine (0; 0,5 ou 1 mg/kg, intrapéritonéal), dix jours suivant la lésion de l’HbL. La locomotion était mesurée dans des chambres d’activité, chacune équipée de deux faisceaux parallèles infrarouges. Le jour du test, les rats étaient pesés et placés dans la chambre d’activité puis leur activité locomotrice de base était mesurée pendant une heure. Les rats recevaient ensuite une dose d’amphétamine ou le véhicule (NaCl 0,9%) par voie intrapéritonéale et l’activité locomotrice était mesurée pendant deux heures supplémentaires. Un groupe de rats distinct a été utilisé dans l’expérience d’ASIC. Commençant sept jours suivant la lésion, les rats étaient entraînés à appuyer sur un levier afin de s’autoadministrer des stimulations électriques, au cours de sessions quotidiennes. Nous avons ensuite mesuré chacun des taux de réponses d’une série de stimulations aux fréquences décroissantes. À partir d’une courbe réponses-fréquences, le seuil de récompense était inféré par la fréquence de la stimulation nécessaire pour produire une réponse semi-maximale. Les seuils de récompense étaient stabilisés à un niveau similaire pour l’ensemble des rats. Enfin, l’effet sur la récompense de l’amphétamine était testé aux mêmes doses employées pour l’expérience de locomotion. RÉSULTATS: Une lésion neurotoxique de l’HbL n’a pas altéré les niveaux de base de l’activité locomotrice dans chaque groupe. Cependant, une telle lésion a potentialisé l’effet de locomotion de l’amphétamine (1 mg/kg) pendant la première heure suivant son administration, et une tendance similaire était observable pendant la seconde heure. À l’inverse, nous n’avons observé aucune interaction entre une lésion à l’HbL et l’effet amplificateur sur la récompense de l’amphétamine. CONCLUSION: Nos résultats révèlent une importante contribution fonctionnelle de l’HbL à la locomotion induite par l’activation de la voie mésolimbique dopaminergique avec une dose de 1 mg/kg d’amphétamine. À l’opposé, aucun effet sur la récompense n’a été observé. Ces résultats suggèrent que l’activation psychomotrice et l’amplifiation de la récompense produite par l’amphétamine dépendent de substrats dissociables, chacun étant différentiellement sensible à la modulation provenant de l’HbL. / The habenula, an epithalamic nucleus, is centrally located within the dorsal diencephalic conduction system. This dorsal pathway connects the limbic forebrain and basal ganglia to midbrain monoaminergic cell groups intricately involved in the control of behavior. In particular, the lateral habenula (LHb) projects to, among other sites, the ventral tegmental area (VTA). Indeed, recent work has revealed direct LHb innervation of VTA dopamine as well as GABA cells. Little is known, however, about the behavioral relevance of this innervation but this knowledge is of potential importance, since the VTA gives rise to the mesolimbic dopamine pathway, a system critically involved in goal-directed behavior. Our aim here was to begin to understand the contribution of the LHb to dopamine-dependent behaviors. To do this, we produced neurotoxic lesions of the LHb and measured amphetamine-enhanced locomotion and intracranial self-stimulation (ICSS), two behaviors highly sensitive to mesolimbic dopamine neurotransmission. METRIALS AND METHODS: Adult male Sprague-Dawley rats were anesthetised with isoflurane and mounted onto a stereotaxic apparatus. Ibotenic acid, an excitatory neurotoxin at glutamatergic receptors, was infused bilaterally into the LHb (0.25 μg/0.25 μl/side). Sham-lesioned rats received infusions of 0.9% sterile saline. Rats in the ICSS experiment were additionally implanted with a monopolar stimulation electrode in the posterior mesencephalon. One group of rats was tested for their locomotor response to amphetamine (0, 0.5 or 1 mg/kg, i.p.), ten days after LHb lesion. Locomotion was measured in rectangular activity chambers, each equipped with two parallel infrared photobeams. On test day, rats were weighed, placed in the activity chamber and baseline locomotor activity was measured for 1 hour. Rats then received amphetamine or vehicle (0.9% saline) and locomotor activity was measured for 2 more hours. A separate group of rats was used in the ICSS experiment. Beginning seven days post-lesion, rats were trained to press a lever in order to self-administer trains of stimulation pulses. We then measured response rates at each of a