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A anandamida, um dos principais endocanabinóides estudados, além de se ligar aos receptores CB1, em altas doses, também é capaz de ativar os receptores vanilóides de potencial transitório tipo-1 (TRPV1). Evidências experimentais indicam que a sinalização mediada por CB1 facilita, enquanto TRPV1 prejudica, a resposta de adaptação a situações de estresse, tornando o animal mais susceptível a suas consequências comportamentais. Estudos demonstram que a inibição da enzima amida hidrolase de ácidos graxos (FAAH), responsável pela hidrólise da anandamida, apresenta efeito tipo-antidepressivo, efeito este também observado quando administrado antagonista de TRPV1. Portanto, a ação combinada de inibição da FAAH e bloqueio de TRPV1 poderia ter potencial efeito antidepressivo. Diante destas evidências, o objetivo do presente trabalho foi investigar se a administração sistêmica de AA-5HT, droga que inibe a FAAH e bloqueia TRPV1, em camundongos submetidos ao teste do nado forçado, promove um efeito tipo-antidepressivo; e ainda, se esse comportamento estaria relacionado com a ativação de receptores canabinóides CB1 e com bloqueio dos receptores vanilóides TRPV1. Camundongos Swiss machos receberam injeção intraperitoneal de AA-5HT (0.1, 0.3, e 1 mg/kg), inibidor da FAAH (URB597 - 0.03, 0.1, 0.3, 1, e 3 mg/kg), antagonista TRPV1 (SB366791 - 0.03, 0.1, 0.3, 1 e 3 mg/kg) e antagonista CB1 (AM251 - 1 e 3 mg/kg) ou o veículo correspondente e, 30 minutos depois, os mesmos animais foram submetidos ao teste do campo aberto. Imediatamente após foram submetidos ao teste do nado forçado. O tratamento com AA-5HT na dose de 0.3mg/kg reduziu significativamente o tempo de imobilidade no teste do nado forçado, sem alterar a atividade locomotora. Por outro lado, as doses testadas de URB597, SB366791 e AM251 não reduziram significativamente o tempo de imobilidade quando comparadas ao grupo veículo. E ainda, não foi observada somação de efeito da coadministração de doses equipotentes e subefetivas de SB366791 e URB597 no teste do nado forçado. Por fim, a pré-administração do antagonista CB1 (AM251) não alterou o tempo de imobilidade de AA-5HT. Apesar disso, quando o AA-5HT foi pré-administrado com o veículo utilizado para diluir o AM251, apresentou aumento significativo no tempo de imobilidade quando comparado aos animais pré-tratados com salina, comprometendo assim a investigação sobre a participação dos receptores CB1 no efeito do AA-5HT. Sendo assim, nossos resultados sugerem que a administração sistêmica de AA-5HT produz um efeito tipo-antidepressivo no teste do nado forçado. Entretanto, mais estudos são necessários para avaliar o envolvimento dos receptores CB1 neste comportamento. / Anandamide, one of the most studied endocannabinoids, acts through interaction with CB1 cannabinoids receptors, and, in higher doses, activate TRPV1 receptor. Experimental evidence shows that CB1-mediated signaling improve, while TRPV1-signaling impairs the adaptative response to stressful situations, thus increasing the susceptibility to behavioral consequences. The administration of inhibitors of fatty acid amide hydrolase (FAAH), responsible for anandamide hydrolysis, exerts antidepressant-like effects in preclinical models. The same effect is observed when TRPV1 antagonist is administered. Therefore, the combined blockade of FAAH and TRPV1 could potentially represent an interesting pharmacological tool to induce antidepressant effects. Based on that, the aim of this study was to investigate if AA-5HT, a FAAH inhibitor and TRPV1 blocker, would induce antidepressant-like effect in mice, and to evaluate the participation of TRPV1 and CB1 receptors in this effect. Male Swiss mice received an intraperitoneal injection of AA-5HT (0.1, 0.3, e 1 mg/kg), FAAH inhibitor (URB597 - 0.03, 0.1, 0.3, 1, e 3 mg/kg), TRPV1 antagonist (SB366791 - 0.03, 0.1, 0.3, 1 e 3 mg/kg) and CB1 antagonist (AM251 - 1 e 3 mg/kg) or the corresponding vehicle and, 30 minutes later, they were individually submitted to the open field test. Immediately after this, the same animal was submitted to the forced swimming test. Our results showed that the treatment with AA-5HT at dose 0,3mg/kg significantly reduced the immobility time in the forced swim test without changing the locomotor activity. On the other hand, the tested dose range of URB597, SB366791 e AM251 did not significantly reduced the immobility time when compared to vehicle group. Furthermore, there was no observed effect of the coadministration of equipotent and sub-effective doses of SB366791 and URB597 on forced swim test. Finally, pre-administration of the CB1 antagonist (AM251) did not alter the immobility time of AA-5HT. However, when AA-5HT was pre-administered with the vehicle used to dilute AM251, it showed a significant increase in immobility time when compared to animals pretreated with saline, thus compromising the study about the participation of CB1 receptors in the effect of AA-5HT. Thus, our results suggest systemic administration of AA-5HT produces an antidepressant-like effect on FST. However, further studies are needed to evaluate the involvement of CB1 receptors in this behavior.

