Neuropsychopharmacology (2009) 34, 2323–2328 & 2009 Nature Publishing Group All rights reserved 0893-133X/09 $32.00 www.neuropsychopharmacology.org Dopamine Modulates Cholinergic Cortical Excitability in Alzheimer’s Disease Patients Alessandro Martorana*,1,2, Francesco Mori1, Zaira Esposito1, Hajime Kusayanagi1, Fabrizia Monteleone1, Claudia Codecà1, Giuseppe Sancesario1,2, Giorgio Bernardi2 and Giacomo Koch1,2 1 Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma ‘Tor Vergata’, Roma, Italy and 2IRCCS S. Lucia, Ospedale di Neuroriabilitazione, Via Ardeatina, Roma, Italy In Alzheimer’s disease (AD) patients dysfunction of cholinergic neurons is considered a typical hallmark, leading to a rationale for the pharmacological treatment in use based on drugs that enhance acetylcholine neurotransmission. However, besides altered acetylcholine transmission, other neurotransmitter systems are involved in cognitive dysfunction leading to dementia. Among others, dopamine seems to be particularly involved in the regulation of cognitive processes, also having functional relationship with acetylcholine. To test whether cholinergic dysfunction can be modified by dopamine, we used short latency afferent inhibition (SLAI) as a neurophysiological tool. First, we tested the function of the cholinergic system in AD patients and in healthy subjects. Then, we tested whether a single L-dopa challenge was able to interfere with this system in both groups. We observed that SLAI was reduced in AD patients, and preserved in normal subjects. L-dopa administration was able to restore SLAI modification only in AD, having no effect in healthy subjects. We conclude that dopamine can modify SLAI in AD, thus confirming the relationship between acetylcholine and dopamine systems. Moreover, it is suggested that together with cholinergic, dopaminergic system alteration is likely to occur in AD, also. These alterations might be responsible, at least in part, for the progressive cognitive decline observed in AD patients. Neuropsychopharmacology (2009) 34, 2323–2328; doi:10.1038/npp.2009.60; published online 10 June 2009 Keywords: transcranial magnetic stimulation; short latency afferent inhibition; L-dopa; acetylcholine; Alzheimer’s disease INTRODUCTION The marked dysfunction of cholinergic neurons is considered a typical disease hallmark in Alzheimer’s disease (AD), supporting the rationale for current pharmacological treatment based on drugs that enhance acetylcholine neurotransmission. However, besides altered acetylcholine transmission, recent advances evidenced that other neurotransmitter systems might be involved in cognitive dysfunction occurring in AD. Among the others, dopaminergic system may play a relevant role in the mechanisms involved in learning and memory processes, showing strong synaptic interaction with acetylcholine in different brain areas (Blokland, 1995; Brooks, 2006; Cao et al, 2005; Di Cara et al, 2007; Millan et al, 2007). Extrapyramidal signs are sometimes observed in patients suffering from AD, and are related to faster cognitive decline and higher mortality (Rosen and Zubenko, 1991). Impaired dopamine transport in several brain areas has been reported in even in absence *Correspondence: Dr A Martorana, Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma ‘Tor Vergata’, via Montpellier, 1- 00133, Rome, Italy. Tel.: + 0039 06 72596020; Fax: + 0039 06 72596022, E-mail: martorana@med.uniroma2.it Received 17 February 2009; revised 5 May 2009; accepted 8 May 2009 of extrapyramidal signs (Murray et al, 1995; Pizzolato et al, 1996). Furthermore, dopamine D2 receptors correlation with memory dysfunction was described in AD (Kemppainen et al, 2003). Within these perspectives, we recently showed that in AD patients the administration of L-dopa determined consistent modifications of cortical activity (Martorana et al, 2008), inducing an increase of short intracortical inhibition (SICI). In that work, we supposed that dopamine could exert its modulatory function influencing, among others, the cortical cholinergic release as well. Here, we aimed to verify this hypothesis by studying the effects of dopamine on the cholinergic cerebral transmission in normal and in AD patients. To do this, we used a technique that is based on the coupling of TMS with peripheral nerve stimulation. Motor-evoked potentials recorded after TMS of the motor cortex can be suppressed by electrical stimulation of the median nerve if the time between stimulation of the median nerve and that of the motor cortex is 2–8 ms longer than the time needed by the peripheral nerve afferent input to reach the cortex. This effect is termed as short latency afferent inhibition (SLAI) of the motor cortex, and in general it is considered a measure of inhibitory interactions between afferent input