![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 3 of 3. This is the beginning of the thread.
Posted by sdb on January 4, 2009, at 5:58:26
interestingly this is very consistent from what I heard from psychiatrists.
sdb
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Antidepressant drugs and memory: insights from animal studies.
Monleón S, Vinader-Caerols C, Arenas MC, Parra A.Department of Psychobiology, University of Valencia, Blasco Ibáñez, 21, E-46010 Valencia, Spain. santiago.monleon@uv.es <santiago.monleon@uv.es>
This is a selective review of the literature concerning the effects of antidepressant drugs on animal memory, which was performed with the aid of the PubMed database. Monoamine oxidase inhibitors tend to either have no effect on memory or result in its improvement. Studies with cyclic antidepressants have reported no effect or, more often, memory impairments. Pre-training administration of selective serotonin reuptake inhibitors (SSRIs) has been shown to have either no effect on memory or undermine it (with some isolated exceptions, in which improvements have been recorded), while post-training administration of SSRIs has been demonstrated to improve memory or have no effect. A small group formed by the remaining antidepressants has been shown to improve memory, with the exception of trazodone, which impairs memory. These findings are discussed in the light of knowledge regarding the actions of antidepressants on several neurotransmission systems. The possibility that the effects of antidepressants on memory are the core of the therapeutic effects of these drugs is also considered.
PMID: 17761406 [PubMed - indexed for MEDLINE]
Posted by sdb on January 4, 2009, at 6:09:35
In reply to AD's and memory (ssri, trazodone, mao, tca, etc.), posted by sdb on January 4, 2009, at 5:58:26
this is for informational support for people who don't have access but have interest because of whatever.
Review
Antidepressant drugs and memory: Insights from animal studies
Santiago MonleónCorresponding Author Contact Information, a, E-mail The Corresponding Author, Concepción Vinader-Caerolsa, M. Carmen Arenasa and Andrés Parraa
aDepartment of Psychobiology, University of Valencia, Blasco Ibáñez, 21, E-46010 Valencia, Spain
Received 17 April 2007;
revised 12 June 2007;
accepted 5 July 2007.
Available online 29 August 2007.Abstract
This is a selective review of the literature concerning the effects of antidepressant drugs on animal memory, which was performed with the aid of the PubMed database. Monoamine oxidase inhibitors tend to either have no effect on memory or result in its improvement. Studies with cyclic antidepressants have reported no effect or, more often, memory impairments. Pre-training administration of selective serotonin reuptake inhibitors (SSRIs) has been shown to have either no effect on memory or undermine it (with some isolated exceptions, in which improvements have been recorded), while post-training administration of SSRIs has been demonstrated to improve memory or have no effect. A small group formed by the remaining antidepressants has been shown to improve memory, with the exception of trazodone, which impairs memory. These findings are discussed in the light of knowledge regarding the actions of antidepressants on several neurotransmission systems. The possibility that the effects of antidepressants on memory are the core of the therapeutic effects of these drugs is also considered.
Keywords: Antidepressants; Memory; Learning; Rats; Mice
Article Outline1. Introduction
2. MAOIs
3. Cyclic ADs
4. SSRIs
5. Other ADs
6. Discussion
7. Conclusions
Role of the funding source
Contributors
Conflicts of interest
Acknowledgements
References1. Introduction
Antidepressant drugs (ADs) are commonly prescribed throughout the world today (e.g. [Hemels et al., 2002], [McManus et al., 2000], [Ortiz and Lozano, 2005] and [Van Marwijk et al., 2001]). They are used to treat a variety of psychiatric disorders in addition to depression. For example, they are the drug therapy of choice for severe anxiety disorders, such as agoraphobia, generalized anxiety disorder, social phobia, obsessivecompulsive disorder and post-traumatic stress disorder (Baldessarini, 2001).If depression is a mood disorder and memory a cognitive process, one might ask why the present review does not focus on the effects of ADs on mood or anxiety rather than on memory? The reasons are as follows:
a) ADs appear to be a therapeutic tool in disorders such as drug addiction (e.g. Schatzberg, 2000), enuresis (e.g. Humphreys and Reinberg, 2005) and chronic pain (e.g. Sindrup et al., 2005), in which mood and anxiety are not the main targets of the pharmacological agent. This lack of specificity in the effects of ADs suggests the existence of a common therapeutic mechanism in all the disorders in which ADs are effective. Parra (2003) hypothesised that memory impairment is central to the therapeutic action of psychotropic medications. In this context, memory should be understood as the trace left in the brain not only by individual experiences but also by genetic and epigenetic phenomena; a trace that ADs modify through a process of neural plasticity. In fact, there is a clear similarity among the molecular changes induced by different causes of neural plasticity: chronic treatment with ADs (Duman et al., 1999) or antipsychotics (Konradi and Heckers, 2001), long-term sensitization of the gill-withdrawal reflex of aplysia (Kandel, 2001), and delayed neural death after ischemic insult (Tsukahara et al., 1998).
b) Alternative treatments for depression (REM sleep deprivation and electroconvulsive shock) impair memory ([Dujardin et al., 1990] and [Mondadori et al., 1977]). Therefore, it seems reasonable to expect the same effect with ADs.
c) There is a considerable body of research but a scarcity of reviews regarding the area referred to by the title of this article. Amado-Boccara et al. (1995) reviewed the effects of ADs on cognitive functions in human beings, paying special attention to memory. However, to our knowledge, no such review of similar studies in animals has been published.
Thus, in the present article, studies of the effects of ADs on animal memory were reviewed. To this end, a PubMed search was conducted using the search terms antidepressant and memory and antidepressant and learning, and was limited to English-language articles describing studies published between 1976 and 2006 in animal subjects. From initial results (#287 and #936, respectively), a further screening was carried out in order to select those articles containing original data about the direct effects of ADs on intact animal memory.
