Neurochemical and behavioural correlates of glutamate and dopamine interaction in the rat nucleus accumbens

The present thesis examined whether activation of the ventral subiculum/cornu ammonis subregion 1 (vSub/CAl) area of the hippocampus by electrical stimulation can modulate the release of dopamine (DA) in the nucleus accumbens (NAc) and elicit locomotor behavior or drug seeking/taking behavior. The first series of experiments employed in vivo microdialysis technique with unanaesthetized rats, and confirmed that electrical stimulation of the vSub/CAl of the ventral hippocampus significantly increased extracellular DA efflux in the NAc and showed it was accompanied by an increase in locomotor activity. Pharmacological experiments revealed that the vSub/CAl-induced DA efflux in the NAc was mediated by ionotropic glutamate receptors (iGluRs) but not metabotropic glutamate receptors (mGluRs) group 1/2 in the NAc, whereas vSub/CAl-induced hyperlocomotion was mediated by glutamate receptors (GluRs) subtypes a-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate (AMPA/KA) and DA D1 receptors. The second series of experiments investigated other neural pathways that may contribute to vSub/CAl-induced DA efflux in the NAc. Transient blockade of neuronal activity in the ventral tegmental area (VTA) and the medial prefrontal cortex (mPFC) by lidocaine attenuated the evoked-DA release induced by vSub/CAl stimulation. Separate experiments found that GluRs in the VTA but not in the mPFC partially mediated these effects. Together, these findings suggest that vSub/CAl-induced DA efflux in the NAc may involve at least three possible neural pathways: a) presynaptic modulation of DA varicosities within the NAc; b) activation of PFC neurons; and c) GABAergic mechanisms in the NAc via the VP. The third series of experiments monitored dynamic changes in DA and DA metabolite efflux in the NAc during a continuous access-abstinence-relapse cycle of dextro-amphetamine (d-AMPH) self-administration in a 48 hr test session. These experiments confirmed previous reports that d-AMPH self-administration is associated with a significant increase in extracellular DA efflux in the NAc and that during abstinence, extracellular DA efflux in the NAc was decreased to values close to pre-drug baseline values. Electrical stimulation of the vSub/CAl, but not of the cortex, reinstated d-AMPH self-administration during abstinence and following extinction of drug-taking behavior. Electrical stimulation of the vSub/CAl again induced a significant increase in extracellular DA efflux in the NAc that coincided with reinstatement of d-AMPH-seeking behavior in rats. Pharmacological experiments revealed that reinstatement of drug-seeking behavior induced by vSub/CAl stimulation was blocked by either DA D1 or D2 receptor antagonists or the mixture of N-methyl-D-aspartate (NMDA) and DA D1 receptor antagonists. Taken together, the present findings provide further understanding of the neural circuits and specific GluRs and DA receptors responsible for vSub/CAl -induced DA efflux in the NAc, and behavioral activation. A possible role for the ventral hippocampus in facilitating relapse to drug seeking/taking behavior was also supported by experiments in this thesis.Medicine, Faculty ofGraduat

Changes in extracellular dopamine levels in the nucleus accumbens induced by low frequency stimulation of the ventral subiculum/CA1 region of the hippocampus

