Molecular design driving tetraporphyrin self-assembly on graphite: a joint STM, electrochemical and computational study.

Tuning the intermolecular interactions among suitably designed molecules forming highly ordered self-assembled monolayers is a viable approach to control their organization at the supramolecular level. Such a tuning is particularly important when applied to sophisticated molecules combining functional units which possess specific electronic properties, such as electron/energy transfer, in order to develop multifunctional systems. Here we have synthesized two tetraferrocene-porphyrin derivatives that by design can selectively self-assemble at the graphite/liquid interface into either face-on or edge-on monolayer-thick architectures. The former supramolecular arrangement consists of two-dimensional planar networks based on hydrogen bonding among adjacent molecules whereas the latter relies on columnar assembly generated through intermolecular van der Waals interactions. Scanning Tunneling Microscopy (STM) at the solid-liquid interface has been corroborated by cyclic voltammetry measurements and assessed by theoretical calculations to gain multiscale insight into the arrangement of the molecule with respect to the basal plane of the surface. The STM analysis allowed the visualization of these assemblies with a sub-nanometer resolution, and cyclic voltammetry measurements provided direct evidence of the interactions of porphyrin and ferrocene with the graphite surface and offered also insight into the dynamics within the face-on and edge-on assemblies. The experimental findings were supported by theoretical calculations to shed light on the electronic and other physical properties of both assemblies. The capability to engineer the functional nanopatterns through self-assembly of porphyrins containing ferrocene units is a key step toward the bottom-up construction of multifunctional molecular nanostructures and nanodevices.

Effects of harmine on dopamine output and metabolism in rat striatum: role of monoamine oxidase-A inhibition.

In vivo microdialysis was used to investigate the effects of acute injections of harmine on extracellular concentrations of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxindoleacetic acid (5-HIAA) in the striatum of awake rats. Administration of harmine in doses of 0.5, 2.5, and 10 mg/kg (i.p.) elicited a dose-dependent increase of the dopamine efflux to 152, 173, and 243% and a decrease in DOPAC to 52, 36, and 10%, and HVA to 67, 45, and 20% throughout, respectively; 5-HIAA concentrations were decreased to 81, 74, and 72% only. In contrast to D-amphetamine, which also increases dopamine release and decreases its metabolites, the stimulatory action of harmine on dopamine release in the striatum was totally abolished in the presence of tetrodotoxin (1 microM). Similar to monoamine oxidase (MAO)-A inhibitors, harmine potentiated the stimulatory effect of D-amphetamine (10 microM), infused by reverse microdialysis in the striatum, on dopamine release. Pre-treatment with the benzodiazepine receptor antagonist flumazenil (5 mg/kg, i.p.) did not modulate the effect of harmine on striatal dopamine release and metabolism. Administration of the reversible MAO-A inhibitor, moclobemide (20 mg/kg, i.p.), induced an increase in dopamine to 256% and a decrease in DOPAC, HVA, and 5-HIAA to 30, 24, and 62%, respectively, reproducing a pattern similar to that of harmine. Taken together, these results indicate that harmine affects the brain dopamine system probably by acting as a MAO-A inhibitor and not as an inverse agonist for the benzodiazepine receptors.

Risperidone: regional effects in vivo on release and metabolism of dopamine and serotonin in the rat brain.

The antipsychotic drug risperidone shows high affinity for both central serotonin (5-HT)2A and dopamine (DA)-D2 receptors in vivo. By employing microdialysis in freely moving rats, the effects of acute risperidone administration on regional brain DA and 5-HT release and metabolism were compared with the corresponding effects of the atypical antipsychotic drug clozapine as well as amperozide, the selective DA-D2 receptor antagonist raclopride and the selective 5-HT2A/5-HT2C receptor antagonist ritanserin. Risperidone (0.2 or 2.0 mg/kg, SC) was found to increase DA release and metabolism to about the same extent in three major projection areas of the mesotelencephalic dopaminergic system, i.e. the nucleus accumbens (NAC), the medial prefrontal cortex (MPC) and the lateral striatum (STR). In contrast, clozapine and amperozide (both 10.0 mg/kg, SC), as well as raclopride (2.0 mg/kg, SC), were all found differentially to affect DA release and metabolism in the three projections areas. Specifically, clozapine and amperozide enhanced DA release in the MPC to a greater extent than in the NAC or the STR, whereas raclopride instead preferentially increased DA release in the NAC and the STR but not in the MPC. Ritanserin (3.0 mg/kg, SC) did not exert any major effects on DA metabolism in the three areas studied. In contrast to the regionally rather homogenous activation of brain DA systems caused by risperidone, the drug was found to enhance brain 5-HT metabolism preferentially in the MPC, as indicated by the elevated extracellular concentration of 5-hydroxyindoleacetic acid (5-HIAA) in this region. A similar elevation of the 5-HIAA level in the MPC was observed after amperozide and, to some extent, after clozapine and ritanserin administration. The risperidone-induced (2.0 mg/kg, SC) elevation of 5-HIAA concentrations in the frontal cortex was found to be paralleled by an increased 5-HT release in this brain area. Consequently, our findings demonstrate a pharmacological profile of risperidone, as reflected in brain DA metabolism, in between that of clozapine and the DA-D2 antagonists. The preferential activation of 5-HT release and metabolism in frontal cortical areas might be of particular relevance for the ameliorating effect of risperidone on negative symptoms in schizophrenia, especially when associated with depression.