The results are presented according to the following groups of ADs: monoamine oxidase inhibitors (MAOIs), cyclic ADs, selective serotonin reuptake inhibitors (SSRIs) and other ADs. The information regarding each group is summarized in two tables, one presenting pre-training administration and the other post-training administration studies. Each table consists of seven columns: Drug (in alphabetical order), Dose (in order of quantity for each treatment), Treatment (acute, sub-chronic or chronic), Subject (rats or mice; sex is not specified because most of the studies employed males exclusively, with the exception of those by the authors of the present article), Task (behavioural paradigm), Effect (positive, negative, or no effect), and Study (reference). The effects of each group of ADs on animal memory are also briefly commented in the text. A general discussion provides an integrated view of the reviewed literature.
2. MAOIsMAOIs were the first effective drugs used in the treatment of major depression (Baldessarini, 2001). Their antidepressant properties were discovered by chance in the 1950s when iproniazid was being developed as a treatment for tuberculosis (Slattery et al., 2004). It was later discovered that the common pharmacological action of these ADs is the inhibition of monoamine oxidase enzyme in the central nervous system, which produces a rise in norepinephrine, serotonin and dopamine in the synaptic cleft. The overall efficacy of MAOIs in major depression is comparable to that of tricyclic ADs, although more severely depressed inpatients may respond better to the latter (Frazer, 1997).
These ADs usually either have no effect on memory or result in its improvement. The scarcity of studies (see Table 1A and Table 1B) about these drugs makes it difficult to draw any firm conclusions with respect to their effects on animal memory. Nevertheless, the existence of only one study demonstrating impairing effects, while several publications report beneficial effects, could lead to the endorsement of the hypothesis of MAOIs' amphetamine-like effects, which has been frequently reported in the literature (e.g., Dilsaver, 1988), and the beneficial effects of pre- and post-training administration of amphetamine on animal learning and memory were well established decades ago (McGaugh, 1973).
Table 1A.Pre-training administration of monoamine oxidase inhibitors
DrugDose (mg/kg)TrSubjectTaskEffectStudy
Clorgyline1; 10 ARatsActive avoidance0Knoll et al. (1977)
1SCRatsActive avoidance+Knoll et al. (1977)
0.2CRatsWater maze0Barbelivien et al. (2001)
Deprenyl1; 10ARatsActive avoidance0Knoll et al. (1977)
1SCRatsActive avoidance+Knoll et al. (1977)
0.25CRatsWater maze0(Yavich et al., 1993) and (Barbelivien et al., 2001)
Moclobemide0.1; 0.5; 1ARatsInhibitory avoidance+Getova et al. (2003)
20ARatsActive avoidance0Frank and Braszko (1999)
20ARatsInhibitory avoidance0Frank and Braszko (1999)
20ARatsRecognition memory0Frank and Braszko (1999)
0.1; 0.5; 1SCRatsActive avoidance+Getova et al. (2003)
20CRatsActive avoidance+Frank and Braszko (1999)
20CRatsInhibitory avoidance+Frank and Braszko (1999)
20CRatsRecognition memory0Frank and Braszko (1999)
Pargyline1; 10CRatsWater maze0Barbelivien et al. (2001)
Phenelzine15; 30ARatsInhibitory avoidance+Parent et al. (1999)
15; 30ARatsWater maze−Parent et al. (1999)
Full-size tableAbbreviations (for this and the following tables): Tr = Treatment; A = Acute administration; SC = Sub-chronic administration (39 days); C = Chronic administration (14 days or longer); 0 = No effect; − = Memory impairment; + = Memory improvement. Doses expressed as μg were centrally administered and doses expressed as mg/kg were systemically administered. In tables of post-training administration, effects in brackets indicate that drugs were not administered immediately after the training phase, but before the test phase.
View Within Article
Table 1B.
Post-training administration of monoamine oxidase inhibitors
DrugDose (mg/kg)TrSubjectTaskEffectStudy
Deprenyl0.25ARatsSpatial maze[+]Nowakowska et al. (2001a)
0.25SCRatsSpatial maze[0]Nowakowska et al. (2001a)
0.25CRatsSpatial maze[0]Nowakowska et al. (2001a)
Moclobemide10ARatsSpatial maze[+](Nowakowska et al., 1998) and (Nowakowska et al., 2001b)
10CRatsSpatial maze[0](Nowakowska et al., 1998) and (Nowakowska et al., 2001b)
Phenelzine15; 30ARatsInhibitory avoidance[0]Parent et al. (1999)
15; 30ARatsWater maze[0]Parent et al. (1999)
Full-size tableView Within Article
Deprenyl (also called selegiline), perhaps the most studied MAOI, deserves special attention. It is widely used in clinical practice as an adjunct to L-dopa in the treatment of Parkinson's disease (e.g. [Lieberman and Frazzini, 1991] and [Murphy et al., 1987]) and has also proved to be beneficial in the treatment of Alzheimer's disease (e.g. [Knoll, 1992], [Knoll, 1993], [Knoll, 1998], [Mangoni et al., 1991], [Tariot et al., 1987] and [Wilcock et al., 2002]). In animals, deprenyl seems to be effective in correcting some of the behavioural deficits of age, which highlights potential cognitive enhancement qualities that are probably due to an increase in dopaminergic activity. For instance, a single injection of this drug facilitates acquisition of active avoidance behaviour and retention of inhibitory avoidance response in aged rats (Drago et al., 1986). Chronic treatment with deprenyl in aged rats also improves active avoidance (Carageorgiou et al., 2003), reverses the age-related deficits in object recognition memory (De Lima et al., 2005) and significantly attenuates memory deficits in the Morris water maze paradigm ([Bickford et al., 1997], [Brandeis et al., 1991], [Kiray et al., 2004], [Kiray et al., 2006] and [Yavich et al., 1996]).