The present study utilized microdialysis in freely-moving rats to investigate 1) changes in extracellular dopamine (DA) level in the nucleus accumben (NAc) induced by electrical stimulation of the ventral subiculum/CAl (Vsub/CAl) area of hippocampus, and 2) the role of metabotropic glutamate receptors (mGluRs) in mediating DA release in the NAc induced by low frequency stimulation of Vsub/CAl. It has been shown that electrical stimulation of Vsub/CAl at 2 Hz for 100 secinduces a significant decrease (p < 0.05) in basal DA levels in the NAc which is long lasting throughout the 2 hr monitoring period. Reverse dialysis of the specific antagonist at mGluRl/2, (+)-α-methyl-4-carboxyphenylglycine (MCPG), at doses 10 μM and 100 μM, did not prevent the suppressive effects on DA levels induced by low frequency stimulation of Vsub/CAl. However, reverse dialysis with the group 2 and 3 mGluR antagonist, (+)-α-methyl-4-phosphonophenylglycine (MPPG), at dose of 100 μM and 1mM, significantly blocked the prolonged suppressive effects of 2 Hz Vsub/CAl stimulation on DA efflux. These results suggest that presynaptic group 2 and 3 mGluRs are likely to be involved in a mechanism underlying the late phase of synaptic transmission at glutamatergic-dopaminergic synapses in the NAc. However, the question which specific mGluR subtypes are responsible for these initial and long lasting suppressive mechanisms will require further research.Medicine, Faculty ofGraduat

Effects of Cultured Cordycep militaris on Sexual Performance and Erectile Function in Streptozotocin-Induced Diabetic Male Rats

Cordyceps militaris (CM), a valuable edible and medicinal fungus, has been used as traditional medicine to treat health conditions, as well as hyposexuality in Asian societies for over a century. Due to the high demand, several artificial cultivation methods have been developed for their biological activities. In this study, CM was cultured on medium that contained white rice and silkworm pupae, and the levels of cordycepin and adenosine, as well as its aphrodisiac effects in diabetes-induced erectile dysfunction (DIED), were evaluated. Diabetic rats were induced by streptozotocin (STZ) injection and administered orally with CM (0.1, 0.5, and 1.0 g/kg BW/day) for 3 weeks. Diabetic rats in negative and positive control groups received vehicle and sildenafil citrate (5 mg/kg), respectively. Results showed the changes in mating behaviour in which mount latency and intromission latency were significantly increased in diabetic rats, compared with the normal control group. Diabetic rats also showed a significant reduction in intracavernosal pressure (ICP) response to cavernous nerve stimulation, sperm count, testosterone level, penile nitric oxide synthase (NOS), and testicular superoxide dismutase (SOD) activities, when compared to the normal control group. Administration of CM (0.1, 0.5, and 1.0 g/kg BW/day) reversed the effects of diabetes on the mating behaviour, and the ICP responses to electrical stimulation. Moreover, the levels of penile NOS, testicular SOD activities, testosterone, and sperm count were significantly increased, and testicular malondialdehyde (MDA) levels were significantly decreased in these treated diabetic rats. Diabetic rats treated with sildenafil showed a significant induction in intromission frequency and NOS and SOD activities, as well as a marked increase in ICP responses. These results suggest that CCM exerts its aphrodisiac effect, possibly through activating testosterone production and suppressing oxidative stress to enhance erectile function in diabetic rats

Aphrodisiac Activity of Eulophia macrobulbon Extract on Erectile Dysfunction in Male Aged Rats

This study investigated the effect of Eulophia macrobulbon (EM) extract on sexual performance in aged-related erectile dysfunction (ED) rats. The ethanol EM extract at the doses of 15, 150, and 450 and sildenafil citrate at the dose of 5 mg/kg body weight (BW) were administered orally to the aged male rats once daily for 21 days. Mating parameters and intracavernosal pressure (ICP) were measured to evaluate their sexual and erection functions. Numbers of sperm and sperm motility as well as the diameter of seminiferous tubules were observed. The serum testosterone and 3’,5’-cyclic guanosine monophosphate (cGMP) concentration in the rat penile tissue were analyzed. The results showed the significant increased sexual motivation, copulatory performance, and ICP of aged rats treated with sildenafil citrate and all doses of EM extract as compared to control aged rats. Moreover, their serum testosterone levels were slightly increased and significant increase in penile cGMP concentration was observed in these aged rats treated with sildenafil citrate and EM extract. The results suggest that treatment with EM could inhibit activity of PDE5 in penile tissue resulting in the increased cGMP level and bring to the improvement of erectile function and sexual performance