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Psychoactive drugs and neuroplasticity



The influence of psychoactive drugs on neuroplasticity, especially on neurogenesis is reviewed. From psychopharmacological point of view most interesting results are those showing neurogenesis that neurogenesis is increased by SSRI. However, the role of serotonin system in neurogenesis as well as significance of neurogenesis in the beneficial effect of psychotropic drugs requires a lot of additional and new inventive research.
Psychiatria Danubina, 2007; Vol. 19, No. 3, pp 202–205 Conference paper
© Medicinska naklada - Zagreb, Croatia
Zdravko Lackoviü
Laboratory of Molecular Neuropsychopharmacology, Department of Pharmacology & Croatian Brain
Research Institute, University of Zagreb Medical School, Zagreb, Croatia
The influence of psychoactive drugs on neuroplasticity, especially on
neurogenesis is reviewed. From psychopharmacological point of view most
interesting results are those showing neurogenesis that neurogenesis is increased by
SSRI. However, the role of serotonin system in neurogenesis as well as significance
of neurogenesis in the beneficial effect of psychotropic drugs requires a lot of
additional and new inventive research.
Key words: neurogenesis – neuroplasticity – SSRI - psychopharmacology
* * * * *
‘‘In the adult centers the nerve paths are
something fixed, ended and immutable.
Everything may die, nothing may be
Ramon y Cajal’s Degeneration
and Regeneration of the Nervous
System (1928).
The acute mechanism of action of
psychoactive drugs is textbook knowledge:
 Antipsychotic (neuroleptic) drugs block D2
dopamine receptors, new generation might
block other dopamine receptors like D4 (for
example clozapine), and some serotonin
receptors like 5-HT A2.
 Antidepressants block monoamine oxidase
(MAO, MAO-An isoenzyme might be more
important) or block reuptake (at molecular
level: synaptic monoamine transporter), classi-
cal antidepressants are monoamine non-
selective, new are selective for some mono-
amine, SSRI being the best known example.
 The most important anxiolytics stimulate
benzodiazepine receptors and thus
alosterically activate a population of GABA-A
 Mood stabilizers might have different
mechanism of acute molecular action but we
learn a lot about it.
 More recent knowledge is that the most
important psychostimulants act as 0 “substrate
like releasers”.
 Hallucinogenic drugs in general have no use in
psychiatry but might be the cause of serious
psychiatric problems. Their mechanism of
action might be very different: stimulation of
5-HT2 receptors (LSD), or kappa opioid
receptor (salvinorin A) partial block of
NMDA glutamate (phencyclidine, PCP)
receptor, muscarinic receptors (QNB) etc.
The acute molecular mechanism of action of
psychoactive drugs is textbook knowledge. The
acute molecular mechanism of action of
psychoactive drugs has been known for 30 or more
years. However, we are still not able to understand
an association, for example, of D2 receptor
blockade and beneficial effect in schizophrenic
patients. It might sound ironically but in acute
mechanism of action of psychotropic drugs it is
more helpful to understand why they are producing
particular side effects (for example extrapiramidal
Psychiatria Danubina, 2007; Vol. 19, No. 3, pp 202–205
in the case of antipsychotic) than why they are
useful in psychiatric patients. In an attempt to
elucidate this question psychiatric research was
tempted to investigate for example possible
alterations in dopamine system in schizophrenia
etc. Every new piece in the puzzle of molecular
psychopharmacology, like the discovery of a new
generation of neuroleptic with serotonin receptor
activity, represented a new boost in biological
psychiatry research. The same excitements
happened with the discovery of recently unknown
or unappreciated phenomenon of neuroplasticity.
Neuroplasticity, brain plasticity, synaptic
plasticity, molecular plasticity are poorly defined
terms (Table 1) used to describe changes in
biochemical mechanisms like the number of
receptors or changes in signaling, functional
changes or microscopic (new synapses formation)
or even macroscopic changes in the brain in
adulthood or in different stages of brain
Biochemical plasticity caused by psychoactive
drugs at synaptic level like adaptive changes in the
number of receptors (supersensitivity or
subsensitivity) prove to be useful, ironically again
mostly in understanding the side effects of
psychotropic drugs.