3. Cyclic ADsA number of ADs belong to this group, which is based on a chemical criterion. The most important sub-group is classified as tricyclic antidepressants (TCAs), according to their chemical structure of a three-ring molecular core. In addition to TCAs, the said group includes other ADs, such as the tetracyclics maprotiline and mianserin. Imipramine was discovered quite by accident some 50 years ago during the search for new and safer antipsychotic compounds, and the TCAs dominated depression pharmacotherapy for almost 30 years, from the late 1950s until the late 1980s, when SSRIs were introduced (Stahl, 1998). Cyclic ADs elicit a wide range of neuropharmacological effects in addition to what is presumed to be their primary action of inhibiting norepinephrine and serotonin transport in the presynaptic nerve endings ([Baldessarini, 2001], [Stahl, 1998] and [Tatsumi et al., 1997]).
Studies with cyclic ADs have reported no effect, or more often memory impairments, with more homogeneous results in post-training administration (see Table 2A and Table 2B). According to several authors the impairing effects of cyclic ADs on memory in patients seem to be mainly related to the anticholinergic action of these drugs (e.g. [Amado-Boccara et al., 1995] and [Riedel and Van Praag, 1995]). Deutsch (1971) argued for the role of the cholinergic system in the storage and retrieval of information during new learning, which has received increasing acceptance. Bartus et al. (1982) stated that a serious loss of cholinergic function in the central nervous system contributes significantly to the cognitive symptoms associated with Alzheimer's disease and advanced age (for a review see Bartus, 2000). It is now clear that some of the side effects produced by many ADs are a consequence of their blocking of muscarinic cholinergic receptors. The muscarinic receptor is the dominant cholinergic receptor in the brain and seems to be primarily involved with memory and learning. Blockade of this receptor can cause, among other effects, memory dysfunction. TCAs, as a group, are clearly more effective in blocking muscarinic receptors than other types of ADs. Amitriptyline tends to produce anticholinergic side effects more frequently than other TCAs, which reflects its higher potency in blocking the said receptors ([Frazer, 1997], [Owens et al., 1997], [Richelson, 2001] and [Stahl, 1998]). The tetracyclic AD maprotiline, although to a somewhat less extent than TCAs, does block muscarinic receptors to a considerable degree ([Pinder et al., 1977] and [Richelson and Nelson, 1984]). Therefore, the deteriorating effects of cyclic ADs on animal memory can be mainly due to their anticholinergic properties. Additional findings support the hypothesis that anticholinergic action plays an important role in the memory impairment produced by these ADs. For instance, it has been found that acute and repeated treatment with desipramine enhances the amnesic effect of low doses of the anticholinergic agent scopolamine on step-through inhibitory avoidance in rats (Daws et al., 1998); it has also been reported that amitriptyline increases scopolamine-induced memory deficit in rats when administered before passive avoidance learning (Yamaguchi et al., 1995); and the impairment induced by amitriptyline can be prevented by the acetylcholinesterase inhibitor tacrine (Pavone et al., 1997).
Table 2A.
Pre-training administration of cyclic antidepressants
DrugDose (mg/kg)TrSubjectTaskEffectStudy
Amitriptyline0.5; 1; 2ARatsInhibitory avoidance0Takahashi et al. (1995)
1; 2ARatsInhibitory avoidance0Shimizu-Sasamata et al. (1993)
4ARatsInhibitory avoidance−(Shimizu-Sasamata et al., 1993) and (Takahashi et al., 1995)
5; 10; 20ARatsActive avoidance0(Archer et al., 1984) and (Danysz et al., 1988)
30AMiceInhibitory avoidance−Arenas et al. (2006)
0.5; 1SCMiceActive avoidance0Sansone (1978)
2.5; 5SCMiceActive avoidance−Sansone (1978)
5SCRatsRadial maze−McMahon et al. (1987)
5; 7.5SCMiceActive avoidance−Sansone et al. (1999)
5; 10SCMiceActive avoidance−Pavone et al. (1997)
10CRatsWater maze+Yau et al. (1995)
30CMiceInhibitory avoidance−(Everss et al., 2005) and (Parra et al., 2006)
Clomipramine5; 10; 20ARatsActive avoidance0Archer et al. (1984)
10; 20AMiceInhibitory avoidance0Fujishiro et al. (2002)
40AMiceInhibitory avoidance−Fujishiro et al. (2002)
10CRatsRadial maze−Burgos et al. (2005)
15CRatsInhibitory avoidance+Prathiba et al. (1995)
Desipramine5; 10; 20ARatsActive avoidance0(Archer et al., 1984) and (Danysz et al., 1988)
10AMiceActive avoidance−Hano et al. (1981)
10SCMiceActive avoidance−Hano et al. (1981)
10CMiceActive avoidance0Hano et al. (1981)
10CRatsRadial maze−Burgos et al. (2005)
Imipramine5; 10; 20ARatsActive avoidance0Archer et al. (1984)
0.5SCMiceActive avoidance+Sansone (1978)
1; 2.5SCMiceActive avoidance0Sansone (1978)
5SCMiceActive avoidance−Sansone (1978)
5CMiceHabituation−De Angelis (1991)
Maprotiline1; 3; 10ARatsInhibitory avoidance0Shimizu-Sasamata et al. (1993)
5; 10; 20ARatsActive avoidance0Archer et al. (1984)
2.5; 5; 10AMiceInhibitory avoidance0Vinader-Caerols et al. (2006)
5; 20AMiceInhibitory avoidance−Parra et al. (2000)
10AMiceInhibitory avoidance0Parra et al. (2000)
15; 20; 25AMiceInhibitory avoidance−Vinader-Caerols et al. (2006)
25AMiceInhibitory avoidance−Arenas et al. (2006)
15; 25SCMiceWater maze−Vinader-Caerols et al. (2002)
20SCMiceWater maze0Vinader-Caerols et al. (2002)
5; 20CMiceInhibitory avoidance−Parra et al. (2000)
10CMiceInhibitory avoidance0Parra et al. (2000)
Mianserin5; 10; 20ARatsActive avoidance0Archer et al. (1984)
10AMiceActive avoidance−Hano et al. (1981)
10SCMiceActive avoidance−Hano et al. (1981)
10CMiceActive avoidance0Hano et al. (1981)
Nortriptyline5; 10; 20ARatsActive avoidance0Archer et al. (1984)
Full-size tableView Within Article
Table 2B.