Effects of D-amphetamine and phencyclidine on behavior and extracellular concentrations of neurotensin and dopamine in the ventral striatum and the medial prefrontal cortex of the rat.

The effects of systemically administered phencyclidine (PCP; 2.5 mg/kg, s.c.) and D-amphetamine (1.5 mg/kg, s.c.) on the extracellular concentrations of neurotensin-like immunoreactivity (NT-LI) and dopamine (DA) in the ventral striatum (vSTR) and the medial prefrontal cortex (mPFC) were studied in freely moving rats using microdialysis. In separate animals, the effects of PCP and D-amphetamine on open field activity were also analyzed. PCP, but not D-amphetamine, caused a significant increase (156% over baseline) of NT-LI levels in the vSTR which was relatively short lasting, i.e., of less than 2 h duration. In contrast, both drugs significantly increased NT-LI concentrations in the mPFC by almost 100% during the same period. PCP and D-amphetamine also significantly increased extracellular levels of DA in the vSTR by 83 and 364%, respectively. However, the peak effect of PCP on DA appeared later than that of D-amphetamine, i.e., at 150 and 60 min, respectively, after drug administration. Also in the mPFC, both PCP and D-amphetamine significantly increased DA concentrations by 98 and 284%, respectively. Generally, effects on DA levels of both PCP and D-amphetamine were, in contrast to their effects on NT-LI levels, clearly more long-lasting, i.e., of 3-4 h duration. Behaviorally, D-amphetamine produced a more pronounced, general activation than PCP, with a faster onset of activation, i.e. within 30 vs 90 min after administration. However, both drugs produced long-lasting effects on the spatial organization of behavioral activity, which lasted for 3-4 h. In conclusion, the more pronounced behavioral stimulation by D-amphetamine (1.5 mg/kg, s.c.) vs PCP (2.5 mg/kg, s.c.) in the rat may largely be explained by its more potent DA-releasing effect in the brain. Initial behavioral suppression by PCP, e.g., of rearing, as well as its rather poor locomotor stimulant action in general, might relate to release of NT in the vSTR. The long-lasting, behavioral disorganization by both PCP and D-amphetamine may, however, be related to increased release of DA rather than NT in the mesolimbocortical areas.

Systemic administration of amperozide, a new atypical antipsychotic drug, preferentially increases dopamine release in the rat medial prefrontal cortex.

The putative atypical antipsychotic drug amperozide (APZ) shows high affinity for serotonin 5-HT2 receptors but only low affinity for dopamine (DA) D2 receptors. By employing microdialysis, we examined the effects of APZ on extracellular concentrations of DA in the nucleus accumbens (NAC), the dorsolateral striatum (STR) and the medial prefrontal cortex (MPC) of awake rats. A 5.0 mg/kg (SC) dose of APZ failed to affect DA concentrations in the NAC, while it increased DA outflow in the STR (by 46%) and the MPC (by 207%). A higher dose of APZ (10 mg/kg, SC) enhanced dialysate DA from the NAC and the STR by 30%, and from the MPC by 326%. Similarly, clozapine (2.5 and 10 mg/kg, SC) produced a greater release of DA in the MPC (+ 127 and + 279%) than in the NAC (+ 52 and + 98%). The selective 5-HT2 receptor antagonist ritanserin (1.5 and 3.0 mg/kg, SC) also produced a slightly higher increase of DA output in the MPC (+ 25 and + 47%) compared with the NAC (+ 19 and + 21%). In contrast, the selective D2 receptor antagonist raclopride (0.5 and 2.0 mg/kg, SC) increased DA release in the NAC (+ 65 and + 119%) to a greater extent than in the MPC (+ 45 and + 67%). These data suggest that the 5-HT2 receptor antagonistic properties of APZ and clozapine may contribute to their preferential effects on DA transmission in the MPC. Infusion of low doses (1, 10 microM, 40 min) of APZ through the probe in the DA terminal areas did not affect significantly DA outflow, while infusion of high doses (100, 1000 microM, 40 min) resulted in a more pronounced elevation of DA levels in the NAC (up to 961%) and the STR (up to 950%) than in the MPC (up to 316%). These findings indicate that the selective action of systemically administered APZ on DA in the MPC is most likely mediated at a level other than the terminal region. Taken together, the present results provide support for the notion that 5-HT2 receptor antagonism may be of considerable significance for the action of atypical antipsychotic drugs on mesolimbocortical dopaminergic neurotransmission.