Several active pharmaceutical ingredients (API) exhibit polymorphism i.e. the ability of a solid material to exist in more than one form or crystal structure (polymorphs). The polymorphs differ somewhat in physical and, sometimes, chemical properties, although their solutions and vapours are identical. Among the different physical properties that are affected by polymorphism are solubility and dissolution rate which have great impact on the bioavailability of the drug. Frequently an API polymorph transforms to another, more thermodynamically stable, phase. When such transformation takes place then a pharmaceutical industry faces problems related to bioavailability of an API as well as litigation problems due to patent protection of specific polymorphs. The pharmaceutical substance that was studied in this current work was, Aripiprazole, an antipsychotic drug. API crystallizes in a large number of polymorphic and solvatomorphic phases. Μore specific 9 polymorphic and 9 solvatomorphic phases have been positively identified, from which Form III and Form V are currently tested as possible candidates for drug formulations. The objective of the present work was to establish methods capable of identification and quantification of Apiprazole crystal forms and their possible transformation to hydrate phase in Aripiprazole powders as well as in the tested tablets. Stability test were also performed on Aripiprazole crystal forms III and V. The analytical techniques applied were X-ray Powder Diffraction (XRPD), Infrared spectroscopy (IR) and Raman spectroscopy. Calibration lines of mixtures of API Form III and Monohydrate were constructed. Results show that all three techniques were capable of identifying and quantifying the monohydrate phase however XRPD is probably the method of choice due to the lower detection limit (0.34%) of monohydrate in Phase III-monohydrate mixtures. Quantitative analysis of these polymorphs in the presence of excipients (tablets) is difficult due to the rather low API percentage in tablets (8%) and the high detection limits of monohydrate in mixtures of III and monohydrate. An effort to increase the low API content was made by dissolving in water a large percentage of excipients at alkaline pH. Even though the stability tests show that no transformation of pure Phase III occurs under these conditions, in tablets with some presence of monohydrate, rapid transformation of the remaining Phase III was observed during the dissolution process of the excipients. Thus, the only way was to apply directly the analytical techniques that were used for the pure mixtures to tablets. It was found that Raman and IR spectra cannot be used due to heavy overlapping with excipients bands. By increasing the scan time the identification of anhydrate phase and the hydrate was possible by using XRPD. In order to avoid any possible transformation of both Form III and Form V (stability tests show transformation to hydrate phase) it was decided to build the calibration line using only the hydrate phase and the placebo. The constructed calibration line was constructed exhibit low detection limit (0.1156%). Based on this calibration line and the calibration lines that were build using pure Form III and hydrate mixtures a methodology was proposed and the polymorphs were determined in finished formulations. / Αρκετές ενεργές φαρμακευτικές ουσίες εμφανίζουν πολυμορφισμό, δηλαδή την ικανότητα μιας στερεής ένωσης να υπάρχει σε παραπάνω από μια κρυσταλλική φάση (πολύμορφα). Τα πολύμορφα διαφέρουν σε φυσικές, και σε μερικές περιπτώσεις, χημικές ιδιότητες παρόλο που τα διαλύματα και οι ατμοί τους είναι πανομοιότυποι. Μεταξύ των διαφόρων