Post-training administration of cyclic antidepressants
DrugDoseTrSubjectTaskEffectStudy
Amitriptyline1 mg/kgAMiceInhibitory avoidance0Kumar and Kulkarni (1996)
5 mg/kgAMiceActive avoidance[−](Pavone et al., 1997) and (Sansone et al., 1999)
5; 10 mg/kgAMiceInhibitory avoidance−Kumar and Kulkarni (1996)
7.5; 15; 30 mg/kgAMiceInhibitory avoidance−(Everss et al., 1999) and (Parra et al., 2002)
30 mg/kgAMiceInhibitory avoidance−Everss et al. (2005)
30 mg/kgAMiceInhibitory avoidance0Arenas et al. (2006)
30 mg/kgCMiceInhibitory avoidance[0]Parra et al. (2006)
Desipramine1 mg/kgARatsActive avoidance[0]McElroy et al. (1989)
3; 10; 30 mg/kgARatsActive avoidance[−]McElroy et al. (1989)
10 mg/kgSCMiceActive avoidance−Sansone et al. (1995)
Imipramine2 μgARatsInhibitory avoidance0Zarrindast et al. (2003)
1; 2; 4; 6 μgARatsInhibitory avoidance−Zarrindast et al. (2004)
4; 6; 8 μgARatsInhibitory avoidance−Zarrindast et al. (2003)
1 mg/kgAMiceInhibitory avoidance0Kumar and Kulkarni (1996)
5 mg/kgAMiceHabituation−De Angelis (1990)
5; 10 mg/kgAMiceInhibitory avoidance−Kumar and Kulkarni (1996)
5; 10; 20; 40 mg/kgARatsInhibitory avoidance−Zarrindast et al. (2004)
16; 28; 50 mg/kgARatsActive avoidance[−]Rodríguez (1992)
20 mg/kgARatsSpatial maze[0]Nowakowska et al. (2003)
20 mg/kgSCRatsSpatial maze[0]Nowakowska et al. (2003)
20 mg/kgCRatsSpatial maze[0]Nowakowska et al. (2003)
Maprotiline5; 10; 20 mg/kgAMiceInhibitory avoidance0Parra et al. (2000)
25 mg/kgAMiceInhibitory avoidance[0]Arenas et al. (2006)
Full-size tableView Within Article
4. SSRIsThese chemically diverse ADs share a common characteristic; namely, their selective blocking of the reuptake of serotonin (5-HT) in vivo ([Frazer, 1997], [Fuller, 1995] and [Hyttel, 1994]). The overall efficacy of these drugs is comparable to that of TCAs (Frazer, 1997), and so they soon became the antidepressant prescription drug of choice after their introduction into the market in the 1980s (Slattery et al., 2004), accounting for over half the antidepressant prescriptions in the United States (Stahl, 1998). The principal advantage of these drugs over the classic MAOIs and TCAs is their greater safety and tolerability (Stahl, 1998), with the exception of zimeldine, which was withdrawn from clinical practice due to toxic side effects that were unrelated to its effects on cognitive functioning (Thompson, 1991).
At a first glance at Table 3A, an unexpected finding stands out: the high number of studies in which an impairing effect is reported. Taking into account that these drugs have a considerably low affinity for muscarinic cholinergic receptors, the said effect must be due to their action on other receptors. The first suspects are the 5-HT receptors. There are a number of studies indicating that serotonergic neurons play a significant role in learning and memory processes (e.g. [Altman et al., 1984], [Altman and Normile, 1988], [Hong and Meneses, 1995] and [Meneses, 1999]), but the precise nature of this regulation is unclear. Nevertheless, the following three studies, which represent three different research strategies, reinforce the idea that memory is impaired by an increased serotonergic activity: (a) microinfusions of 8-HO-DPAT, a 5-HT1A agonist, interfered with short-term memory of inhibitory avoidance when administered to the hippocampus, and interfered with long-term memory formation and promoted short-term memory when administered to the entorhinal cortex (Izquierdo et al., 1998); (b) SSRIs enhance the action of the 5-HT pathway, which suppresses pyramidal neuron activity in the hippocampus (Mongeau et al., 1997); and (c) the serotonin agonist m-chlorophenylpiperazine produced a deterioration in recent memory and knowledge memory in patients with Alzheimer's disease and, to a less degree, in controls (Lawlor et al., 1989).
Table 3A.