and motor output. It is suggested that cholinergic system modulates these inhibitory interactions. Therefore, SLAI is currently Dopamine and Acetylcholine in Alzheimer’s Disease A Martorana et al 2324 considered a non-invasive way to test cholinergic activity in the cerebral cortex in the healthy subjects (Tokimura et al, 2000). On the other hand, other authors suggested that SLAI may depend on the integrity of circuits linking sensory input and motor output rather than on cholinergic function, and thus its modifications may reflect impaired transmission of the sensory afferents (Sailer et al, 2003). Although apparently distant, these two hypotheses might be reasonably reconciled. The fact that cholinergic drugs can modify SLAI values did not necessarily indicate that a cholinergic dysfunction or deficit underlies its modification. Other neurotransmitters, in particular dopamine, are supposed to play a modulatory role on the cholinergic transmission. However, as both the transmitters can serve as neuromodulators, it is conceivable that the functional cholinergic dysfunction may be the consequence of abnormal neuromodulation of dopamine (Orth et al, 2005). Thus, in conditions in which dopamine or acetylcholine system are impaired, SLAI modifications might occur as seen in Parkinson’s disease (Sailer et al, 2003, 2007), Tourette’s syndrome (Orth et al, 2005), and AD (Di Lazzaro et al, 2002, 2004). Even pharmacological manipulation may unexpectedly induce imbalance in the transmitters release, modifying the electrophysiological findings in course of such pathologies. In fact, as clarified later in the Discussion, the pharmacological manipulation of the dopaminergic system might induce modifications of cortical acetylcholine release acting on nuclei of the non-motor regions of the brain, resulting in the modification of SLAI not observed before (Sailer et al, 2003). With these premises, here, we tested whether a single dose of orally administered L-dopa can interfere with SLAI test in AD patients compared with healthy controls. We hypothesized that if L-dopa administration could modulate cholinergic activity, in AD patients, changes in the level of SLAI should also be observed more easily. Subjects We examined 10 patients with a diagnosis of probable AD according to the NINCDS-ADRDA criteria (Varma et al, 1999) and 10 neurologically healthy age-matched control subjects. The mean (SD) age of the patients was 72.5 (6.1) years, whereas that of controls was 71.7 (4.9) years. All patients underwent a complete clinical investigation, including medical history, neurological examination, minimental state examination (MMSE), a complete blood screening (including, routine exams, thyroid hormones, and level of B12), neuropsychological examination (Pierantozzi et al, 2004), a complete neuropsychiatric evaluation, and neuroimaging consisting of magnetic resonance imaging (1.5 T MRI). Exclusion criteria were the following: patients with isolated deficits and/or unmodified MMSE (X25/30) on revisit (6, 12, 18 months follow-up), patients with clinically manifest acute stroke in the last 6 months showing an Hachinsky scale 44, and a radiological evidence of sub-cortical lesions. None of patients showed pyramidal and/or extrapyramidal signs at the neurological examination. At the time of enrolment, in the 30 days before participating in this study, none of the patients had been treated with drugs that might have modulated cerebral cortex excitability, such as antidepresNeuropsychopharmacology sants, or any other neuroactive drugs (ie, benzodiazepines, anti-epileptic drugs, or neuroleptics), even patients assuming drugs like a- or b-blockers were excluded from that work, as possible interactions with SLAI are not excluded. However, none of the patients has been treated before with cholinesterase inhibitors. The study was performed according to the Declaration of Helsinki and approved by the ethics committee of the Tor Vergata University in Rome. All AD patients showed a cognitive profile consistent with moderate dementia, as assessed by a neuropsychological evaluation, including the MMSE and a standardized neuropsychological battery (Carlesimo et al, 1996). On the MMSE, AD patients scored a mean of 18.23 (±3.2) and Clinical Dementia Rating (CDR) was 1.75 (±1.6). All participants or their legal guardian gave the written informed consent after receiving an extensive disclosure of study. The local ethic committee approved the study procedures. TMS Procedure Magnetic stimulation was performed using a high-power Magstim 200 magnetic stimulator (Magstim Co., Whitland, Dyfed, UK). The magnetic stimuli had a nearly monophasic pulse configuration, with a rise time of 100 ms, decaying back to zero over 0.8 ms. A figure of eight coils with external loop diameters of 9 cm