φυσικών ιδιοτήτων που επηρεάζει ο πολυμορφισμός είναι η διαλυτότητα και ο ρυθμός διάλυσης, οι οποίες έχουν μεγάλη επίδραση στην βιοδιαθεσιμότητα του φαρμάκου. Συχνά ένα πολύμορφο μιας φαρμακευτικής ουσίας μετατρέπεται σε ένα άλλο πολύμορφο το οποίο είναι θερμοδυναμικά πιο σταθερό. Όταν ένας τέτοιος μετασχηματισμός λαμβάνει χώρα, μια φαρμακευτική βιομηχανία είναι πιθανόν να αντιμετωπίσει προβλήματα που σχετίζονται με την βιοδιαθεσιμότητα της φαρμακευτικής ουσίας καθώς επίσης και νομικά προβλήματα που αφορούν τα διπλώματα ευρεσιτεχνίας των συγκεκριμένων πολυμόρφων. Η φαρμακευτική ουσία που μελετήθηκε στην συγκεκριμένη εργασία ήταν ένα αντιψυχωσικό φάρμακο, η αριπιπραζόλη. Η αριπιπραζόλη κρυσταλλώνεται σε ένα μεγάλο αριθμό πολυμορφικών και επιδιάλυτων φάσεων (solvatomorphic- ένυδρων φάσεων αλλά και φάσεων με διάφορα άλλα μόρια διαλυτών ενσωματωμένα στη δραστική). Πιο συγκεκριμένα έχουν ταυτοποιηθεί 9 πολυμορφικές και 9 επιδιάλυτες φάσεις, εκ των οποίων η Φάση ΙΙΙ και η Φάση V εξετάζονται επί του παρόντος σαν υποψήφιες για την παρασκευή φαρμακευτικών σκευασμάτων. Σκοπός της συγκεκριμένης ερευνητικής προσπάθειας ήταν η ανάπτυξη μεθοδολογιών για τον ποιοτικό και ποσοτικό προσδιορισμό των διαφόρων φάσεων της αριπιπραζόλης και την πιθανή μετατροπή τους στην ένυδρη φάση σε μίγματα καθαρών δραστικών ουσιών καθώς επίσης και στα εξεταζόμενα δισκία. Επίσης διενεργήθηκε έλεγχος σταθερότητας στις πολυμορφικές φάσεις ΙΙΙ και V. Οι αναλυτικές τεχνικές που χρησιμοποιήθηκαν στην παρούσα εργασία είναι η Περίθλαση Κόνεως Ακτινών Χ (XRPD), η Φασματοσκοπία Υπέρυθρου (IR) και η Φασματοσκοπία Raman. Κατασκευάστηκαν καμπύλες βαθμονόμησης μιγμάτων Φάσης ΙΙΙ και Μονοένυδρης Φάσης αριπιπραζόλης. Τα αποτελέσματα έδειξαν ότι και οι τρεις τεχνικές είναι μπορούν να χρησιμοποιηθούν για τον ποιοτικό και τον ποσοτικό προσδιορισμό της ένυδρης φάσης, η μέθοδος όμως της Περίθλασης Ακτινών Χ είναι πιθανώς καλύτερη εξαιτίας των χαμηλότερων ορίων ανίχνευσης (0,34%) της ένυδρης φάσης σε μίγματα Μονοένυδρης Φάσης-Φάσης ΙΙΙ. Η ποσοτική ανάλυση των πολυμορφικών φάσεων αυτών σε δισκία δηλαδή παρουσία εκδόχων κατέστη πολύ δύσκολη εξαιτίας του σχετικά μικρού ποσοστού δραστικής ουσίας στο δισκίο (8%) και των υψηλών ορίων ανίχνευσης της μονοένυδρης φάσης σε μίγματα αυτής με την φάση ΙΙΙ. Έγινε προσπάθεια να αυξηθεί η ποσότητα της δραστικής ουσίας στο δισκίο διαλύοντας σε νερό ένα μεγάλο ποσοστό των εκδόχων σε αλκαλικό pH. Παρόλο που ο έλεγχος σταθερότητας έδειξε ότι δεν λαμβάνει χώρα μετατροπή της καθαρής Φάσης ΙΙΙ σε μονοένυδρη φάση κάτω από αυτές τις συνθήκες, στα δισκία με κάποια παρουσία μονοένυδρης φάσης λαμβάνει χώρα ταχεία μετατροπή της εναπομείνουσας φάσης ΙΙΙ κατά την διαδικασία διάλυσης των εκδόχων. Κατ' επέκταση ο μόνος τρόπος ήταν η εφαρμογή των αναλυτικών τεχνικών στα δισκία χωρίς περαιτέρω επεξεργασία τους. Βρέθηκε ότι τα φάσματα Raman και IR δεν μπορούν να χρησιμοποιηθούν λόγω των μεγάλων αλληλοεπικαλύψεων των κορυφών τους με τις κορυφές των εκδοχών. Ο προσδιορισμός της ένυδρης φάσης και της άνυδρης φάσης κατέστη δυνατός αυξάνοντας το χρόνο σάρωσης στην Περίθλαση Ακτινών Χ (XRPD). Προκείμενου να αποφευχθεί οποιαδήποτε μετατροπή των δυο Φάσεων ΙΙΙ και V (ο έλεγχος σταθερότητας έδειξε μετατροπή στην ένυδρη φάση), αποφασίστηκε να δημιουργηθεί καμπύλη βαθμονόμησης χρησιμοποιώντας μόνο την ένυδρη φάση και τα μίγμα των εκδόχων (placebo). Η καμπύλη βαθμονόμησης που κατασκευάστηκε παρουσιάζει χαμηλά όρια ανίχνευσης (0,12 %). Με βάση αυτήν την καμπύλη βαθμονόμησης σε συνδυασμό και με τις καμπύλες που δημιουργήθηκαν χρησιμοποιώντας μίγματα της Φάσης ΙΙΙ και της ένυδρης Φάσης, προτάθηκε μια μεθοδολογία με την οποία προσδιορίζονται τα πολύμορφα στα τελικά σκευάσματα.

