Murrin LC, Sanders JD, Bylund DB. Comparison of the maturation of the adrenergic and serotonergic neurotransmitter systems in the brain: Implications for differential drug effects on juveniles and adults

Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985800 Nebraska Medical Center, Omaha, NE 68198-5800, USA.
Biochemical Pharmacology (Impact Factor: 5.01). 05/2007; 73(8):1225-36. DOI: 10.1016/j.bcp.2007.01.028
Source: PubMed


Our understanding of the development of neurotransmitter systems in the central nervous system has increased greatly over the past three decades and it has become apparent that drug effects on the developing nervous system may differ considerably from effects on the mature nervous system. Recently it has become clear there are significant differences in the effectiveness of antidepressant drug classes in children and adolescents compared to adults. Whereas the selective serotonin reuptake inhibitors are effective in treating all ages from children to adults, the tricyclic antidepressants, many of which inhibit norepinephrine reuptake, have been shown to be ineffective in treating children and adolescents even though they are effective in adults. We review here the development of the noradrenergic and serotonergic nervous systems, both in terms of neurotransmitter system markers and function. Both of these neurotransmitter systems are primary targets of antidepressant medications as well as of central nervous system stimulants. It is clear from a comparison of their development that the serotonin system reaches maturity much earlier than the norepinephrine system. We suggest this may help explain the differences in response to antidepressants in children and adolescents compared to adults. In addition, these differences suggest that drugs acting preferentially on either neurotransmitter system may impact the normal course of CNS development at different time points. Consideration of such differences in the development of neurotransmitter systems may be of significance in optimizing treatments for a variety of centrally mediated disorders.

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    • "Serotonin regulation shows age-dependent adaptations; 5-HT uptake measured in animal studies is higher in the developing brain as compared with adult values [5]. In rats mRNA for SERT can be determined by embryonic day 13, and the uptake of 5-HT reaches adult levels at birth in brain synaptosomes, at five weeks of age the amount of uptake is doubled and then decreases to adult levels again [6]. "
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    ABSTRACT: Forced swimming test (FST) is an animal model which evaluates behavioral despair and the effect of antidepressants such as the selective serotonin reuptake inhibitors; the FST modifies the expression of some receptors related to antidepressant response, but it is not known whether serotonin transporter (SERT), their main target, is affected by this test in animals of different ages. Antidepressant response has shown age-dependent variations which could be associated with SERT expression. The aim of the present study was to analyze changes in the SERT immunoreactivity (SERT-IR) in dorsal raphe and lateral septum of male rats from different age groups with or without behavioral despair induced by their exposure to the FST, since these two structures are related to the expression of this behavior. Prepubertal (24 PN), pubertal (40 PN), young adult (3-5 months) and middle-age (12 months) male rats were assigned to a control group (non-FST) or depressed group (FST, two sessions separated by 24 h). Changes in SERT-IR in dorsal raphe and lateral septum were determined with immunofluorescence. Pubertal and middle-aged rats showed higher levels of immobility behavior compared to prepubertal rats on the FST. SERT-IR showed an age-dependent increase followed by a moderate decrease in middle-aged rats in both structures; a decreased in SERT-IR in lateral septum and dorsal raphe of pubertal rats was observed after the FST. Age differences were observed in the SERT-IR of structures related to behavioral despair; SERT expression was modified by the FST in lateral septum and dorsal raphe of pubertal rats.
    Behavioral and Brain Functions 02/2014; 10(1):3. DOI:10.1186/1744-9081-10-3 · 1.97 Impact Factor
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    • "Although the serotonin system develops to near maturity in the first years of life, maturational changes continue to occur throughout adolescence and into adulthood (Crews et al. 2007; Karanges and McGregor 2011). The adolescent brain is characterized by increased serotonin levels and 5-HT1A and 5-HT2A receptor densities (Crews et al. 2007; Murrin et al. 2007) but lower 5-HTT density and serotonin turnover (Crews et al. 2007; Moll et al. 2000). The serotonin system is diverse and neurochemically complex; however, it is understood to play a critical inhibitory role in the PFC (Fuster 2008; Puig and Gulledge 2011) and is implicated in a variety of behaviors including impulsivity (Depue and Spoont 1986; Robbins and Crockett 2009), aggression (Carrillo et al. 2009), and suicide (Mann 2003; Mann 1998). "
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    ABSTRACT: Rationale Black box warnings for young adults under the age of 25 years indicate that antidepressants may increase risk of suicide. While underlying mechanisms for age-related treatment effects remain unclear, vagally mediated cardiovascular function may play a key role. Decreased heart rate (HR) and an increase in its variability (HRV) improve one’s capacity to adapt to environmental stress and attenuate risk for suicide. Objectives Using a double blind, randomized, placebo-controlled, crossover, experimental study, we examine whether a single dose of escitalopram (20 mg) attenuates cardiovascular responses to stress under experimental conditions and determine whether age moderates these effects. Methods Forty-four healthy females received a single dose of escitalopram (20 mg) and placebo treatment separated by a 1-week interval (>5 half-lives). HR and high frequency HRV (HF HRV normalized units; 0.15–0.40 Hz) were measured during resting state and stress. Results While escitalopram attenuated the increase in HR and increased HF HRV, these moderate to large effects were only significant in participants over 25 years of age. No beneficial cardiovascular effects of escitalopram were observed in those under the age of 25. Conclusions Maturational differences in the development of the prefrontal cortex—a critical region in the central network of autonomic control—may underpin these differential findings. This study provides a theoretical framework on which future research on treatment-emergent suicidality in clinical populations could be based.
    Psychopharmacology 12/2013; DOI:10.1007/s00213-013-3374-4 · 3.88 Impact Factor
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    • "The requirement for 5-HT 1A receptors in the third week of life coincides with the emergence of behaviors that are consistent with conflict-based anxiety. Thus, exploration of and habituation to novel environments emerge at this time (Murrin et al. 2007). In addition, postnatal day 21 is the earliest timepoint in which behavioral differences in anxiety measures can be detected in the 5-HT 1A knockout mice (Kristin Klemenhagen, personal communication). "
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    ABSTRACT: Serotonin (5-HT) neurotransmission is intimately linked to anxiety and depression and a diverse body of evidence supports the involvement of the main inhibitory serotonergic receptor, the serotonin-1A (5-HT1A) subtype, in both disorders. In this review, we examine the function of 5-HT1A receptor subpopulations and re-interpret our understanding of their role in mental illness in light of new data, separating both spatial (autoreceptor versus heteroreceptor) and the temporal (developmental versus adult) roles of the endogenous 5-HT1A receptors, emphasizing their distinct actions in mediating anxiety and depression-like behaviors. It is difficult to unambiguously distinguish the effects of different populations of the 5-HT1A receptors with traditional genetic animal models and pharmacological approaches. However, with the advent of novel genetic systems and subpopulation-selective pharmacological agents, direct evidence for the distinct roles of these populations in governing emotion-related behavior is emerging. There is strong and growing evidence for a functional dissociation between auto- and heteroreceptor populations in mediating anxiety and depressive-like behaviors, respectively. Furthermore, while it is well established that 5-HT1A receptors act developmentally to establish normal anxiety-like behaviors, the developmental role of 5-HT1A heteroreceptors is less clear, and the specific mechanisms underlying the developmental role of each subpopulation are likely to be key elements determining mood control in adult subjects.
    Psychopharmacology 12/2013; 231(4). DOI:10.1007/s00213-013-3389-x · 3.88 Impact Factor
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