Pre-training administration of selective serotonine reuptake inhibitors
DrugDoseTrSubjectTaskEffectStudy
Alaproclate3; 30 mg/kgARatsInhibitory avoidance0Shimizu-Sasamata et al. (1993)
5; 10; 20 mg/kgARatsActive avoidance0Archer et al. (1984)
10 mg/kgARatsInhibitory avoidance+Shimizu-Sasamata et al. (1993)
10; 20; 40 mg/kgARatsActive avoidance0Danysz et al. (1988)
20 mg/kgARatsFear conditioning0Archer et al. (1984)
2.5 mg/kgSCRatsWater maze0Riekkinen et al. (1991)
5; 10; 20 mg/kgSCRatsActive avoidance0Archer et al. (1984)
7.5; 20 mg/kgSCRatsWater maze−Riekkinen et al. (1991)
Citalopram1; 3 mg/kgARatsInhibitory avoidance0Shimizu-Sasamata et al. (1993)
5 mg/kgARatsActive avoidance0Archer et al. (1984)
10 mg/kgARatsInhibitory avoidance+Shimizu-Sasamata et al. (1993)
10; 20 mg/kgARatsActive avoidance−Archer et al. (1984)
1; 2 mg/kgSCRatsWater maze0(Naghdi and Majlessi, 2000) and (Majlessi and Naghdi, 2002)
4; 8 mg/kgSCRatsWater maze−(Naghdi and Majlessi, 2000) and (Majlessi and Naghdi, 2002)
Fluoxetine70 μgAMiceActive avoidance0Flood et al. (1988)
0.25 mg/kgAMiceActive avoidance0Flood and Cherkin (1987)
0.5; 1; 2.5; 5; 10 mg/kgAMiceActive avoidance+Flood and Cherkin (1987)
3; 10 mg/kgARatsActive avoidance0Joly and Sanger (1986)
3; 10 mg/kgARatsInhibitory avoidance0Joly and Sanger (1986)
5; 10 mg/kgARatsActive avoidance0Archer et al. (1984)
10 mg/kgARatsConditioned R.−Meneses and Hong (1995)
15 mg/kgAMiceInhibitory avoidance0Arenas et al. (2006)
15 mg/kgARatsShock-probe test0Degroot and Nomikos (2005)
20 mg/kgARatsActive avoidance−Archer et al. (1984)
20 mg/kgAMiceActive avoidance0Flood and Cherkin (1987)
25; 30; 35 mg/kgAMiceActive avoidance−Flood and Cherkin (1987)
30 mg/kgARatsActive avoidance−Joly and Sanger (1986)
30 mg/kgARatsInhibitory avoidance−Joly and Sanger (1986)
1; 2; 4 mg/kgSCRatsWater maze0Majlessi and Naghdi (2002)
2.5; 5; 10 mg/kgSCRatsActive avoidance−McElroy et al. (1982)
8; 16 mg/kgSCRatsWater maze−Majlessi and Naghdi (2002)
10 mg/kgSCRatsWater maze0Yau et al. (2001)
10 mg/kgSCMiceRadial maze−Jaffard et al. (1991)
10 mg/kgSCRatsActive avoidance−Nelson et al. (1997)
1 mg/kgCRatsWater maze0Stewart and Reid (2000)
10 mg/kgCRatsWater maze0Yau et al. (2002)
20 mg/kgCMiceInhibitory avoidance−Monleón et al. (2002)
20 mg/kgCRatsInhibitory avoidance−Ulak et al. (2006)
Fluvoxamine5; 10; 20 mg/kgARatsActive avoidance0Archer et al. (1984)
20; 40, 80 mg/kgAMiceInhibitory avoidance0Fujishiro et al. (2002)
Paroxetine8 mg/kgAMiceInhibitory avoidance0Fujishiro et al. (2002)
16; 32 mg/kgAMiceInhibitory avoidance−Fujishiro et al. (2002)
Zimeldine2.5 mg/kgARatsActive avoidance0(Archer et al., 1984) and (Danysz et al., 1988)
3; 30 mg/kgARatsInhibitory avoidance0Shimizu-Sasamata et al. (1993)
5; 10 mg/kgARatsActive avoidance−Danysz et al. (1988)
5; 10; 20 mg/kgARatsActive avoidance−Archer et al. (1984)
5; 10; 20 mg/kgARatsInhibitory avoidance0Joly and Sanger (1986)
10 mg/kgARatsInhibitory avoidance+Shimizu-Sasamata et al. (1993)
20 mg/kgARatsFear conditioning0Archer et al. (1984)
2.5 mg/kgSCRatsActive avoidance0Archer et al. (1984)
5 mg/kgSCRatsRadial maze0McMahon et al. (1987)
5; 10; 20 mg/kgSCRatsActive avoidance−Archer et al. (1984)
Full-size tableView Within Article
With respect to the post-training administration of SSRIs, the most striking finding is the absence of impairing effects (see Table 3B), which were expected based on the frequency with which they are observed after pre-training administration. In the case of memory-impairing drugs, for example scopolamine (Rush, 1988), the effects of post-training administration are slighter than those of pre-training administration. Meneses (2003), evaluating the involvement of the 5-HT function in a Pavlovian/instrumental autoshaped memory consolidation exercise, attributed facilitatory or inhibitory effects to actions on specific 5-HT receptor subtypes. Consulting Table 3A and Table 3B, it can be seen that, depending on whether administration is pre- or post-training, the effects are inhibitory or facilitatory, respectively. As SSRIs increase the presence of 5-HT in every subtype of these receptors, it can be hypothesised that the role of each 5-HT receptor subtype is more crucial at a given moment than at another. It seems that the effects of SSRIs are memory phase-dependent, being inhibitory during acquisition/consolidation (pre-training administration) and facilitatory during consolidation and retrieval (post-training administration).Table 3B.