A esquizofrenia é uma doença que, de acordo com a Organização Mundial de Saúde, acomete cerca de 1% da população mundial. Tendo em vista a sua alta incidência e, portanto, sua relevância, o presente trabalho objetivou estudar uma classe de compostos derivados do aripiprazol, substância ativa que estimula os receptores dopaminérgicos e serotoninérgicos, receptores esses de suma importância para o entendimento da fisiopatologia da esquizofrenia. Para isso, o estudo de QSAR foi realizado através dos métodos PLS e ANN, gerando dois modelos para tentar entender a relação entre a estrutura química e a atividade biológica. Os dois modelos gerados, PLS e ANN, foram satisfatórios, explicando 82,52% e 72,90% respectivamente, da variabilidade da atividade biológica. No entanto, como o modelo obtido através do método PLS foi considerado melhor, conclui-se que as variáveis selecionadas possuem comportamento linear frente à atividade biológica. / The Schizophrenia is a disease that affects about 1% of world population, according to the World Health Organization. Looking into its high incidence and therefore its relevance, the goal of this study was to investigate a class of compounds derived from aripiprazole, the active substance that stimulates dopamine and serotonin receptors, those essential for understanding the pathophysiology of schizophrenia. For the investigation to go on, the QSAR study was performed through PLS and ANN methods, generating two models in order to understand the relationship between chemical structure and biological activity. Both model results, PLS and ANN, were considered satisfactory, explaining 82.52% and 72.90%, respectively, of the variability of the biological activity. However, since the model obtained by the PLS method showed more satisfactory results, it can be concluded that the selected variables have a linear behavior concerning the biological activity.

The positive symptoms of schizophrenia primarily result from an excess of high affinity D2-like receptors (i.e. D2High receptors). First-generation antipsychotics, such as haloperidol, are D2-like antagonists that can cause severe extrapyramidal effects. Aripiprazole, a dopamine and serotonin partial agonist, has fewer side effects, making it tolerable for adults and children. Extrapyramidal effects (e.g. Parkinsonism, dystonia, and akathisia) are among the most problematic side effects produced by antipsychotic compounds, which likely result from an excess of D2-like receptors in the dorsal striatum. In order to examine the effects of repeated antipsychotic treatment on dopamine system functioning, this thesis compared the molecular effects of repeated haloperidol and aripiprazole administration on D2High receptors, as well as various indices of dopamine second messenger system functioning. Preadolescent and adult rats were pretreated with haloperidol or aripiprazole for 11 consecutive days. After either a 4- or 8-day drug abstinence period dorsal striatal tissue was extracted. [35S]GTPγS binding assays were conducted to assess the effects of repeated haloperidol and aripiprazole treatment on the efficacy and potency of D2-like receptors. PKA subunits and components of the Akt pathway were measured using Western Blots. Results showed that repeated treatment with haloperidol or aripiprazole did not significantly affect D2-like receptor efficacy or potency in young or adult rats. In both age groups, haloperidol significantly increased the expression of PKA-Cα, PKA-Cβ, and PKA-RII, but not p-PKA. Haloperidol also significantly increased PKA-Cβ and PKA-RII levels relative to aripiprazole. Repeated administration of haloperidol significantly increased p-GSK-3β levels in young and adult rats, but neither haloperidol nor aripiprazole significantly affected GSK-3β, Akt, or p-Akt levels. Overall, the results of this thesis indicate that repeated aripiprazole and haloperidol treatment differentially affects D2 signaling pathways in the dorsal striatum. Aripiprazole has less extreme or prolonged effects on D2 receptor signaling pathways than haloperidol, as evidenced by the lack of post-treatment upregulation in the cAMP and Akt pathways. Upregulation of D2-like receptors and, in turn, upregulation of proteins in the cAMP and Akt pathways may be partially responsible for the side effects induced by long-term antipsychotic treatment.

