5-HT Pathways, Receptors and Transporter

Memory Functions and Dysfunctions

5-HT pathways project to almost all brain areas and diverse 5-HT mechanisms might be useful in the treatment of learning and memory dysfunctions. Aging, AD and amnesia are associated to decrements in 5-HT markers such as SERT and in the number of 5-HT receptors. Emerging evidence also indicates that memory formation; amnesia, promnesic and amnesic drugs modify serotonergic markers, including 5-HT receptors, SERT. It should be noted that amnesia and forgetting differ in mechanistic pharmacological and neuroanatomical terms. Alterations of markers of cognitive processes, including memory formation and memory disorders and even diverse serotonergic manipulations alter memory. Certainly, 5-HT1A/1B, 5-HT2A/2C, 5-HT3, 5-HT4, 5-HT6 and 5-HT7 receptors have attracted more scientific interest regarding memory. Probably, since their agonists and/or antagonists seem to have promnesic and/or anti-amnesic effects. This apparent paradox remains to be explored.

3.1

Rationale for using behavioral memory tasks rests on the notion that hippocampus (and rhinal cortices) is paramount for this cognitive process. The cognitive and behavioral requirements are illustrated as well as the differential complexity (based in the brain areas implicated). Herein, we are briefly mentioning passive avoidance, water maze and autoshaping tasks used for the investigation of 5-HT systems. In this context, an important issue is convergent and divergent findings among laboratories using similar or different memory tasks, animals employed, etc. Certainly, it is a complex and multi focal issue; hence, we are briefly addressing a few aspects. Diverse animal models allow the investigation of the various aspects of the memory and its dysfunctions; providing convergent validation of the research findings. Likewise, analysis of protocols of training/testing, memory tasks and drugs remains as a crucial issue as well as using better devices for measuring memory. For instance, new instruments for measuring behavior in autoshaping memory tasks are addressing issues like variability inter-laboratories, inter-memory tasks, inter-subjects represent significant advances. The interaction drug and behavioral task results a heuristic issue for investigating. The inter-subjects variability is a biological feature, which might be reduced by improving the instruments for measuring memory or study them about the propensity to use psychoactive substances together with gene expression for 5-HT receptors or individual propensity for cue-directed orienting. About the water maze, a mechanistic approach to individual differences in spatial learning, memory, and navigation had been reported. Finally, the pharmacological characterization of selective drugs regarding Pavlovian/instrumental autoshaping learning task, brain areas and neurobiological findings are discussed.

3.2

The investigation of 5-HT systems regarding memory, has revealed direct participation of 5-HT in memory in animals, normal elderly people, AD patients and schizophrenics, 5-HT uptake inhibitors and involving multiple 5-HT receptors distributed pre- and post-synaptically in brain areas related to memory.

Keywords

5-HT markers; receptors; SERT; brain areas; memory; amnesia

memory tasks; amnesia; brain areas; measuring memory; individual differences; 5-HT receptors; drugs

memory; amnesia; l-trytophan; 5-HT; 5-HT uptake inhibitors; molecular; neurobiological markers

5-HT pathways project to almost all brain areas (Jacobs and Azmitia, 1992; Hoyer et al., 1994; Steinbush, 1984) and diverse 5-HT mechanisms might be useful in the treatment of learning and memory dysfunctions. Aging, AD, and amnesia are associated to decrements in 5-HT markers such as SERT and in the number of 5-HT1A/1B, 5-HT2A/2C, 5-HT4, 5-HT6, and 5-HT7 receptors (Rodríguez et al., 2012; Xu et al., 2012). Importantly, emerging evidence also indicates that memory formation, amnesia, promnesic and amnesic drugs modify serotonergic markers, including 5-HT receptors, SERT, and serotonergic tone (Belcher et al., 2005; Callaghan et al., 2012; Da Silva Costa-Aze et al., 2012; Eriksson et al., 2008, 2012a; Fournet et al., 2012; Garcia-Alloza et al., 2004; Haahr et al., 2012; Hermann et al., 2012; Huerta-Rivas et al., 2010; Jones and Moller, 2011; Lorke et al., 2006; Malá et al., 2013; Marin et al., 2012b; Marcos et al., 2006, 2008; Marshall and O’Dell, 2012; Mathur and Lovinger, 2012; Meneses, 2007a, 2007b; Meneses et al., 2011a; Na et al., 2012; Perez-Garcia et al., 2006; Perez-Garcia and Meneses, 2008a, 2009; Tellez et al., 2010, 2012a, 2012b). Importantly, amnesia and forgetting differ in mechanistic pharmacological and neuroanatomical terms (Tellez et al., 2012b).