Post-training administration of selective serotonine reuptake inhibitors
DrugDoseTrSubjectTaskEffectStudy
Alaproclate20 mg/kgAMiceInhibitory avoidance[0]Altman et al. (1984)
40, 60 mg/kgAMiceInhibitory avoidance[+]Altman et al. (1984)
Fluoxetine1; 3; 10 μgARatsInhibitory avoidance0Introini-Collison et al. (1992)
3; 12 μgARatsInhibitory avoidance0Lee et al. (1992)
4 μgAMiceActive avoidance0Flood and Cherkin (1987)
6 μgARatsInhibitory avoidance+Lee et al. (1992)
8; 16; 20; 24 μgAMiceActive avoidance+Flood and Cherkin (1987)
70 μgAMiceActive avoidance+Flood et al. (1988)
1 mg/kgARatsConditioned R.0Meneses (2002)
1; 5; 10 mg/kgAMiceInhibitory avoidance0Kumar and Kulkarni (1996)
1.25; 2.5 mg/kgARatsConditioned R.0Meneses and Hong (1995)
2.5 mg/kgAMiceActive avoidance0Flood and Cherkin (1987)
5 mg/kgARatsInhibitory avoidance[+]Nowakowska et al. (1996)
5 mg/kgARatsSpatial maze[+](Nowakowska et al., 1996) and (Nowakowska et al., 2000)
5; 10 mg/kgAMiceInhibitory avoidance0(Flood and Cherkin, 1987) and (Monleón et al., 2001)
5; 10 mg/kgARatsConditioned R.+(Meneses and Hong, 1995) and (Meneses, 2002)
10 mg/kgARatsConditioned R.+Hong and Meneses (1995)
5; 10; 15 mg/kgAMiceActive avoidance+Flood and Cherkin (1987)
15 mg/kgAMiceInhibitory avoidance+Flood and Cherkin (1987)
15 mg/kgAMiceInhibitory avoidance[0]Arenas et al. (2006)
15 mg/kgARatsInhibitory avoidance+Introini-Collison et al. (1992)
20 mg/kgAMiceInhibitory avoidance+Monleón et al. (2001)
20; 25 mg/kgAMiceInhibitory avoidance0Flood and Cherkin (1987)
5 mg/kgSCRatsInhibitory avoidance[0]Nowakowska et al. (1996)
5 mg/kgSCRatsSpatial maze[+](Nowakowska et al., 1996) and (Nowakowska et al., 2000)
5 mg/kgCRatsInhibitory avoidance[+]Nowakowska et al. (1996)
5 mg/kgCRatsSpatial maze[+](Nowakowska et al., 1996) and (Nowakowska et al., 2000)
20 mg/kgCMiceInhibitory avoidance[0]Monleón et al. (2002)
Sertraline3.3; 10 mg/kgARatsInhibitory avoidance[+]Barros et al. (2002)
Zimeldine5 μgARatsInhibitory avoidance0Lee et al. (1992)
10 μgARatsInhibitory avoidance+Lee et al. (1992)
20 mg/kgAMiceInhibitory avoidance[0]Altman et al. (1984)
40, 60 mg/kgAMiceInhibitory avoidance[+]Altman et al. (1984)
Full-size tableView Within Article
The positive effects of some SSRIs on memory have also been shown by counteracting the memory impairment produced by other agents. For instance, fluoxetine reverses inhibitory avoidance impairment in rats induced by olfactory bulbectomy ([Broekkamp et al., 1980] and [Garrigou et al., 1981]), hypoxia (Strek et al., 1989), scopolamine and electroconvulsive shock (Nowakowska et al., 1996).
5. Other ADsThis section deals with a heterogeneous group of antidepressants whose efficacy is reported to be comparable to that of standard ADs (Frazer, 1997). These drugs have distinct pharmacological profiles. Bupropion acts through a dual inhibition of norepinephrine and dopamine reuptake, and has no clinically significant serotonergic effects or direct effects on postsynaptic receptors (Stahl et al., 2004). By inhibiting dopamine reuptake, this drug provides effective treatment during smoking cessation, when craving due to nicotine withdrawal may be mitigated by boosting dopamine ([Stahl, 1998] and [Stahl et al., 2004]). Mirtazapine is best described as a noradrenergic and specific serotonergic antidepressant (NaSSA) (Stimmel et al., 1997). Tianeptine is a compound with structural similarities to TCAs (McEwen and Olié, 2005) but which, unlike TCAs or SSRIs, possesses the unique property of increasing serotonin uptake and decreasing extracellular serotonin ([Datla and Curzon, 1993], [Fattaccini et al., 1990] and [Mennini et al., 1987]). Trazodone is a potent serotonin receptor-blocking agent with no significant affinity for muscarinic cholinergic receptors (Frazer, 1997). Its action in the serotonergic system is complex, as the parent compound and its metabolite exert opposite effects, the former inhibiting and the latter stimulating this neurotransmission system (Maj et al., 1979). Venlafaxine is a norepinephrine and serotonin reuptake inhibitor antidepressant ([Artigas, 1995] and [Slattery et al., 2004]) which, similarly to trazodone, has no significant affinity for muscarinic cholinergic receptors. This atypical AD has a side effect profile similar to that of SSRIs, but it does not seem to exert the stimulant effect seen with fluoxetine (Frazer, 1997).
The ADs of this heterogeneous group tend to improve memory, with the main exception of trazodone, which has been found to impair memory. The improving effects of some of these atypical ADs on memory have also been shown by alleviating memory deficits of several origins (not included in Tables). For example, tianeptine completely alleviates the T-maze deficit induced by long-term ethanol consumption in mice (Jaffard et al., 1991); prevents the stress-induced impairments of spatial memory in the radial maze (Luine et al., 1994) and Y-maze (Conrad et al., 1996); enhances memory retention in rats whose rate of spatial memory loss in the water maze had been augmented through partial lesions of the diagonal band of Broca, a structure that carries important neuromodulatory input to the hippocampus (Morris et al., 2001); reverses the impairment of memory produced by scopolamine in a conditioned response in rats (Meneses, 2002); and blocks the deleterious effects of predator stress on spatial memory in the same species (Campbell et al., 2003).