A esquizofrenia é uma doença que, de acordo com a Organização Mundial de Saúde, acomete cerca de 1% da população mundial. Tendo em vista a sua alta incidência e, portanto, sua relevância, o presente trabalho objetivou estudar uma classe de compostos derivados do aripiprazol, substância ativa que estimula os receptores dopaminérgicos e serotoninérgicos, receptores esses de suma importância para o entendimento da fisiopatologia da esquizofrenia. Para isso, o estudo de QSAR foi realizado através dos métodos PLS e ANN, gerando dois modelos para tentar entender a relação entre a estrutura química e a atividade biológica. Os dois modelos gerados, PLS e ANN, foram satisfatórios, explicando 82,52% e 72,90% respectivamente, da variabilidade da atividade biológica. No entanto, como o modelo obtido através do método PLS foi considerado melhor, conclui-se que as variáveis selecionadas possuem comportamento linear frente à atividade biológica. / The Schizophrenia is a disease that affects about 1% of world population, according to the World Health Organization. Looking into its high incidence and therefore its relevance, the goal of this study was to investigate a class of compounds derived from aripiprazole, the active substance that stimulates dopamine and serotonin receptors, those essential for understanding the pathophysiology of schizophrenia. For the investigation to go on, the QSAR study was performed through PLS and ANN methods, generating two models in order to understand the relationship between chemical structure and biological activity. Both model results, PLS and ANN, were considered satisfactory, explaining 82.52% and 72.90%, respectively, of the variability of the biological activity. However, since the model obtained by the PLS method showed more satisfactory results, it can be concluded that the selected variables have a linear behavior concerning the biological activity.

Bakgrund: Det har visat sig under de senaste 20 åren att användning av aripiprazol ökar risken för spel- och impulskontrollstörningar. Aripiprazol är ett första generationens antipsykotiska läkemedel och fungerar som en partiell serotonin 5-HT1A-receptoragonist, en 5-HT2A-receptorantagonist och en specifik partiell dopamin D2/D3-agonist.  Syfte: Syftet är att studera hur förekomsten av spel- och impulskontrollstörningar skiljer sig mellan neurologiska patienter som får Aripiprazol respektive andra antipsykotiska läkemedel som komplement till behandling med Parkinsons sjukdom eller Restless Legs Syndrome.  Metoder: Detta är en retrospektiv registerstudie som analyserar läkemedelsdata som täcker åren 2005 till 2022 och patientdata som innehåller diagnoser för Parkinsons sjukdom och Restless Legs Syndrome samt spel- och impulskontrollstörningar. Data analyserades genom att mäta frekvensen av recept för att analysera antalet händelser av spelstörningar, impulskontrollstörningar och kontrollgrupper hos personer med Parkinsons sjukdom och Restless Legs Syndrome.  Resultat: Det finns en tydlig skillnad mellan de antipsykotiska läkemedlen. Första och andra generationens antipsykotika, inklusive litium, olanzapin, levomepromazin och aripiprazol, har visats vara associerade med störningar i spel och impulskontroll hos patienter med Parkinsons sjukdom och Restless Legs Syndrome. Aripiprazol visade sig ha det starkaste sambandet med störningar i impulskontroll och litium hade det starkaste sambandet med spelstörningar hos personer med Restless Legs Syndrome. Dessutom hade Levomepromazin det starkaste sambandet med störningar i impulskontroll och Olanzapin hade det starkaste sambandet med spelstörningar hos personer med Parkinsons sjukdom.  Slutsatser: Denna studie har konsekvenser för framtiden då den hjälper till att veta om det finns risk för spel- och impulskontrollstörningar vid användning av antipsykotiska läkemedel. Så det hjälper till att skapa maximal säkerhet för antipsykotiska läkemedel och hantera risken för spel- och impulskontrollstörningar på bästa möjliga sätt.