Table 1. Fundamental biological processes and
pathophysiological mechanisms (Muresanu 2007)
Neurotrophicity Excitotoxicity
Free radicals
Neuroprotection Metabolic dysfunction
Neuroplasticity Apoptosis like processes
Protein misfolding
Genetic conditions
The most important observation influencing
plasticity in adult brain includes:
1. Research on neurodegeneration, through
which, as the most important discovery, we
learned about factors permitting axonal
regeneration in peripheral nerves and
preventing it in the brain. Starting with research
from Aguayo group in early 80-ies (David &
Aguayo 1981) we know that 3 most important
inhibitors of regeneration have been identified
in myelin in the brain: (1) Myelin-Associated
Glycoprotein (MAG), (2) Nogo
-A, and (3)
Oligodendrocyte-Myelin glycoprotein (OMgp).
This is now a process we can manipulate for
example with: (a) - Nogo neutralizing
antibodies, active vaccination/T cell therapy
(b), Nogo gene deletions, Nogo mRNA
antisense (c), the NgR blocking peptide NEP1–
40 (d), and signaling molecules: Rho-A or
ROCK inactivation (e), cAMP (Rolipram™
(PDE-IV inhibitor). Different approaches can
lead to enhanced sprouting of fibers rostral to
the lesion and to fibres crossing the lesion on
remaining tissue bridges into the caudal spinal
cord and growing down the spinal cord over
long distances. Spared fibers also show
enhanced sprouting in the caudal spinal cord.
However, up to now there has been no
consistent demonstration that the regeneration
process can be consistently influenced by
psychotropic drugs, and thus it seems that this
area of research is for the time being more
important for neurology than for psychiatry.
2. Research on neurogenesis.
One of the long–lasting dogmas of
neurobiology is that when nerve cells in the
vertebrate brain die, they are not replaced by new
ones. However, in the mid 60-ies researchers
observed that new neurons formation continue into
adulthood in discrete regions of the adult rat brain,
but those discoveries did not attract as much
attention as they deserved. It has been known for a
long time that when the adult canary needs to learn
new songs, it does grow some new neurons and,
due to the reasons unknown, the importance of
neurogenesis was for a long time viewed by many
scientists as being important primarily for a canary
song. Although neurogenesis in human brain was
noted almost 20 years ago, major attention was
attracted by the observation of Eriksson at all.
Psychiatria Danubina, 2007; Vol. 19, No. 3, pp 202–205
1988 who first using more sophisticated methods
(bromodeoxyuridine and one of the neuronal
markers, NeuN, calbindin or neuron specific
enolase) demonstrated neurogenesis in adult
human hippocampus. Since that time, discovery
interest in neurogenesis has been growing slowly,
maybe with more theoretical interest than hard
research (table 2).
Table 2. Number of papers on neurogenesis (Title/Title abstract) after demonstration of its existence in
human hippocampus (Eriksson et al. 1998)
1998 187 45 232
1999 178 68 246
2000 253 62 315
2001 323 74 397
2002 321 110 431
2003 339 130 469
2004 433 143 576
2005 675 159 734
2006 690 164 854
In adult mammalian brain, significant rates of
adult neurogenesis are restricted to two brain
regions, the olfactory bulb and the hippocampus.
In the hippocampus, progenitor cells are located in
the subgranular zone where they divide and give
rise to new neurons. A recent detailed analysis of
neurogenesis reports that there are approximately
9,000 new cells per day in an adult rodent
hippocampus. Approximately 50% of these cells
differentiate and express cellular markers
characteristic of neurons. These findings indicate
that the number of new neurons, presumably with
distinct characteristics, would be sufficient to
contribute in a significant manner to the function
of hippocampus. Exact determinations of the
number of new neurons in primate brain have not
been conducted, but it has been estimated that
there may be 10 to 20% of the number of newborn
cells observed in a rodent brain. Such number of
new neurons would be sufficient to influence the
function of hippocampus (Cameron & McKay
2001). Adult neurogenesis seems to be a dynamic
process, regulated by neuronal activity and
environmental factors. It has been suggested that
neurogenesis plays a role in several important
neuronal functions, including learning, memory,
and response to novelty. In addition, exposure to
psychotropic drugs or stress regulates the rate of
neurogenesis in adult brain, suggesting a possible
role for neurogenesis in the pathophysiology and
treatment of neurobiological illnesses such as
depression, post-traumatic stress disorder, and drug
abuse (Duman et al. 2001).