Exposição a estressores incontroláveis leva a mudanças comportamentais e neuroquímicas, que têm sido associadas ao mau funcionamento da via Núcleo Mediano da Rafe (NMnR) Hipocampo Dorsal (HD). Estas mudanças comportamentais podem ser atenuadas por injeções intra hipocampais de NMDA ou de agonistas 5-HT1a. Ativação de receptores NMDA (NMDAr) aumentam os níveis de serotonina tanto no NMnR quanto no HD. Neste trabalho, nosso obejtivo foi analisar, em animais expostos ao Teste do nado forçado, se a ativação ou bloqueio dos receptores NMDA antes da exposição ao agente estressor ou 24 horas após essa exposição podem prevenir ou atenuar os efeitos do estresse. Ratos Wistar machos receberam duas injeções intra-NMnR de Salina (Sal), NMDA (1nmoles/0,2µL; agonista NMDAr) e/ou AP-7 (3nmoles/0,2µL; antagonista NMDAr) compondo os grupos experimentais: Sal+Sal, Sal+NMDA, AP-7+Sal, AP-7+NMDA. As drogas foram administradas em dois grupos experimentais, antes da pré-exposição ao nado forçado ou 24 horas após a pré-exposição e antes do teste. Foram analisados o tempo de latência para o primeiro episódio de imobilidade e o tempo total de imobilidade. A análise dos resultados mostrou que a administração de AP-7 antes da pré-exposição ou antes do teste e a administração de NMDA antes do teste, atenuaram os efeitos comportamentais causados pelo estresse, mostrando o envolvimento desses receptores nos mecanismos de adaptação a eventos aversivo e também que o momento no qual ocorre a intervenção farmacológica influencia essa adaptação. / Exposure to uncontrollable stressors leads to behavioral and neurochemical changes, which has been associated to mal functioning of the Median Raphe Nucleus (MnRN)-Dorsal Hippocampus (DH) serotoninergic pathway. These deficits can be attenuated by intra-hippocampal injections of NMDA antagonists or 5-HT1a agonists. Activation of MnRN glutamatergic NMDA receptors (NMDAr) increases serotonin release in both MnRN and DH. We previously showed that MnRN injections of NMDA (NMDAr agonist) and/or AP7 (NMDAr antagonist) after pre-test attenuated total time spent immobile in the forced swim test (FST). In this study we used the forced swim test to investigated whether activation and/or blockade of MnRN NMDAr before exposure to swim stress or 24 hours after the exposure, could prevent the effects of this stressor. Rats with cannulas aimed to the MnRN received two intracerebral injections (0.2µl each) of Saline (Sal), AP7 (3nmols) and/or NMDA (1nmol)(5 min interval), administered as follows: Sal+Sal, Sal+NMDA, AP7+Sal and AP7+NMDA. The animals were forced to swim for 15 min and 24 hrs later rats were re-exposed to FST One group received the treatment before exposure to stress and another group received it 24 hrs later, right before the test. Latency to display immobility and total time spent immobile were registered. After test, all animals were sacrificed under deep anesthesia, perfused and had their brains removed for histological analysis to confirm site of injection. Only animals who had their sites of injection confirmed were used in the analysis (ONEWAY ANOVA/Tukey test). Our data suggest that blockade of glutamatergic neurotransmission in the MnRN before exposure and 24 hrs later, and activation of this transmission 24 hrs later to stress prevents the behavioral consequences of forced swim stress.