Patients with schizophrenia are normally treated with one of several antipsychotic medications that differ from one another in the areas of the brain they affect including the dorsal striatum, a subcortical section of the forebrain, and the prefrontal cortex (PFC), located in the anterior part of the frontal lobes. Two different tests of implicit memory, the probabilistic classification learning (PCL) and the Iowa gambling task (IGT), have been shown to rely on the dorsal striatum and the PFC, respectively. Studies have previously shown that patients with schizophrenia treated with antipsychotics that affect the dorsal striatum (e.g., risperidone), have altered performance on the PCL, and those treated with antipsychotics that affect the PFC (e.g., clozapine), have altered performance on the IGT. We tested the hypothesis that patients with schizophrenia treated with olanzapine would have a poorer performance on the IGT, but not the PCL, when compared with controls. This study aimed to clarify conflicting results from prior experiments observing the effects of olanzapine on implicit memory in people with schizophrenia. We also hypothesized that performance of patients taking aripiprazole would be comparable to those taking risperidone, or an FGA; however, we were unable to recruit a sufficient amount of participants to test this hypothesis. Patients with schizophrenia, a mental disorder characterized by a breakdown in relation between thoughts, emotion, and behavior, treated with olanzapine were recruited through local psychiatric clinics or using a newspaper ad. Administration of the Brief Psychiatric Rating Scale (BPRS) and the Mini Mental State Examination (MMSE) preceded a brief questionnaire of demographic information. Participants were tested on the PCL and the IGT using a personal computer. Results revealed poorer performance on both the MMSE and BPRS for patients when compared with controls. Patients taking olanzapine were impaired in learning the PCL but not the IGT when compared with controls. Results suggest that olanzapine acts on the PFC to augment IGT performance but further studies are needed. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2013-07-23 15:09:21.55

Only one third of depressed patients experience a beneficial therapeutic effect after using a first-line medication, leaving two-thirds of patients without effective treatment. It has been shown that a combination of two drugs with different modes of action result in an increase in the number of patients responding to treatment. One of the most effective strategies is the addition of low doses of an atypical antipsychotic. In depth evaluation of the neurobiological properties of atypical antipsychotics have revealed that these agents produce antidepressant effects and enhance the therapeutic response of first-line medications through antagonism of the 5-HT2A, 5-HT2C, 5-HT1B/D, 5-HT7 receptors and NET; agonism of the 5-HT1A receptor; and/or D2/3 partial agonism. The present experiments focused on determining the mode of action of this combination of drugs to help design better antidepressant treatment in the future. A series of electrophysiological experiments were proposed to assess 5-HT and NE neurotransmission in the rat hippocampus, as well as DA transmission in the rat forebrain.

Introduction: major depressive disorder is a common psychiatric disorder associated with high economic cost, severe human suffering, and low remission rates. Imbalanced neurotransmission of the monoaminergic serotonin (5-HT), dopamine (DA) and norepinephrine (NE) systems is implicated in this disorder. However, the etiology underlying this presumed imbalance and the mechanism by which antidepressant strategies restore this imbalance requires further exploration. Accordingly, the present work assessed the effects of depressogenic and antidepressant-like conditions on these systems. Methodology: Electrophysiological extracellular single unit recordings from 5-HT, DA, NE, and hippocampal pyramidal neurons were obtained in adult male chloral hydrate anaesthetized Sprague-Dawley rats. Effects on relevant receptors were characterized using established electrophysiological and/or pharmacological strategies. Prenatal stress was used to model depressogenic-like conditions. The effects on monoamine systems of asenapine and brexpiprazole, two atypical antipsychotics with antidepressant potential, were characterized after acute (brexpiprazole) and sustained administration. These sustained regimens resulted in clinically relevant blood plasma levels. Results: Prenatal stress exposure altered monoamine system activities but did not produce detrimental effects on behavior. Asenapine and brexpiprazole had unique effects on the activities of monoamine systems. Unlike other antipsychotics, both agents did not produce a cessation of the firing of dopamine neurons in the ventral tegmental area, thereby providing novel insights in the role of this system in the treatment of mood disorders. Furthermore, both agents enhanced the tonic activation of postsynaptic 5-HT1A receptors, similarly to the effects of all antidepressant strategies. Conclusion: Prenatal stress altered the activities of 5-HT, NE and DA neurons. Since these central changes were obtained in animals displaying normal behavior, they presumably reflect adaptations to depressogenic-like conditions. The characterization of asenapine and brexpiprazole contributed to a further understanding of their mechanisms of action. Together, these studies provide insight in neural substrates presumably relevant to the antidepressant response.