In the field of depression research the major
findings are the observations that treatment with
antidepressant drugs increases hippocampal
neurogenesis. The most promising in that respect,
SSRI as well as serotonergic system, seem to be
one of the most important neurotransmitter poten-
tially regulating neurogenesis in the brain. Additio-
nally the clinical effects of antidepressants take
several weeks to manifest, suggesting that these
drugs induce adaptive changes in brain structures
affected by anxiety and depression. In this respect
neurogenesis perfectly fits expectations of clinical
science (Malberg et al. 2000, Manev et al. 2001,
Nakagawa et al. 2002). Unfortunately, the effect of
other serotonergic drugs is less consistent (see for
example Brezun & Daszuta 1999, Jhaa 2006).
Although hippocampus, where neurogenesis is
most intensive, does not directly influence mood,
connections with other brain regions such as the
amygdala and prefrontal cortex could result in the
regulation of emotional state and news about
neurogenesis have been accompanied with
increasing enthusiasm.
Psychiatria Danubina, 2007; Vol. 19, No. 3, pp 202–205
However, not all authors share enthusiasm
about neurogenesis and depression. The data from
the animal models tested to date show that
decreasing the rate of neurogenesis does not lead to
depressive behavior. Furthermore, evidence shows
that an effective treatment for depression,
transcranial magnetic stimulation, does not alter
rates of neurogenesis.
On the other hand, it is usually cited that
neurogenesis is increased by antidepressant,
enriched environment, physical exercise and
decreased by opioids, stress, old age etc. By
selection of the data factors increasing
neurogenesis are desirable and good while factors
with opposite activity resemble “bad guys”.
However, neurogenesis might be increased in
conditions far away from our perception of
desirable and healthy events. For example:
 When epileptic activity is induced in animal
models a prominent induction of neurogenesis
is observed in the dentate gyrus. This increase
in neurogenesis is observed regardless of the
mechanism for the induction of seizures (e. g.,
chemical or electrical stimulation) (Kuhn at al
 Brain injury induced by traumatic lesions can
cause a transient increase in the proliferation
of stem cells of the ventricle wall but these
studies were not able to demonstrate any
euronal contribution of stem cells to the lesion
site (Kuhn at al 2001).
 Focal and global ischemia were also shown to
be potent in inducing neurogenesis in the
dentate gyrus (Kuhn at al 2001).
Indeed, arguments pro and contra should be
reviewed carefully and completely (without
desirable selection) and balanced since practically
all observations are done on experimental animals
(usually healthy) or even on tissue culture.
1. Altman J, Das DA, Autoradiographic and
histological evidence of postnatal hippocampal
neurogenesis in rats, J. Comp. Neurol. 1965; 124;
2. Brezun JM, Daszuta A. Depletion in serotonin
decreases neurogenesis in the dentate gyrus and the
subventricular zone of adult rats. Neuroscience.
1999;89: 999-1002
3. Cameron HA, McKay RDG. Adult neurogenesis
produces a large pool of new granule cells in the
dentate gyrus. Journal of Comparative Neurology.
2001; 435; 406–417.
4. David S, and Aguayo A.J., Axonal elongation into
peripheral nervous system ‘bridges’ after central
nervous system injury in adult rats. Science 1981;
214; 931–933
5. P.S. Eriksson PS, E. Perfilieva E, Bjork-Eriksson T,
Alborn AM, C. Nordborg C, Peterson DA and Gage
FH, Neurogenesis in the adult human hippocampus,
Nat. Med. 1998; 4; 1313–1317.