Voluntary wheel running is rewarding and believed to activate the same brain reward system as in alcohol and drug addiction. Brain-derived neurotrophic factor (BDNF), a well-known growth factor widely expressed in the brain, is modulated by both voluntary exercise and alcohol consumption. The aim of this study was to evaluate how voluntary exercise affects the expression levels of BDNF and its receptor TrkB in brain regions involved in positive and negative reinforcement. Additionally we wanted to evaluate the effect it may have on alcohol drinking behaviors in C57BL/6 mice, a mouse model which are naturally prone for engaging in voluntary exercise and voluntary alcohol consumption. We found a small upregulation in DG and CA1 after three weeks of exercise, confirming findings by others, and a significant 3-fold downregulation of BDNF in NAc after both three weeks of exercise and exercise followed by a five week period of either ethanol intake or not. Interestingly, we here show a significant 100-fold increase in BDNF after exercise and a 120-fold increase after both exercise and alcohol consumption in amygdala, a region involved in regulation of anxiety-related behavior and negative reinforcement. Additionally a slightly lower 10-fold increase in BDNF was seen after exercise and a 15-fold increase after exercise followed by ethanol in prefrontal cortex, a structure contributing to reward-related behavior. Behaviorally, we could not either directly following exercise or at five weeks post-exercise detect any significant effect of wheel-running on depression-related behavior. However, we did find that exercise significantly increased the alcohol intake.

Exposição a estressores incontroláveis leva a mudanças comportamentais e neuroquímicas, que têm sido associadas ao mau funcionamento da via Núcleo Mediano da Rafe (NMnR) Hipocampo Dorsal (HD). Estas mudanças comportamentais podem ser atenuadas por injeções intra hipocampais de NMDA ou de agonistas 5-HT1a. Ativação de receptores NMDA (NMDAr) aumentam os níveis de serotonina tanto no NMnR quanto no HD. Neste trabalho, nosso obejtivo foi analisar, em animais expostos ao Teste do nado forçado, se a ativação ou bloqueio dos receptores NMDA antes da exposição ao agente estressor ou 24 horas após essa exposição podem prevenir ou atenuar os efeitos do estresse. Ratos Wistar machos receberam duas injeções intra-NMnR de Salina (Sal), NMDA (1nmoles/0,2µL; agonista NMDAr) e/ou AP-7 (3nmoles/0,2µL; antagonista NMDAr) compondo os grupos experimentais: Sal+Sal, Sal+NMDA, AP-7+Sal, AP-7+NMDA. As drogas foram administradas em dois grupos experimentais, antes da pré-exposição ao nado forçado ou 24 horas após a pré-exposição e antes do teste. Foram analisados o tempo de latência para o primeiro episódio de imobilidade e o tempo total de imobilidade. A análise dos resultados mostrou que a administração de AP-7 antes da pré-exposição ou antes do teste e a administração de NMDA antes do teste, atenuaram os efeitos comportamentais causados pelo estresse, mostrando o envolvimento desses receptores nos mecanismos de adaptação a eventos aversivo e também que o momento no qual ocorre a intervenção farmacológica influencia essa adaptação. / Exposure to uncontrollable stressors leads to behavioral and neurochemical changes, which has been associated to mal functioning of the Median Raphe Nucleus (MnRN)-Dorsal Hippocampus (DH) serotoninergic pathway. These deficits can be attenuated by intra-hippocampal injections of NMDA antagonists or 5-HT1a agonists. Activation of MnRN glutamatergic NMDA receptors (NMDAr) increases serotonin release in both MnRN and DH. We previously showed that MnRN injections of NMDA (NMDAr agonist) and/or AP7 (NMDAr antagonist) after pre-test attenuated total time spent immobile in the forced swim test (FST). In this study we used the forced swim test to investigated whether activation and/or blockade of MnRN NMDAr before exposure to swim stress or 24 hours after the exposure, could prevent the effects of this stressor. Rats with cannulas aimed to the MnRN received two intracerebral injections (0.2µl each) of Saline (Sal), AP7 (3nmols) and/or NMDA (1nmol)(5 min interval), administered as follows: Sal+Sal, Sal+NMDA, AP7+Sal and AP7+NMDA. The animals were forced to swim for 15 min and 24 hrs later rats were re-exposed to FST One group received the treatment before exposure to stress and another group received it 24 hrs later, right before the test. Latency to display immobility and total time spent immobile were registered. After test, all animals were sacrificed under deep anesthesia, perfused and had their brains removed for histological analysis to confirm site of injection. Only animals who had their sites of injection confirmed were used in the analysis (ONEWAY ANOVA/Tukey test). Our data suggest that blockade of glutamatergic neurotransmission in the MnRN before exposure and 24 hrs later, and activation of this transmission 24 hrs later to stress prevents the behavioral consequences of forced swim stress.