Beaucoup de personnes consomment des drogues d’abus de façon récréative ou expérimentale dans leur vie, mais peu d’entre elles développent une toxicomanie. Nous avons exploré, chez le rat, deux facteurs impliqués dans la transition vers la toxicomanie, soit la vitesse à laquelle la drogue parvient au cerveau et le fait d’être sous traitement antipsychotique. Dans une première étude, notre objectif était de déterminer si augmenter la vitesse de livraison de la cocaïne (0.5 mg/kg) par auto-administration intraveineuse (i.v.; livrée en 5 secondes dans un groupe versus 90 secondes dans l’autre) mènerait à une plus grande consommation de celle-ci lors d’un accès prolongé (6 h/j versus 1 h/j), et à une plus grande motivation à obtenir la drogue telle que mesurée sous un ratio de renforcement progressif à une vitesse différente (10 secondes). Nous avons trouvé que le groupe 5 s consommait plus de cocaïne que le groupe 90 s en accès prolongé, mais aussi en accès limité. Cependant, la motivation des deux groupes était la même à la vitesse de 10 s, ainsi qu’à leurs vitesses initiales. Nous pensons que ceci peut être dû à une forme de plasticité du système méso-cortico-limbique survenue suite à l’auto-administration en accès prolongé en conjonction avec l’augmentation de consommation, chez les deux groupes, rendant impossible une distinction de leur motivation. Dans une deuxième série d’études nous avons émis l’hypothèse que l’antipsychotique typique, halopéridol (HAL, 0.5 mg/kg/j), et non l’atypique, aripiprazole (ARI, 1 mg/kg/j), un modulateur dopaminergique, induirait une augmentation de la poursuite de récompense conditionnée (RC) et de la locomotion (LOCO) en réponse à l’amphétamine (AMPH). Cependant, nous avons trouvé une augmentation chez le groupe HAL, mais non ARI, de la réponse RC, trois semaines, mais non une semaine post traitement, ainsi qu’une augmentation de la LOCO, chez le groupe HAL, mais non ARI, une semaine mais non trois semaines post traitement. L’incohérence des résultats entre les deux tests (RC et LOCO) rend leur interprétation difficile. Ces études restent à être explorées d’avantage afin de pouvoir en tirer des conclusions plus éclairées quant à l’impact de la vitesse d’administration de la cocaïne et du traitement antipsychotique sur le développement d’une toxicomanie. / Many people take drugs of abuse on a recreational or experimental basis in their lifetime, but few develop an addiction. We explored, in the rat, two factors involved in the transition to addiction: the speed at which the drug reaches the brain, and antipsychotic treatment. In the first study, our objective was to determine if increasing the speed of intra-venous (i.v.) delivery of cocaine (0.5 mg/kg) through i.v. self administration (delivered in 5 seconds in one group versus 90 seconds in the other) would lead to greater consumption with long access to the drug (6 hours/ day versus 1hr/day) and if the motivation to obtain the drug, as measured by a progressive ratio schedule would also be greater at a different speed (10 seconds). We have found that the 5 s group had a greater consumption than the 90 s group, in long access, but also in short access. However, the motivation of the two groups did not differ at the speed of 10 s, nor at their initial speeds. We suggest that this might be due to a form of plasticity of the mesocorticolimbic system, following the extended self-administration access, in both groups, in conjunction with the escalation in consumption, thus making it impossible to distinguish their motivation. In a second study series, we hypothesised that the typical antipsychotic, haloperidol (HAL, 0.5mg/kg/d), but not the atypical, aripiprazole (ARI, 1mg/kg/d), would increase the pursuit of conditioned reward (CR; here sound and tone) and locomotion (LOCO) in response to amphetamine (AMPH). We found an increase in the CR response, in the HAL group, but not the ARI group, three weeks, but not one week, post treatment, as well as an increase in the LOCO, in the HAL group, but not in the ARI group, one week but not three weeks post treatment. The incoherence of the results from the two tests (CR and LOCO) renders their interpretation difficult. These studies remain to be explored more thoroughly so as to obtain more enlightened conclusions as to the influence of speed of administration and antipsychotic treatment on addiction development.