Nevertheless, the scarcity of studies about these drugs (see Table 4A and Table 4B) hinders the establishment of a consensus regarding their effects. Furthermore, only one post-training study (Meneses, 2002) has evaluated the direct effects of these drugs on memory consolidation (see Table 4B).
Table 4A.
Pre-training administration of other antidepressants
DrugDose (mg/kg)TrSubjectTaskEffectStudy
Tianeptine2.5; 5AMiceT-maze0Jaffard et al. (1991)
10AMiceT-maze+Jaffard et al. (1991)
2.5SCMiceRadial maze0Jaffard et al. (1991)
5; 10SCMiceRadial maze+Jaffard et al. (1991)
Trazodone5; 10SCMiceActive avoidance−Sansone et al. (1985a)
Venlafaxine20ARatsWater maze+Nowakowska et al. (2006)
10SCRatsWater maze0Yau et al. (2001)
20CRatsInhibitory avoidance−Ulak et al. (2006)
20CRatsWater maze+(Nowakowska and Kus, 2005) and (Nowakowska et al., 2006)
Full-size tableView Within Article
Table 4B.
Post-training administration of other antidepressants
DrugDose (mg/kg)TrSubjectTaskEffectStudy
Bupropion20; 60ARatsInhibitory avoidance[+]Barros et al. (2002)
Mirtazapine2.5ARatsActive avoidance[0]Nowakowska et al. (1999)
2.5ARatsSpatial maze[+]Nowakowska et al. (1999)
2.5SCRatsSpatial maze[0]Nowakowska et al. (1999)
2.5CRatsSpatial maze[0]Nowakowska et al. (1999)
Tianeptine1; 2.5ARatsConditioned R.0Meneses (2002)
5ARatsSpatial maze[0]Nowakowska et al. (2000)
5; 10ARatsConditioned R.+Meneses (2002)
5SCRatsSpatial maze[0]Nowakowska et al. (2000)
5CRatsSpatial maze[0]Nowakowska et al. (2000)
Trazodone2AMiceActive avoidance[0]Sansone et al. (1985b)
4.5; 9; 18; 36ARatsActive avoidance[−]Martin et al. (1989)
5, 10AMiceActive avoidance[−](Sansone et al., 1983) and (Sansone et al., 1985b)
10AMiceActive avoidance[−]Vetulani et al. (1984)
Venlafaxine20ARatsSpatial maze[+](Nowakowska et al., 2002) and (Nowakowska et al., 2003)
20ARatsWater maze[+]Nowakowska et al. (2002)
20SCRatsSpatial maze[+](Nowakowska et al., 2002) and (Nowakowska et al., 2003)
20SCRatsWater maze[+]Nowakowska et al. (2002)
20CRatsSpatial maze[+](Nowakowska et al., 2002) and (Nowakowska et al., 2003)
20CRatsWater maze[+]Nowakowska et al. (2002)
Full-size tableView Within Article
6. DiscussionThe impairing effects of ADs on memory are not necessarily or exclusively due to anticholinergic actions, as said impairment has been observed with drugs with no anticholinergic properties, as in the case of pre-training administration of some SSRIs (see Table 3A). In addition, it has been suggested that serotonergic and cholinergic systems interact in a complex manner in the regulation of learning and memory functions ([Ögren et al., 1985] and [Vanderwolf, 1987]). Noradrenergic pathways are also thought to play an important role in the modulation of learning and memory (e.g. [Introini-Collison et al., 1992] and [Zarrindast et al., 2003]). Therefore, the effects of ADs on memory may be attributable to a combination of the neuropharmacological properties of these drugs, including anticholinergic, antihistaminergic, serotonergic and noradrenergic activity. Furthermore, the administration of a selective drug directly affects the neurotransmitter system whose neurons have receptors with affinity for that drug, and indirectly affects the systems that interact with it (Tremblay and Blier, 2006).
In the case of every AD group, a small proportion of the studies carried out have evaluated chronic administration; however, acute or sub-chronic administrations are not appropriate models for clinical practice. Further studies of chronic administration are necessary in order to subsequently extrapolate findings to human beings. Nevertheless this extrapolation will always be difficult because memory impairment is a part of depression (e.g. Burt et al., 1995).
Although not numerous, existing studies report significant effects of chronic AD administration on memory. This reveals a lack of tolerance, which suggests that the influence of ADs on memory is independent of the actions responsible for their side effects in human beings, since tolerance to these effects tends to develop when treatment is prolonged (Baldessarini, 2001).
It has been proposed that the effect on memory of ADs and other psychotropic medication underlies the therapeutic effects of these drugs (Parra, 2003). Memory is understood in this context as the trace left in the brain not only by individual experiences but also by genetic and epigenetic phenomena. It can be considered that the brain contains a variety of neural systems, each of which is integrated by those parts that work together in order to produce one of the species' common behaviours. For example, the neural system of aggression in rodents has been well defined (Moyer, 1980). There are other neural systems, although not yet well understood, that work to develop complex mental states such as mood. These systems are hereditary, but every subject expresses individual differences. Moreover, a given system oscillates in its sensitivity. These individual differences and oscillations can be interpreted, in the sense defined above, as memory. From this point of view, memory systems are not the only systems with memory in the brain. It can be said that each neural system has its own memory, and ADs would seem to modify the memory of each of these systems (Parra, 2003). Unfortunately, most of the studies reviewed here did not consider memory from this perspective, which makes it difficult to draw an integrated conclusion. In any case, it has recently been suggested that inhibition on the function of NMDA (N-methyl-d-aspartate)-Ca++-NOS (nitric oxide synthase) signal pathway appears to be one of the common actions for antidepressants despite their remarkably different structures (Li et al., 2006), and the relationship between NMDA receptors and learning and memory processes is well established (Castellano et al., 2001).