series of pulse frequencies during daily sessions. From these response-frequency curves, we obtained estimates of reward thresholds, defined as the pulse frequency necessary for half-maximal responding. Baseline reward thresholds were matched across all rats and once stable, we tested the reward-enhancing effect of amphetamine, at the same doses tested in the locomotion experiment. RESULTS: Neurotoxic lesions of the LHb did not alter baseline locomotor activity in either group. Amphetamine enhanced locomotor activity throughout the entire 2 hour test. Importantly, the locomotor stimulant effect of amphetamine (1 mg/kg) was significantly greater in lesioned rats during the first hour, and a similar tendency was observed during the second hour. On the other hand, we did not observe any difference in amphetamine-induced enhancement of reward between lesioned and sham rats, at any dose or any time post-injection. CONCLUSION: Our findings reveal an important functional contribution of the LHb to dopamine-mediated locomotion. On the other hand, the clear dissociation between the locomotor-stimulant and rewarding effects of amphetamine suggests that the neural substrates mediating these two are dissociable and differentially sensitive to LHb modulation.

La contribution de la neurotransmission dopaminergique dans le noyau accumbens à l’effet de récompense induit par la stimulation électrique du cerveau a été l’objet de plusieurs années de recherche. Cependant, d’autres sites recevant des terminaisons dopaminergiques pourraient contribuer à moduler la récompense dans d’autres régions cérébrales. Parmi elles, on retrouve l’habenula qui reçoit des projections dopaminergiques de l’aire tegmentale ventrale. La contribution de cette voie au phénomène de récompense en général et à l’effet de recompense induit par l’autostimulation intracrânienne est peu connue. Le but de cette recherche était d’étudier la contribution de la dopamine mésohabenulaire à l’effet de recompense induit par la stimulation électrique du raphé dorsal. Des rats ont été implantés d’une bicanule dans l’Hb et d’une électrode dans le raphé dorsal. Le paradigme du déplacement de la courbe a été utilisé pour évaluer les changements dans l’effet de récompense à la suite de l’injection intra-habenulaire d’amphétamine (10-40 μg). À titre de contrôles positifs, des rats ont reçu l’amphétamine dans le core et dans le shell (1-20 μg) du noyau accumbens. Les injections d’amphétamine dans l’habenula n’ont pas changé l’effet de récompense induit par la stimulation électrique. Dans le noyau accumbens, les injections dans le shell et le core provoquent des augmentations dans l’effet de récompense comme il a déjà été démontré. Nos résultats suggèrent que la neurotransmission dopaminergique dans l’habenula latérale ne contribue pas significativement au circuit soutenant l’effet renforçant de la stimulation électrique du cerveau. / The contribution of nucleus accumbens dopamine neurotransmission to reward and reinforcement has been the focus of many years of study. Other terminal sites have received comparatively less research attention, but may be potentially important. One of these sites is the lateral habenula, which receives dopaminergic innervation from cells arising from the ventral tegmental area. Very little is known about the contribution of this pathway to reward in general and to the rewarding effect of electrical brain stimulation in particular. The goal of this study was to study the contribution of mesohabenular dopamine to reward induced by electrical stimulation of the dorsal raphe. Male Sprague-Dawley rats were implanted with bilateral cannulae in the lateral habenula and a stimulation electrode aimed at the dorsal raphe nucleus. Using the curveshift paradigm, we measured the rewarding effect of intra-habenular infusions of amphetamine (10-40 μg). Control rats received amphetamine infusions into nucleus accumbens core or shell subregions (1-20 μg). Our findings show that regardless of concentration, intra-habenular amphetamine did not alter brain stimulation reward. Infusions into the nucleus accumbens enhanced the rewarding effectiveness of the stimulation, as previously shown. Our findings suggest that dopaminergic neurotransmission within the lateral habenula does not contribute significantly to the circuitry that mediates the rewarding effect of electrical brain stimulation.