Beaucoup de personnes consomment des drogues d’abus de façon récréative ou expérimentale dans leur vie, mais peu d’entre elles développent une toxicomanie. Nous avons exploré, chez le rat, deux facteurs impliqués dans la transition vers la toxicomanie, soit la vitesse à laquelle la drogue parvient au cerveau et le fait d’être sous traitement antipsychotique. Dans une première étude, notre objectif était de déterminer si augmenter la vitesse de livraison de la cocaïne (0.5 mg/kg) par auto-administration intraveineuse (i.v.; livrée en 5 secondes dans un groupe versus 90 secondes dans l’autre) mènerait à une plus grande consommation de celle-ci lors d’un accès prolongé (6 h/j versus 1 h/j), et à une plus grande motivation à obtenir la drogue telle que mesurée sous un ratio de renforcement progressif à une vitesse différente (10 secondes). Nous avons trouvé que le groupe 5 s consommait plus de cocaïne que le groupe 90 s en accès prolongé, mais aussi en accès limité. Cependant, la motivation des deux groupes était la même à la vitesse de 10 s, ainsi qu’à leurs vitesses initiales. Nous pensons que ceci peut être dû à une forme de plasticité du système méso-cortico-limbique survenue suite à l’auto-administration en accès prolongé en conjonction avec l’augmentation de consommation, chez les deux groupes, rendant impossible une distinction de leur motivation. Dans une deuxième série d’études nous avons émis l’hypothèse que l’antipsychotique typique, halopéridol (HAL, 0.5 mg/kg/j), et non l’atypique, aripiprazole (ARI, 1 mg/kg/j), un modulateur dopaminergique, induirait une augmentation de la poursuite de récompense conditionnée (RC) et de la locomotion (LOCO) en réponse à l’amphétamine (AMPH). Cependant, nous avons trouvé une augmentation chez le groupe HAL, mais non ARI, de la réponse RC, trois semaines, mais non une semaine post traitement, ainsi qu’une augmentation de la LOCO, chez le groupe HAL, mais non ARI, une semaine mais non trois semaines post traitement. L’incohérence des résultats entre les deux tests (RC et LOCO) rend leur interprétation difficile. Ces études restent à être explorées d’avantage afin de pouvoir en tirer des conclusions plus éclairées quant à l’impact de la vitesse d’administration de la cocaïne et du traitement antipsychotique sur le développement d’une toxicomanie. / Many people take drugs of abuse on a recreational or experimental basis in their lifetime, but few develop an addiction. We explored, in the rat, two factors involved in the transition to addiction: the speed at which the drug reaches the brain, and antipsychotic treatment. In the first study, our objective was to determine if increasing the speed of intra-venous (i.v.) delivery of cocaine (0.5 mg/kg) through i.v. self administration (delivered in 5 seconds in one group versus 90 seconds in the other) would lead to greater consumption with long access to the drug (6 hours/ day versus 1hr/day) and if the motivation to obtain the drug, as measured by a progressive ratio schedule would also be greater at a different speed (10 seconds). We have found that the 5 s group had a greater consumption than the 90 s group, in long access, but also in short access. However, the motivation of the two groups did not differ at the speed of 10 s, nor at their initial speeds. We suggest that this might be due to a form of plasticity of the mesocorticolimbic system, following the extended self-administration access, in both groups, in conjunction with the escalation in consumption, thus making it impossible to distinguish their motivation. In a second study series, we hypothesised that the typical antipsychotic, haloperidol (HAL, 0.5mg/kg/d), but not the atypical, aripiprazole (ARI, 1mg/kg/d), would increase the pursuit of conditioned reward (CR; here sound and tone) and locomotion (LOCO) in response to amphetamine (AMPH). We found an increase in the CR response, in the HAL group, but not the ARI group, three weeks, but not one week, post treatment, as well as an increase in the LOCO, in the HAL group, but not in the ARI group, one week but not three weeks post treatment. The incoherence of the results from the two tests (CR and LOCO) renders their interpretation difficult. These studies remain to be explored more thoroughly so as to obtain more enlightened conclusions as to the influence of speed of administration and antipsychotic treatment on addiction development.