Diverse techniques have been used in the identification of serotonergic and/or other neurotransmitter (Ersche et al., 2011; Meyer, 2012) alterations as markers of cognitive processes, including memory formation and memory disorders, ranging from autoradiography, real-time polymerase chain reaction (RT-PCR), Western blot, etc. (for review, see Meneses, 2013; Meneses and Liy-Salmeron, 2012). Even diverse serotonergic manipulations alter memory (Hindi Attar et al., 2012), certainly, 5-HT1A, 5-HT2A/2C, 5-HT3, 5-HT4, 5-HT6, and 5-HT7 receptors have attracted more scientific interest regarding memory (Bockaert et al., 2008, 2011; Cowen and Sherwood, 2013; Meneses, 1999, 2003, 2013; King et al., 2008; Ögren et al., 2008; Roth et al., 2004; Terry et al., 2008). Particularly, 5-HT1A/1B, 5-HT2A/2C, 5-HT3, 5-HT4, 5-HT6, and 5-HT7 receptors have in common that their agonists and/or antagonists seem to have promnesic and/or antiamnesic effects (Bockaert et al., 2008; Borg, 2008; Bombardi and Di Giovanni, 2013; Elvander-Tottie et al., 2009; Hajjo et al., 2012; Ivachtchenko and Ivanenkov, 2012; Ivachtchenko et al., 2012b; King et al., 2008; Meneses, 1999, 2003; Ögren et al., 2008; Pennanen et al., 2013; Roth et al., 2004; Ruiz and Oranias, 2010; Sawyer et al., 2012; Terry et al., 2008; van Praag, 2004; Youn et al., 2009; Yun and Rhim, 2011a, b; Table 2.1). The above apparent paradox remains to be explored, but before continuing discussing 5-HT systems and memory, it is important to mention the problem of protocols of training/testing, memory tasks used, and convergent and divergent findings among laboratories (Meneses, 2013).

3.1 Protocols of Training/Testing, Memory Tasks, and Drugs

Considering that the number of behavioral memory tasks is abundant (Lynch, 2004; Myhrer, 2003; Peele and Vincent, 1989; Figure 3.1). Rationale for using behavioral tasks rests on the notion that the hippocampus (and rhinal cortices) are paramount for memory formation; in consequence, the cognitive and behavioral requirements are illustrated as well as the differential complexity (based on the brain areas implicated) (Figure 3.2). Herein, we are briefly mentioning three memory tasks used for the investigation of 5-HT systems. In this context, an important issue is convergent and divergent findings among laboratories using similar or different memory tasks, animals employed, etc. (Meneses, 2013). Certainly, it is a complex and multifocal issue; hence, we are briefly addressing a few aspects. Diverse animal models allow the investigation of the various aspects of the memory and its dysfunctions, providing convergent validation of the research findings. Likewise, analysis of protocols of training/testing, memory tasks, and drugs remains as a crucial issue as well as using better devices for measuring memory (Gonzalez et al., 2013; Mar et al., 2013). Indeed, improving behavioral memory tasks and instruments for measuring memory is also important. For instance, new instruments for measuring behavior in autoshaping memory tasks are addressing issues such as variability inter-laboratories, inter-memory tasks, inter-subjects (Cook et al., 2004; Gonzalez et al., 2013; Meneses, 2003) representing significant advances (Bussey et al., 2012; Horner et al., 2013; Mar et al., 2013; Markou et al., 2013). Notably, Vanover et al. (2004) reported that the clozapine (which displays affinity for different receptors, see e.g., Meneses, 2014) failed to reach statistical significance due to individual variability but not a 5-HT2A receptor inverse agonist neither haloperidol (see Vanover et al, 2004). Of course, the interaction of drug and behavioral task results a heuristic issue for investigating. Doubtless, the inter-subject variability is a biological feature, which might be reduced by improving the instruments for measuring memory and/or as Gallistel (2009) suggests that a general solution is a sensitivity analysis: compute the odds for or against the null as a function of the limit(s) on the vagueness of the alternative. If the odds on the null approach 1 from above as the hypothesized maximum size of the possible effect approaches 0, then the data favor the null over any vaguer alternative to it. This same author suggests that the simple computations and the intuitive graphic representation of the analysis (Gallistel, 2009). Otherwise, in the...