Master of Science / Department of Psychological Sciences / Mary Cain / Individuals suffering from depression primarily rely on pharmacological interventions to alleviate the incapacitating symptoms of the disorder. In addition to genetic differences underlying the etiology of depression, environmental factors play a key role as well. For example, environmental enrichment results in various neurotransmitter alterations, significantly affecting serotonin. To test the efficacy of novel antidepressant drugs in the preclinical laboratory setting, researchers commonly implement the forced swim test (FST) for rats or mice. However, the effect of environmental enrichment on the expression of depressive-like states in the FST is unclear, and it is unknown whether environmental enrichment or social isolation can alter the efficacy of the commonly prescribed antidepressant drug, fluoxetine. In the present study, locomotor activity and FST performance were measured after 30 days of rearing in enriched (EC), standard (SC), and isolated (IC) conditions. Results showed that regardless of the significant effect of fluoxetine on locomotor activity in EC, SC, and IC rats, fluoxetine failed to increase swimming and decrease immobility in all three environmental conditions, with enriched-fluoxetine rats displaying significantly less swimming behavior in the FST than enriched rats receiving vehicle control injections. These results suggest that differential rearing, specifically environmental enrichment, can alter the efficacy of antidepressants and may suggest that enrichment reverses the effects of fluoxetine.

Acredita-se que quantidades elevadas de glutamato estejam relacionadas à neurobiologia da depressão e trabalhos recentes indicam que a quantidade de glutamato cortical está aumentada em pacientes depressivos quando comparada a indivíduos sadios. Dentre as estruturas corticais, o córtex pré-frontal medial ventral (CPFMv), dividido em infralímbico (IL) e pré-límbico (PL), tem sido mais frequentemente implicado no desenvolvimento de transtornos mentais, como a depressão. Considerando evidências de que o IL e o PL podem agir de forma diferente quanto ao controle emocional em resposta ao estresse, o presente trabalho visou avaliar a hipótese de participação da neurotransmissão glutamatérgica do CPFMv, IL e PL, no desenvolvimento das respostas comportamentais ao estresse de nado forçado, um modelo preditivo de efeitos antidepressivos. Para tal, investigamos os efeitos induzidos pela administração no IL ou no PL, de LY 235959, um antagonista dos receptores glutamatérgicos do tipo NMDA, em três momentos diferentes, em animais submetidos ao teste do nado forçado. A administração de LY 235959, no IL ou PL, produziu efeitos do tipo antidepressivo, sendo esse efeito sensível ao tempo de administração da droga em relação à exposição ao nado forçado. Sendo assim, foi observado efeito antidepressivo quando o bloqueio glutamatérgico no PL ocorreu imediatamente após o nado ou antes da re-exposição ao estresse; enquanto no IL, o tratamento promoveu efeito antidepressivo apenas quando administrado antes da re-exposição ao nado. Portanto, os resultados sugerem que a neurotransmissão glutamatérgica mediada por receptores NMDA no CPFMv contribui para o desenvolvimento de consequências comportamentais do estresse, de modo que o bloqueio desses receptores facilitaria a adaptação ao estresse e induziria efeitos do tipo-antidepressivo. Os resultados sugerem, ainda, que o PL e o IL participam de maneira semelhante na modulação desses processos. / It is believed that high amounts of glutamate are related to the neurobiology of depression. Recent studies indicate that the amount of cortical glutamate is increased in depressed patients compared to healthy subjects. Among the cortical structures, the ventral medial prefrontal cortex (CPFMv), divided into infralimbic (IL) and prelimbic (PL) has been most often implicated in the development of mental disorders, such as depression. Considering that IL and PL play different roles on the emotional control in response to stress, this study was aimed to evaluate the hypothesis that the activation of glutamate NMDA receptors within the CPFMv, IL and PL, would facilitate the development of forced swimming-induced behavioral responses, an animal model predictive of antidepressants effects. To this end, we investigated the effects induced by the administration in the PL or the IL of LY 235959, an antagonist of NMDA receptors, at three different times, in animals submitted to the forced swimming test. The administration of LY 235959, in the IL or PL, produced antidepressant-like effects, and this effect is sensitive to moment of drug administration in relation to exposure to forced swimming. Thus, the antidepressant-like effect was observed when blocking the NMDA blockade into the PL occurred immediately after swimming or before re-exposure to stress, whereas in the IL, such treatment promoted antidepressant-like effect only when administered before re-exposure to swimming. Therefore, the results suggest that the glutamatergic neurotransmission mediated by NMDA receptors in the CPFMv contributes to the development of behavioral consequences of stress, so that blocking these receptors would facilitate the adaptation to stress and induce antidepressant-like effects. The results also suggest that PL and IL may be similarly involved in modulating these processes.

Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2007.

Sildenafil, a selective phosphodiesterase type 5 (PDE5) inhibitor, is registered for the treatment of male erectile dysfunction (Viagra®) and pulmonary hypertension (Revatio®) in the United States. PDE5 is found in the endothelium of blood vessels in the penile corpus cavernosum, pulmonary vessels and also brain and other peripheral tissue. Sildenafil crosses the blood brain barrier, leading to side-effects such as headache and dizziness, as well as behavioural manifestations including depression, anxiety and aggression (Milman & Arnold, 2002). According to the Food and Drug Administration (2001), 12378 adverse events were reported after the use of sildenafil and 274 of these reports implicated sildenafil in neurologic, emotional, or psychological disturbances between January 1998 and 21 February 2001. In addition, in vivo studies in rats indicate that sildenafil has anxiogenic and stressogenic actions (Harvey et al., 2005; Volke et al., 2003). This is a clear indication that sildenafil influences neurological processes in the brain and may influence various signalling systems, which play major roles in the neural circuitry of the above-mentioned disturbances. Recent in vitro studies in our laboratory suggest that sildenafil may potentiate cholinergic muscarinic receptor signalling (Eager, 2004). These results suggest potential depressogenic actions, since an increase in acetylcholine is associated with depression-like symptoms (El- Yousef et al., 1973). It was therefore postulated that sildenafil may in fact possess antidepressant activity that is masked by a cholinergic-driven depressogenic activity. In a study conducted by Muller and Benkert in 2000, patients reported a decrease in depression-like symptoms when treated with sildenafil for erectile dysfunction. This implied that sildenafil not only had a direct effect on erectile function in about 50-80% of men with erectile dysfunction (Langtry and Markham, 1999; Padma-Nathan, 1999) but might also improve anhedonia and depression. The substantial correlation between the International Index of Erectile Function and Epidemiologic Studies-Depression Scale scores supported this assumption (Muller & Benkert, 2000). In addition, Raffaele et al. (2002) reported an indirect improvement in depressive-like symptoms in patients treated for erectile dysfunction with idiopathic Parkinson's disease. Aims: The current study investigated the behavioural and neuroreceptor properties of sildenafil in a rat model of depression. We also investigated a hypothesis that sildenafil displays antidepressant-like properties, but which are masked by its potentiation of the cholinergic system. Methods: The experimental layout was divided into three pilot studies. Pilot Study 1 validated the FST under our laboratory conditions, Sprague-Dawley rats received saline intraperitoneally (i.p.) for 7 days, whereafter half of the rats were pre-exposed to a 15 minute swim trial, while the remaining rats were not pre-exposed. All rats were then evaluated 24 hours later in the 5 minute scored swim trial. In Pilot Study 2 Sprague-Dawley rats were treated for 3, 7 or 11 days with vehicle (control) or 20 mg/kg fluoxetine to establish the time-dependency of the onset of antidepressant-like effects in a rat model of depression. We measured immobility in the rat forced swim test (FST), as well as changes in P-adrenergic receptor (P-AR) concentration in rat frontal cortex. In pilot study 3, rats were treated for 7 days with vehicle (control), 20 mg/kg fluoxetine, 10 mg/kg sildenafil, 1 mg/kg atropine or various combinations of these drugs. Again we employed the FST and measured cortical p-AR concentration. Results: In the FST pre-exposure to a 15 minute swim trial 24 hours before the scored swim trial significantly increased immobility. Fluoxetine inhibited this development of increased immobility in FST and decreased P-AR concentration after 7 and 11 days of treatment with fluoxetine, but not after 3 days. Seven days of treatment with atropine and sildenafil alone did not exert any changes in immobility in the FST or changes in p-AR concentration. However, a combination of atropine and sildenafil exerted a significant antidepressant-like behavioural effect, comparable with fluoxetine. Moreover, the combination of atropine and fluoxetine as well as the a triple combination of fluoxetine, sildenafil and atropine was superior to fluoxetine alone. Conclusion: Muscarinic cholinergic mechanisms mask the antidepressant-like properties of sildenafil in a rat model of depression. The antidepressant properties of the combination of sildenafil and atropine are comparable to that of fluoxetine in an animal model of depression. The combination of fluoxetine with atropine, and atropine and sildenafil enhances the antidepressant-like properties of fluoxetine. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2007.