was held over the left motor cortex at the optimum scalp position to elicit motor responses in the contralateral first dorsal interosseous (FDI) muscle. The optimal position was marked on the scalp with a felt pen to ensure identical placement of the coil throughout the experiment. The handle of the coil pointed backward and was perpendicular to the presumed direction of the central sulcus, about 451 to the midsagittal line. The direction of the induced current was from posterior to anterior and was optimal to activate the motor cortex trans-synaptically. Surface muscle responses were obtained through two 9 mm diameter Ag-AgCl electrodes with the active electrode over the motor point of the muscle and the reference on the metacarpophalangeal joint of the index finger. Muscle responses were amplified and filtered (bandwidth 3– 3000 Hz) by D150 amplifiers (Digitimer, Welwyn Garden City, Hertfordshire, UK). Data were collected on a computer with a sampling rate of 10 kHz per channel and stored for later analysis using a CED 1401 A-D converter (Cambridge Electronic Design, Cambridge, UK). All the AD patients selected were able to understand and carry out the simple task required for this electrophysiological studyFthat is, to keep fully relaxed. The resting motor threshold (RMT) was defined as the lowest intensity that produced MEPs of 450 mV in at least five out of 10 trials with the muscles relaxed (Rossini et al, 1994). Determination of RMT was done in step width of 1% of maximal stimulator output (MSO). Short latency inhibition was studied using the technique that has been recently described (Di Lazzaro et al, 2002; Sailer et al, 2003). Conditioning stimuli were single pulses (200 ms) of electrical stimulation applied through bipolar electrodes to the right median nerve at the wrist (cathode proximal). The intensity of the conditioning stimulus was set at just over motor threshold for evoking a visible twitch of the thenar muscles. The intensity of the test cortical magnetic stimulus was adjusted to evoke a Dopamine and Acetylcholine in Alzheimer’s Disease A Martorana et al 2325 muscle response in relaxed right FDI with an amplitude of B1 mV peak-to-peak. The conditioning stimulus to the peripheral nerve preceded the magnetic test stimulus by different interstimulus intervals (ISIs). ISIs were determined relative to the latency of the N20 component of the somatosensory evoked potential induced by stimulation of the right median nerve. The active electrode for recording the N20 potential was attached 3 cm posterior to C3 (10–20 system) and the reference was 3 cm posterior to C4. A total of 500 responses were averaged to identify the latency of the N20 peak. ISIs from the latency of the N20 plus 2 ms to the latency of the N20 plus 8 ms were investigated in steps of 2 ms. A total of 10 stimuli were delivered at each ISI. The subject was given audiovisual feedback at high gain to assist in maintaining complete relaxation. The inter-trial interval was set at 5 s (±10%), for a total duration of B 5 min. Measurements were made on each individual trial. The mean peak-to-peak amplitude of the conditioned MEP at each ISI was expressed as a percentage of the mean peak-topeak amplitude size of the unconditioned test pulse in that block. To test whether short latency inhibition was sensitive to the changes in L-dopa activity, we examined the motor threshold and the SLAI in 10 patients before and after the administration of a single dose (125 mg) of L-dopa. Measurements were made before and 1 h after the administration, when L-dopa presented its maximal effects (Martorana et al, 2008). Figure 1 Short latency afferent inhibition at different interstimulus intervals in AD patients (black diamonds) and control (open squares) subjects. The interval between median nerve stimulation and cortical stimuli was corrected for the latency of the N20 component of the somatosensory evoked potential in each subject (see text). The size of MEPs is expressed as a percentage of the MEP evoked by magnetic stimulation alone. Short latency afferent inhibition was reduced in AD patients at all explored intervals. Error bars indicate standard deviations. (*Po0.05). Statistical Analysis The electrophysiological parameters of AD patients were compared with those of controls by means of repeated measures ANOVA with GROUP (AD vs healthy subjects) as between subjects factor and ISI ( + 2, 4, 6 and 8 ms plus the latency of the N20) and TREATMENT (pre- vs postL-DOPA) as within-subject factors. When a significant main effect was reached, t-tests with Bonferroni’s correction were employed to characterize the different effects of the specific ISIs. For all statistical analyses, a p-value of o0.05 was considered to be significant. Mauchley’s test examined for sphericity. The