As mentioned before, SPECT studies using the non-selective radioligand [¹²³I]ß-CIT revealed contradictory results with respect to seasonal effects on SERT binding (Neumeister et al. 2000; Ruhe et al. 2009). A PET study by Praschak-Rieder et al. conducted in a larger group of healthy drug-naïve subjects (n = 88) (Praschak-Rieder et al. 2008) was able to demonstrate a considerable effect of season on SERT by using the specific SERT radioligand [¹¹C]3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzonitrile ([¹¹C]DASB) and PET. This study revealed high [¹¹C]DASB binding potential (BP_ND) values in autumn and winter in six different predefined regions of interest (ROI). A uniform decrease of regional BP_ND values was found in spring and summer (Fig. 8.1). Peak differences in [¹¹C]DASB BP_ND values between months with highest and lowest binding potential values as large as 40 %. Furthermore, [¹¹C]DASB BP_ND values showed a negative correlation with the duration of daily sunshine and day length. In accordance with this study, Kalbitzer et al. (2010) reported a negative correlation of [¹¹C]DASB BP_ND values and daylight minutes. In the latter study, 54 healthy subjects were investigated using [¹¹C]DASB PET and genotyped for a polymorphism in the promoter region of the SERT gene (5-HTTLPR). Only carriers of 5-HTTLPR s-allele showed significant effects of season in [¹¹C]DASB binding. In contrast, 5-HTTLPR l-allele homozygous subjects did not exhibit seasonal variation of SERT availability. The methodology used in both studies does not allow for differentiation between the influence of daily sunshine and the astronomical photoperiod (daylight minutes) on [¹¹C]DASB binding because both parameters are highly intercorrelated. Although the negative correlation between [¹¹C]DASB binding and duration of daylight was found in both studies, a study by Murthy et al. (2010) did not replicate these findings.

Additionally, effects of season on SERT binding were demonstrated by Buchert and colleagues (2006) using PET and the radioligand trans-1,2,3,5,6,10b-hexahydro-6-[4-(methylthio)-phenyl]pyrrolo-[2,1-a]-isoquinoline ([¹¹C]-(+)McN5652). This study investigated age-related effects on SERT binding in 29 healthy subjects. In line with the results obtained by [¹¹C]DASB PET, SERT binding measured with [¹¹C]-(+)McN5652 PET was higher in winter, while age did not show any effect on SERT availability in this sample.

In summary, variations in SERT, with higher serotonin transporter availability in times of less light, as shown by the aforementioned studies, may facilitate extracellular serotonin loss during winter, potentially leading to hyposerotonergic symptoms and lower mood. To our knowledge, there are no studies on seasonal variations in SERT binding in patients with SAD. However, the data provided by Ruhe et al. (2009) suggest that there is a similar increase in SERT binding in patients with major depressive disorder in winter.

Recently, a study by Spindelegger et al. (2012) revealed light-dependent alterations of brain serotonin 1A (5-HT_1A) receptor binding. Among the different subtypes of serotonin receptors, the inhibitory 5-HT_1A receptor has a particular role. Located on GABAergic and glutamatergic neurons in limbic and cortical brain regions, the receptor mediates the inhibition of postsynaptic firing (Varnas et al. 2004). In contrast, 5-HT_1A receptors located on serotonergic neuronal somatodendrites inhibit serotonergic cell firing and modulate 5-HT transmitter release into the synaptic cleft. Consequently, these 5-HT_1A autoreceptors constitute the decisive factor in a negative auto-regulatory loop of serotonin release (Bundgaard et al. 2006). Alterations in 5-HT_1A receptor binding have been reported in several neuropsychiatric disorders such as anxiety (Akimova et al. 2009) and depression (Drevets et al. 2007). One recent animal study provided evidence for seasonal alterations in 5-HT_1A receptor expression (Naumenko et al. 2008). The study by Spindelegger et al. investigated 36 healthy drug-naïve subjects by quantifying 5-HT_1A BP_ND using PET and the highly specific ¹¹C-labelled tracer [N-(2-(1-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl))-N-(2-pyridyl)-cyclohexane-carboxamide] (carbonyl-[¹¹C]WAY-100635). Individual exposure to external factors such as global radiation (defined as total of direct solar radiation and diffuse sky radiation received by a unit horizontal surface) correlated with regional 5-HT_1A BP_ND, demonstrating a positive correlation between the accumulated (5 days prior to PET scan) amount of global radiation and 5-HT_1A receptor binding. Moreover, this investigation showed a significant difference between the groups of subjects exposed to low versus high amounts of global radiation (see Fig. 8.2). Up to 30 % differences in regional 5-HT_1A BP_ND were found between the different exposure groups.

In regard to the effects of season on serotonergic neurotransmission, higher SERT availability in times of less light was revealed in four different studies using SPECT and PET. Furthermore, serotonin receptor binding has been shown to be influenced by external factors such as global radiation. However, these results warrant independent replication. Altogether, these findings underline the importance of research in the field of the effects of season on the serotonergic system, as they provide additional insights into regulatory processes in 5-HT neurotransmission. Consequently, future studies investigating serotonergic target structures such as SERT or serotonin receptors should consider seasonal effects.

Dopamine neurotransmission has been suggested to be regulated in part by photoperiodic and light-dependent rhythms. Dopamine is strongly involved in physiological functions such as motor control, cognition, reward, emotion and memory processes (Dalley and Everitt 2009). Limited evidence for seasonal effects on dopamine neurotransmission is provided by SPECT studies mentioned before (Neumeister et al. 2001; Tsai et al. 2011) and a PET study by Eisenberg et al. (2010) reporting higher striatal fluorine-18-L-dihydroxyphenylalanine ([¹⁸F]DOPA) uptake in autumn and winter as compared to spring and summer. Eisenberg and colleagues investigated a large sample of healthy subjects (n = 86) showing higher striatal K_i values in subjects scanned during the fall and winter season. The increased K_i values in the posterior putamen were interpreted as greater presynaptic dopamine synthesis and storage capacity in this region. Based on the resulting higher levels of dopamine in times of less light, these results would be in line with recent findings of lower striatal [¹²³I]IBZM binding in times of less light exposure (Tsai et al. 2011) due to greater competition at postsynaptic D_2/3 receptors. Since there is only limited evidence supporting this hypothesis, further investigations are needed to clarify the underlying mechanisms.