Scientists uncover delayed effects of citalopram on brain’s reward system

A new study on mice reveals that the brain’s response to rewards is temporarily suppressed after the first dose of citalopram, an antidepressant, but gradually returns with continued use. The findings, published in the Journal of Pharmacological Sciences, shed light on the neurobiological mechanisms behind the delayed effects of selective serotonin reuptake inhibitors (SSRIs), a commonly prescribed class of antidepressants.

Depression is a debilitating mental health disorder characterized by persistent sadness, loss of interest in daily activities, and an inability to experience pleasure. It affects hundreds of millions worldwide and remains one of the leading causes of disability. Despite the widespread use of antidepressants, at least 30% of patients fail to respond to treatment, highlighting the urgent need for a deeper understanding of how these medications work.

SSRIs, including fluoxetine (Prozac) and citalopram (Celexa), function by increasing serotonin levels in the brain, which is thought to enhance mood and restore normal emotional processing. However, their effects do not take hold immediately—most patients experience a delay of several weeks before noticeable improvements occur. Scientists have long speculated that this lag is due to complex neural adaptations, but the precise mechanisms remain unclear.

To explore this phenomenon, Masashi Koda and colleagues conducted a study on mice, focusing on serotonin-producing neurons in the dorsal raphe nucleus (DRN), a brain region involved in mood regulation and reward processing. Their goal was to determine how citalopram affects neural responses to pleasurable stimuli (such as sugar) after a single dose versus after prolonged treatment. By using fiber photometry, an advanced technique that measures brain activity in real time, they sought to uncover why antidepressants take time to become effective and whether their effects could be accelerated.

The dorsal raphe nucleus is the largest cluster of serotonin-producing neurons in the brainstem. It plays a key role in regulating mood, processes related to the feeling of pleasure (reward processing), and the stress response by projecting serotonin to various brain regions, including the prefrontal cortex and the limbic system.

The study was conducted on adult male C57BL/6JmsSlc mice. The mice were 8-12 weeks old. They were kept in a plastic cage with wooden bedding and had free access to food and water.

Study authors applied a technique called fiber photometry to study the activity of neural cells of interest in the brains of these mice. Fiber photometry is a technique that uses a tiny fiber optic cable to detect brain activity in live animals by measuring light signals from neurons in real time. To achieve this, neurons of interest are first genetically modified to produce the needed light signal when active.

Mice were first exposed to chronic stress to make them display symptoms similar to those found in depressed humans. The most important of these symptoms for this study was a reduced response to rewards—sugar, in this case. Study authors examined how this response changed after giving mice a single dose of citalopram and what happened after continued use. They also used a drug called (S)-WAY100135 dihydrochloride, which blocks a specific type of serotonin receptor in the brain (5-HT1A receptors), to see how the effects of the antidepressant would change after that.

Results showed that, after a single dose of citalopram, neural response in the dorsal raphe nucleus to sugar (i.e., reward) was decreased. In other words, instead of becoming more sensitive to rewarding experiences (due to increased serotonin levels), mice became less sensitive. It turned out that the first dose of citalopram increases the amount of serotonin in the brain. However, it also triggers an autoinhibitory reaction that initially suppresses the antidepressant effects. With continued intake of citalopram, the brain adapts, and the autoinhibition effect gradually decreases, allowing the antidepressant effects of citalopram to become more visible.

Further investigation showed that this initial suppression of neural activity is achieved through 5-HT1A receptors (a type of serotonin receptor). When the study authors injected mice with (S)-WAY100135, a drug that blocks 5-HT1A receptors, the suppression of neural activity caused by the first dose of citalopram disappeared.

“By using the fiber photometry technique in free-moving animals, this study demonstrated that acute SSRI treatment reduces sucrose licking-induced activation of DRN [dorsal raphe nucleus] serotonin neurons via 5-HT1A autoreceptors, and co-treatment with SSRIs and 5-HT1AR antagonists partly mimic the effects of chronic SSRI treatment within a shorter timeframe,” the study authors concluded.

The study sheds light on the biochemical mechanisms of citalopram’s antidepressant effects. However, it should be noted that this was a study on mice, not on humans. While mice and humans share many physiological similarities, they are still very different species. Effects on humans might not be identical.

The paper, “Effect of antidepressants and social defeat stress on the activity of dorsal raphe serotonin neurons in free-moving animals,” was authored by Masashi Koda, Hiroyuki Kawai, Hisashi Shirakawa, Shuji Kaneko, and Kazuki Nagayasu.