Greenhouse–Geisser correction was used for non-spherical data. RESULTS None of patients suffered from side effects following assumption of the single dose of L-dopa. The N20 latency and amplitude were within normal limits in all AD patients and control subjects and did not differ between the two groups (20.5±3.2 vs 20.8±2.9). The mean (SD) RMT to TMS was significantly lower in AD patients than in controls (45.9% vs 49.9%) of MSO; t ¼ 3.14; po0.05) (Figure 1). RMT was not significantly modified by the administration of L-dopa (p ¼ 0.48 at paired t-test analysis). For unconditioned TS MEPs amplitude pre-and post-L-dopa did not differ being 1.08±0.33 mV and 1.04±0.31 mV in AD and 1.13±0.25 mV and 1.14±0.34 mV in controls, respectively. Repeated measures ANOVA performed on SLAI measures showed significant main effects of GROUP (F ¼ 4.26; po0.05; Z2 ¼ 0.36) and ISI (F ¼ 7.78; po0.001; Z2 ¼ 0.61), as well-significant GROUP  TREATMENT Figure 2 In AD patients, administration of L-dopa was effective in modulating SLAI. (a) SLAI in AD patients was increased after L-dopa administration at + 2 ms and + 4 ms ISIs. (b) No significant change was observed in healthy subjects. Error bars indicate standard deviations (*po0.05). (F ¼ 3.96; po0.05; Z2 ¼ 0.31) and ISI  TREATMENT (F ¼ 8.23; po0.001; Z2 ¼ 0.40) interactions. The triple interaction GROUP  ISI  TREATMENT was not significant. In fact, post hoc analysis showed that before administration of L-dopa the amount of inhibition was significantly smaller in AD patients than in normal controls for all the ISIs tested (all po0.05) (Figure 2). The amount of Neuropsychopharmacology Dopamine and Acetylcholine in Alzheimer’s Disease A Martorana et al 2326 Table 1 ISI t p-values (a) Comparison of SLAI mean values in AD and HS before L-dopa administration at different ISIs. 2 ms 3.52 0.001 4 ms 3.09 0.009 6 ms 2.87 0.012 8 ms 3.10 0.009 (b) Comparison of SLAI mean values in AD before and after L-dopa administration at different ISIs 2 ms 2.88 0.009 4 ms 2.81 0.010 6 ms 1.82 0.102 8 ms 0.62 0.554 Figure 3 In AD patients, individual changes in SLAI before and after Ldopa administration (measured as the difference of % SLAI values before and after L-dopa administration) did correlate with scores obtained at MMSE. inhibition was increased only in AD patients after L-dopa administration at + 2 ms and + 4 ms ISIs (all po0.05) (Figure 2a). On the other hand, when the same analysis was performed in a group of healthy controls, no significant difference emerged (Figure 2b). Furthermore, in subsequent analysis, we found that in AD patients the individual amount of increase of SLAI induced by L-dopa (at ISI ¼ + 4 ms, measured as the difference of % values pre-and post-L-dopa) did correlate with cognitive impairment as assessed by MMSE (R ¼ 0.70; p ¼ 0.02) (Figure 3 and Table 1). DISCUSSION In this work, we confirm that SLAI of the motor cortex is significantly reduced (dis-inhibited) in AD patients compared with age-matched normal subjects (Di Lazzaro et al, 2002). In addition, we observed that SLAI dis-inhibition could be promptly restored by the acute administration of L-dopa to these patients. Our results therefore suggest that dopamine is able to modulate cortical cholinergic function in AD patients. In general, SLAI depends on the integrity of corticocortical inhibitory circuits, and is suggested to be modulated at least in part by cholinergic system (Tokimura et al, 2000). In particular, acetylcholine is thought to be involved in the modulation of intracortical circuits mediated by groups of GABAergic interneurons, rather than directly acting on pyramidal cells (Di Lazzaro et al, 2000; 2002, 2004). At this regard, Di Lazzaro et al (Di Lazzaro et al, 2005) showed that different types of benzodiazepines, such as diazepam and lorazepam, resulted in distinct effects on both SICI and SLAI. In particular, diazepam increased both SLAI and SICI, whereas lorazepam reduced SLAI but increased SICI, suggesting that the interactions between cholinergic and GABA-ergic circuits may require the activation of a variety of different receptor subtypes. In this context, we recently described that L-dopa administraNeuropsychopharmacology tion was able to change the excitability of GABAergic intracortical circuits in AD patients (Martorana et al, 2008). The current findings show that dopamine plays a critical role in modulating cortical cholinergic activity also, presumably interacting with such GABAergic intracortical circuits. Several anatomical (Beckstead et al, 1979; Gaykema and Zaborszky, 1996; Smiley et al, 1999) and pharmacological (Hersi et al, 2000; Millan et al, 2007) studies showed that dopamine and acetylcholine are tightly interconnected, being involved in various cognitive functions, such as memory, attention, and learning (Blokland, 