RELACIÓN ENTRE PARÁMETROS Y COMENTARIOS FINALES

BDNF f

Figure 1.11 (Adapted from Skolnick, 1999)

The relationship between increased BDNF levels and alterations in NMDA functioning has been explored by a series of pivotal experiments performed by Brandoli et al (1998). They have shown that chronic, but not acute, infusion of BDNF into the rat brain

reduces the expression of NMDA receptor protein, to an extent comparable to that seen after chronic imipramine treatment (Brandoli et al, 1998). Thus, in addition to its neurotrophic effect, BDNF is able to dampen NMDA receptor mediated transmission. This is confirmed by the observation that chronic BDNF attenuates the intracellular Ca^^ response to NMDA treatment (Brandoli et ah, 1998) an effect that is readily demonstrated by treatment with an NMDA antagonist.

The aforementioned observations support the hypothesis that the alterations in NMDA functioning, which occur after chronic antidepressant treatment, are elicited by the primary rise in synaptic concentrations o f monoamines. In addition they form a plausible explanation for the molecular mechanisms underlying this adaptation. Altogether, it is evident that future research will provide tools to develop new treatment strategies aimed at intervention beyond the monoaminergic systems, thereby reducing side effects and therapeutic lag as well as increasing the efficacy o f treatment.

1.15 Principle drugs used in this study: Mechanisms of action

1.15.1 Paroxetine

Paroxetine (commercially known as Seroxat®, Paxil®), a phenyl-piperidine derivative (Figure 1.12), belongs to the AD class of SSRIs and it has been successfully used in the treatment of depression for over a decade. Paroxetine proves to be an effective treatment for anxiety disorders [eg. panic disorder, obsessive compulsive disorder (OCD), etc.]. However this property is not unique for paroxetine but is a general feature o f SSRIs. Paroxetine is a more potent inhibitor of 5-HT reuptake in vitro than most SSRIs, having a K] of 1.1, 350 and 2000 nM for the serotonin, noradrenaline and dopamine transporters, respectively (Thomas et al., 1987). In contrast to the TCAs, paroxetine displays low affinity for monoamine and histamine H] receptors (Thomas et al, 1987; Gunasekara et al, 1998). However, the relative affinity for the cholinergic muscarinic receptor is greater than other SSRIs. The relative low affinity of paroxetine for neurotransmitter receptors is believed to account for the superior side- effect profile compared to TCAs and MAOIs.

Numerous clinical trials have compared paroxetine with other antidepressants from different classes (reviewed by Gunasekara et al, 1998, Fujishiro et al, 2002). Paroxetine was found to be superior to fluoxetine on measures o f agitation and psychic anxiety after only one week of treatment (Chouinard et al, 1999). The antidepressant potency of paroxetine is equivalent to that of TCAs and other SSRIs (Gunasekara et al, 1998; Feighner et a l , 1993). The most common adverse effects occurring during treatment are nausea, headache, somnolence and anticholinergic effects such as dry mouth and constipation. However, most of the adverse effects associated with paroxetine tend to be mild and transient and it is generally well tolerated by elderly patients (Gunasekara et

al, 1998). Having a long half-life o f approximately 24 hours in human, with no active metabolites, paroxetine is well suited for a once daily treatment regime of 40 mg/day.

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1.15.2 Clomipramine

Clomipramine (Figure 1.13) is a tricyclic antidepressant that inhibits NA and 5-HT re­ uptake and causes p, Œ] and 5-HT2 receptor downregulation. After oral administration,

it is absorbed in 2-3 hours, undergoes hepatic metabolisation to demethylclomipramine (Fujita et al, 1991), which is pharmacologically active with a higher affinity for the NA transporter than the parent drug (Benfield et al, 1980). Its plasma half life is about 20-50 hours and it is excreted in the urine and faeces. The most important side effects are postural hypotension, anticholinergic effects, weight gain, sedation and cardiotoxic effects (Gareri et al, 2000).

1.16 Aims of this study

The psychopathology and treatment of depression is outlined in the introduction above along with evidence supporting a crucial role for the NMDA receptor in this disorder. Whatever AD is used to treat clinical depression, there is in general a 3-week delay or

‘therapeutic lag’ before a clear therapeutic effect is obtained.

Information on the effects o f chronic ADs on NMDA receptors stems from the work of Skolnick and Colleagues (1994) using radioligand binding assays. This group observed that chronic, but not acute treatment with a range o f antidepressants including SSRIs decreases the binding affinity o f NMDA receptors (Paul et al, 1994). The purpose of this present study was to investigate the effects of acute, subchronic (7 days) and chronic (21 days) paroxetine or clomipramine treatment on NMDA-evoked DA and 5-HT efflux in the frontal cortex and their respective metabolites, DO?AC and 5-HIAA using in vivo microdialysis. This was prompted by the work o f Paul and colleagues (1994) who report that AD-induced properties o f the NMDA receptor complex require 7 to 14 days o f treatment and persist for 5 to 10 days after the cessation o f treatment. The effects on AD cessation on NMDA-evoked monoamine changes were also investigated.

As it has been suggested that chronic AD treatments can affect NMDA receptor ftmction in the brain, this study was aimed to answer the following questions:

• Do ADs of different classes e.g. SSRI and TCA, have similar effects on extracellular DA/5-HT efflux in the frontal cortex when given acutely, subchronically and chronically? (Chapter 3 and 4)

• What are the effects o f acute, subchronic (7-days) and chronic (21-days) treatment on local NMDA-evoked monoamine efflux in the frontal cortex? (Chapter 3 and 4) • Are these changes reversed following AD cessation? (Chapter 3 and 4)

• What are the effects of polypharmacy studies involving the administration of NMDA antagonists as adjuncts to paroxetine? (Chapter 5)

Chapter 2