Sildenafil, a selective phosphodiesterase type 5 (PDE5) inhibitor, is registered for the treatment of male erectile dysfunction (Viagra®) and pulmonary hypertension (Revatio®) in the United States. PDE5 is found in the endothelium of blood vessels in the penile corpus cavernosum, pulmonary vessels and also brain and other peripheral tissue. Sildenafil crosses the blood brain barrier, leading to side-effects such as headache and dizziness, as well as behavioural manifestations including depression, anxiety and aggression (Milman & Arnold, 2002). According to the Food and Drug Administration (2001), 12378 adverse events were reported after the use of sildenafil and 274 of these reports implicated sildenafil in neurologic, emotional, or psychological disturbances between January 1998 and 21 February 2001. In addition, in vivo studies in rats indicate that sildenafil has anxiogenic and stressogenic actions (Harvey et al., 2005; Volke et al., 2003). This is a clear indication that sildenafil influences neurological processes in the brain and may influence various signalling systems, which play major roles in the neural circuitry of the above-mentioned disturbances. Recent in vitro studies in our laboratory suggest that sildenafil may potentiate cholinergic muscarinic receptor signalling (Eager, 2004). These results suggest potential depressogenic actions, since an increase in acetylcholine is associated with depression-like symptoms (El- Yousef et al., 1973). It was therefore postulated that sildenafil may in fact possess antidepressant activity that is masked by a cholinergic-driven depressogenic activity. In a study conducted by Muller and Benkert in 2000, patients reported a decrease in depression-like symptoms when treated with sildenafil for erectile dysfunction. This implied that sildenafil not only had a direct effect on erectile function in about 50-80% of men with erectile dysfunction (Langtry and Markham, 1999; Padma-Nathan, 1999) but might also improve anhedonia and depression. The substantial correlation between the International Index of Erectile Function and Epidemiologic Studies-Depression Scale scores supported this assumption (Muller & Benkert, 2000). In addition, Raffaele et al. (2002) reported an indirect improvement in depressive-like symptoms in patients treated for erectile dysfunction with idiopathic Parkinson's disease. Aims: The current study investigated the behavioural and neuroreceptor properties of sildenafil in a rat model of depression. We also investigated a hypothesis that sildenafil displays antidepressant-like properties, but which are masked by its potentiation of the cholinergic system. Methods: The experimental layout was divided into three pilot studies. Pilot Study 1 validated the FST under our laboratory conditions, Sprague-Dawley rats received saline intraperitoneally (i.p.) for 7 days, whereafter half of the rats were pre-exposed to a 15 minute swim trial, while the remaining rats were not pre-exposed. All rats were then evaluated 24 hours later in the 5 minute scored swim trial. In Pilot Study 2 Sprague-Dawley rats were treated for 3, 7 or 11 days with vehicle (control) or 20 mg/kg fluoxetine to establish the time-dependency of the onset of antidepressant-like effects in a rat model of depression. We measured immobility in the rat forced swim test (FST), as well as changes in P-adrenergic receptor (P-AR) concentration in rat frontal cortex. In pilot study 3, rats were treated for 7 days with vehicle (control), 20 mg/kg fluoxetine, 10 mg/kg sildenafil, 1 mg/kg atropine or various combinations of these drugs. Again we employed the FST and measured cortical p-AR concentration. Results: In the FST pre-exposure to a 15 minute swim trial 24 hours before the scored swim trial significantly increased immobility. Fluoxetine inhibited this development of increased immobility in FST and decreased P-AR concentration after 7 and 11 days of treatment with fluoxetine, but not after 3 days. Seven days of treatment with atropine and sildenafil alone did not exert any changes in immobility in the FST or changes in p-AR concentration. However, a combination of atropine and sildenafil exerted a significant antidepressant-like behavioural effect, comparable with fluoxetine. Moreover, the combination of atropine and fluoxetine as well as the a triple combination of fluoxetine, sildenafil and atropine was superior to fluoxetine alone. Conclusion: Muscarinic cholinergic mechanisms mask the antidepressant-like properties of sildenafil in a rat model of depression. The antidepressant properties of the combination of sildenafil and atropine are comparable to that of fluoxetine in an animal model of depression. The combination of fluoxetine with atropine, and atropine and sildenafil enhances the antidepressant-like properties of fluoxetine. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2007.