1995; Brooks, 2006, Cao et al, 2005, Di Cara et al, 2007, Millan et al, 2007). It is still unclear, however, whether dopamine modulation of acetylcholine release from cortical neurons occurs through synaptic or non-synaptic (volume transmission) mechanisms or possibly through a combination of both. However, on the anatomical ground the dopaminergic control of cortical acetylcholine release likely occurs at different levels. Dopamine released from terminals directly in the motor cortex could have favorable effects either acting on intracortical cholinergic interneurons bearing receptors for dopamine (Berlanga et al, 2005), or could act at subcortical level facilitating the glutamatergic excitatory drive from thalamo-cortical pathway, on the classic basalganglia-thalamo-cortical loop (DeLong, 1990). In this view, the thalamo-cortical inputs would in turn excite cortical cholinergic neurons bearing glutamatergic receptors (Conti et al, 1999). Alternatively, dopamine could act through the modulation of the projections originating from the Nucleus Accumbens (NAcc) to the cholinergic basal forebrain neurons (Ingham et al, 1998; Sarter et al, 1999). The NAcc is a subcortical nucleus considered the ventral homolog of caudate-putamen and the NAcc neurons give rise to a massive GABAergic projection to the basal forebrain neurons. Several line of evidence showed that the pharmacological manipulation of accumbal dopamine receptors, can influence the acetylcholine release in cortex. In particular, the accumbal dopamine, D2-like receptor stimulation has a negative effect on the acetylcholine release Dopamine and Acetylcholine in Alzheimer’s Disease A Martorana et al 2327 from the basal forebrain cholinergic neurons projecting to the cortex (Del Arco et al, 2007; Brooks et al, 2007), whereas the dopamine D1-like receptor activation has opposite effects (Löffler et al, 2006). The suggested mechanisms, that may be not mutually exclusive, could in turn influence the cortical excitability acting on cortical GABA interneurons, modulating cortical hyperexcitability (Di Lazzaro et al, 2002 and Martorana et al, 2008), therefore, explaining SLAI changes observed in our recordings. In this perspective, the finding that L-dopa was able to restore SLAI in AD patients may reside in the anatomofunctional modifications induced by the degenerative processes observed in AD. In fact pathological studies showed that in AD, in addition to b-amyloid and senile plaques deposits, changes in several neurotransmitter systems occur. Together with the cholinergic system, the serotoninergic and noradrenergic systems also seem to be strongly altered (Langlais et al, 1993; Nazarali and Reynolds, 1992; Reinikainen et al, 1988; Zaborszky and Cullinan, 1996). However, the dopaminergic is also implicated (Allard et al, 1994; McNeill et al, 1984). In particular, the reduced levels of dopamine transporters restricted to the NAcc together with altered receptors expression for dopamine recently described (McNeill et al, 1984; Kumar and Patel, 2007), provide sufficient evidence that dopamine content deficit also occurs during the neurodegenerative process of AD. These alterations, in association with the changes because of the progressive neurodegenerative processes (aberrant growth of dendritic trees and amyloid deposit) (Arendt et al, 1995; Preda et al, 2008; Wu et al, 2007) can induce, as a consequence a perturbation in the balance of the other neurotransmitter systems, leading to altered cortical excitability and cognitive decline. In this view, the prompt effect of L-dopa on SLAI has to be interpreted as the result of a momentarily restored transmitter deficiency, leading to restored electrophysiological patterns. In this view, further studies are needed to verify whether chronic therapy with L-dopa may lead to persistent modifications of cholinergic activity and in which direction. Thus, additional studies with larger samples of patients could determine if the L-dopa effects on cholinergic circuit may be related to disease duration. Finally, it has to be noticed that L-dopa had no effect in control patients. Healthy subjects with a preserved dopaminergic (and cholinergic) system are probably capable of storing additional external loads of L-dopa or dopamine in their terminals, so that significant extra-stimulation of dopamine receptors did not occur. In conclusion, our results suggest that in AD dopamine may influence cortical cholinergic activity. Further electrophysiological and pharmacological studies are required to better understand the role exerted by specific dopamine receptors on cholinergic circuits. Moreover, the current findings may imply new strategies of intervention even to ameliorate cognitive disturbances in AD. 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