The effects of ADs on memory processes could be mediated by additional cerebral mechanisms. For instance, a significant property of some ADs is their promotion of neurogenesis in the hippocampus when administered chronically ([Malberg et al., 2000] and [Manev et al., 2001a]). In this way, fluoxetine particularly increases the content of neurotrophic factors in this region (Manev et al., 2001b). Considering that neurogenesis could subserve long-term potentiation (Snyder et al., 2001) and learning (Shors et al., 2001), it could be argued that ADs only improve memory. Their impairment of memory could, nevertheless, still be a reality, as experimental extinction of previously learned behaviours seems to be a result of the learning of new behaviours that are incompatible with those acquired earlier (Rescorla, 2001). Furthermore, some studies show that extinction involves the synthesis of new proteins ([Nader et al., 2000] and [Vianna et al., 2001]). Thus, the role of ADs could be their impairment of old memories through the promotion of new ones.
Although it is unclear which brain regions are involved in the behavioural effects of ADs, a number of studies suggest that antidepressant treatment increases synaptic plasticity in brain regions associated with mood disorders and memory, such as hippocampus, amygdala and prefrontal cortex (e.g. [Perera et al., 2007], [Sairanen et al., 2007] and [Vouimba et al., 2006]).
Studies in our laboratory are the only ones among those referred to in the present review to have employed subjects of both sexes. Most preclinical trials involve only males, due to a supposedly higher variability among females, although this seems a somewhat inappropriate policy given that women consume more psychotropic medication than men (Cafferata et al., 1983). Moreover, phases 1 and 2 of clinical trials are carried out mainly in men. United States guidelines dating from 1977 stipulated the exclusive use of males in clinical trials. In 1993, new guidelines (Merkatz et al., 1993) recommended the use of women and minorities in phase 3. The reason for the inclusion or exclusion of males and females in such studies should be based not on politics, but on scientific rationale. There are data showing that the theoretically higher variability of females is not a general phenomenon (Parra et al., 1999 A. Parra, M.C. Arenas, S. Monleón, C. Vinader-Caerols and V.M. Simón, Sex differences in the effects of neuroleptics on escapeavoidance behavior in mice: a review, Pharmacol. Biochem. Behav. 64 (1999), pp. 813820. Article | PDF (92 K) | View Record in Scopus | Cited By in Scopus (15)Parra et al., 1999). Furthermore, there are important reasons for evaluating the impact of ADs on both male and female subjects: (a) the gender differences in the epidemiology of depression, which has a higher incidence in women than in men ([American Psychiatric Association, 1994] and [Kornstein, 1997]); (b) the gender differences in the efficacy of some ADs, such as maprotiline and fluoxetine (Martényi et al., 2001); and finally, (c) differences in pharmacokinetics and pharmacodynamics between men and women have been reported for several drugs, including ADs ([Frackiewicz et al., 2000] and [Gandhi et al., 2004]).
In order to form a global view, it is useful to note that there is an imbalance among the proportions of groups of animals receiving positive or negative rewards. Specifically, the percentage of those positively rewarded was 12%. More equilibrated proportions could also clarify the nature of the relationship of ADs and memory.
7. ConclusionsAnimal studies provide several valuable insights into the effects of ADs on memory:
1. The observed memory impairment produced by several ADs is not confined to those with anticholinergic properties.
2. Although the studies involving chronic AD administration are relatively few, they reveal an absence of tolerance, which has to be present whatever the mechanism responsible of the therapeutic effects of ADs is.
3. When the effects of ADs are assessed, in addition to their effects on mood and anxiety, those on cognitive processes, such as learning and memory, should also be considered.
4. The plethora of studies performed with aversive stimuli is understandable given the negative reality of depression. However, the scarcity of studies involving female subjects is less comprehensible and indeed inexcusable given that the incidence of depression is much higher among women than among men.
Role of the funding source
Funding for this study was provided by Ministerio de Ciencia y Tecnología of Spain and the European Regional Development Fund (ERDF) of the European Union (Grant, BSO2003-07163). These sponsors had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
ContributorsAndrés Parra designed this study and the working protocol. Santiago Monleón coordinated the work, managed the literature searches and wrote the first draft of the manuscript. M. Carmen Arenas, Concepción Vinader and Andrés Parra revised the manuscript and suggested improving modifications. All authors contributed to and have approved the final manuscript.
Conflicts of interestAll authors declare that they have no conflicts of interest.
AcknowledgementsThe authors wish to thank the Ministerio de Ciencia y Tecnología of Spain and the European Regional Development Fund (ERDF) of the European Union (Grant, BSO2003-07163) for their funding. We also wish to thank Mr. Brian Normanly for his English editorial assistance.
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Posted by greenmtn on January 10, 2009, at 6:35:40
In reply to Re: AD's and memory (full text), posted by sdb on January 4, 2009, at 6:09:35
This is very interesting in light of my experience with Emsam (transdermal Selegiline- an MAOI)...the 9 mg patch. I am a 54 old male and have been on Emsam for almost 2 years. I returned to college in spring of '08 after over 30 years of stressful life in a management job. In my early 20's I attended college and was an OK 2.85 GPA student. Now my GPA is over 3.5 and am taking more difficult courses. A's in easier courses. I got a B in Anatomy & Physiology 1 this past fall semester with a teacher who is quite difficult.
The upshot of all this is that I believe that Emsam (Selegiline) is a potent brain stimulant to an older person like myself.
By the way my recent experience with Gabapentin is that it really slowed my brain down. I'm going off it.
This is the end of the thread.
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