A change in NMDA receptor subunit composition?

The potential role of NMDA receptors in AD treatment was first proposed by Trullas and Skolnick (1990) who observed that antagonists o f NMDA receptor function exerted an AD like action in the forced swim test. Subsequently, a number of compounds, acting at different sites on the NMDA receptor complex, have shown AD- like activity (Maj et al, 1992ab; Layer et al, 1995). Papp and Moryl (1993, 1994) found that chronic treatment with both competitive and non-competitive antagonists to be as effective as imipramine in a rodent behavioural model o f depression. In mice it has been shown that chronic antidepressant treatment leads to a decrease in the affinity of (^H)- 5, 7- dichlorokinurenic acid for the NMDA receptor complex associated glycine site in the frontal cortex (Paul et al, 1994), which could lead to a decrease in excitatory transmission via NMDA receptors in vivo. This chronic AD-induced adaptive change in the ligand binding properties of the NMDA receptor complex persist for 5-10 days after the cessation of treatment (Paul et al, 1994) and this may explain why after a 14 day

drug holiday the effects of chronic paroxetine/clomipramine treatment on 5-HT efflux in the frontal cortex were diminished when the NMDA receptor was stimulated.

The effect of ADs on the NMDA receptor complex are regionally specific, as imipramine’s action on NMDA receptors only manifests in membranes prepared from cortex and not hippocampus or striatum (Nowak et al, 1993). A study by Porter and Greenamyre (1995) used quantitative autoradiography to study the regional binding characteristics of a number of NMDA receptor antagonists including amantadine and MK-801. These authors reported regional variations in the pharmacology o f NMDA receptor channel blockers, suggesting that the pharmacological properties of NMDA receptors are region-specific.

More recently, Boyer et al (1998) reported more widespread decreases in NMDA subunit mRNA throughout the rat brain following AD treatment (imipramine and citalopram). To date, this study is the only o f its kind which determines the effects of chronic AD treatment on the expression of NMDA receptor subunit mRNA in the rat brain. Both the drugs used in the study were observed to have altered the levels of mRNA encoding the Ç subunit in several brain regions including the cortex, thalamus, striatum and the cerebellum while having no significant effect in the hippocampus. The mouse Ç subunit is thought to be analogous to the NRl subunit while the s i and s2 subunits to be analogous to NR2A and NR2B subunits respectively. The authors found that imipramine produced widespread reductions in levels o f s2 mRNA subunits in the cortex, hippocampus and amydala while citalopram had a different effect on the subunits. Citalopram reduced s i mRNA levels in the same areas. Ongoing research by our colleagues (Hutson et al, personal communication) reveal that N R l protein levels in the frontal cortex, hippocampus but not the amygdala are decreased upon chronic AD (clomipramine and roboxetine) treatment. The greatest effect was seen in the frontal cortex. We are currently extending these studies using paroxetine. These 3 brain regions were chosen as they are reported to be vital in the processing o f emotions and are implicated in depression (Marano, 1999). Thus the studies undertaken by Boyer et al (1998) and Hutson et al (2001 unpublished results) are in agreement with our data suggesting that chronic AD treatment produces region-specific changes in NMDA receptor fimction most probably altering NMDA receptor subunit composition. These different subunit compositions in different brain regions dictate the physiological and the pharmacological differences of regional NMDA receptors and may influence the

therapeutic actions of ADs. A parallel study by Riva et al (1997) using acute and chronic dosing with antipsychotic drugs (such as haloperidol and clozapine) showed significant differences in the composition o f NMDA receptor subunits following treatment. Therefore, variability in NMDA receptor subunit composition and the adaptive changes exerted on these subunits by pharmaceutical agents may not apply to depression but to a wide range of neurological disorders.

This data suggest an association between repeated AD treatment with paroxetine/clomipramine and the regulation of serotonergic transmission by NMDA receptors in the frontal cortex (Figure 4.16). The observation that acute paroxetine and clomipramine treatment had no significant effect on NMDA-evoked changes in extracellular 5-HT levels indicates that the effects of chronic treatment may be significant in the therapeutic action o f paroxetine, clomipramine and most likely other ADs.

In addition to the NMDA receptor population, other neuronal components, e.g. the

5-HT carrier and 5 - H Tib receptors, may have also undergone adaptive changes.

Findings by our colleagues (Hutson et al, unpublished results) that clomipramine and roboxetine decrease N Rl NMDA subunit would support these interpretations.

N MDA (NMDA R function) Frontal \ ▼ cortex

GABA

transmission

Figure 4.16 Sketch to show the effects of chronic antidepressants on 5-HT transmission.

Chronic ADs (e.g. paroxetine and clomipramine) cause:

• A functional desensitisation of both 5-HTia and 5-HTib autoreceptors, resulting in disinhibition o f neuronal firing and a reduction in feedback inhibition of transmitter release from the terminals.

• A decrease in SERT mRNA which leads to decrease 5-HI A A levels.

• A decrease in NMDA receptor function which will cause an increase in 5-HT levels.

• These effects cause an overall INCREASE IN 5-HT TRANSMISSION.

Chapter 5

The effects o f co-administration o f