6. Kuhn G, Palmer TD, Fuchs E, Adult neurogenesis:
a compensatory mechanism for neuronal damage
Eur Arch Psychiatry Clin Neurosci. 2001;251:152-
7. Jhaa S, Rajendrana R, Davdab J and Vaidya VV.
Selective serotonin depletion does not regulate
hippocampal neurogenesis in the adult rat brain:
Differential effects of p-chlorophenylalanine and
5,7-dihydroxytryptamine Brain Research 2006;
1075, 48-59
8. J.E. Malberg JE, Eisch AJ, Nestler EJ and Duman
RS, Chronic antidepressant treatment increases
neurogenesis in adult rat hippocampus, J Neurosci
2000; 20; 9104–9110.
9. Manev et al., 2001 H. Manev, T. Uz, N.R.
Smalheiser and R. Manev, Antidepressants alter cell
proliferation in the adult brain in vivo and in neural
cultures in vitro, Eur J Pharmacol 2001; 411; 2001;
10. Muresanu DF: Neuroprotection and neuroplasticity
– A holistic approach and future perspectives J
Neurol Sci. 2007; 257, 38-43.
Zdravko Lackoviþ, MD, PhD
University of Zagreb, Medical School
Šalata 11, 10000 Zagreb, Croatia
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The origin, termination, and length of axonal growth after focal central nervous system injury was examined in adult rats by means of a new experimental model. When peripheral nerve segments were used as "bridges" between the medulla and spinal cord, axons from neurons at both these levels grew approximately 30 millimeters. The regenerative potential of these central neurons seems to be expressed when the central nervous system glial environment is changed to that of the peripheral nervous system.
In the autoradiograms of young rats injected with thymidine-H3 many of the granule cells of the dentate gyrus were found labeled. The number of labeled cells declined rapidly with increased age at the time of injection. Histological studies showed the presence in young rats of a large germinal matrix of mitotic cells in the ependymal and subependymal layers of the third and lateral ventricles. The areal extent and cell population of this germinal pool declined rapidly from birth on, with a transient rise with a peak at about 15 days. During this latter period the number of “undifferentiated” cells near the granular layer of the dentate gyrus showed a rapid rise with a subsequent decline. The decline in the number of “undifferentiated” cells was accompanied by a rise in the number of differentiated granule cells. Cell counts in homologous parts of the dentate gyrus indicated a six-fold increase in the number of differentiated granule cells from birth to three months. We postulated that undifferentiated cells migrate postnatally from the forebrain ventricles to the hippocampus where they become differentiated. The possible functional significance of delayed hippocampal neurogenesis is discussed with reference to our finding of incorporation of testosterone-H3 by cells of the hippocampus, implicating that they may function as receptors of gonadal hormones.
During adulthood, neuronal precursor cells persist in two discrete regions, the subventricular zone and the hippocampal subgranular zone, as recently demonstrated in primates. To date, a few factors such as adrenal steroids and trophic factors are known to regulate adult neurogenesis. Since neuronal activity may also influence cellular development and plasticity in brain, we investigated the effects of serotonin depletion on cell proliferation occurring in these regions. Indeed, in addition to its role as a neurotransmitter, 5-hydroxytryptamine (serotonin) is considered as a developmental regulatory signal. Prenatal depletion in 5-hydroxytryptamine delays the onset of neurogenesis in 5-hydroxytryptamine target regions and 5-hydroxytryptamine promotes the differentiation of cortical and hippocampal neurons. Although in the adult brain, a few studies have suggested that 5-hydroxytryptamine may play a role in neuronal plasticity by maintaining the synaptic connections in the cortex and hippocampus, no information is actually available concerning the influence of 5-hydroxytryptamine on adult neurogenesis. If further work confirms that new neurons can be produced in the adult human brain as is the case for a variety of species, it is particularly relevant to determine the influence of 5-hydroxytryptamine on neurogenesis in the hippocampal formation, a part of the brain largely implicated in learning and memory processes. Indeed, lack of 5-hydroxytryptamine in the hippocampus has been associated with cognitive disorders, such as depression, schizophrenia and Alzheimer's disease. In the present study, we demonstrated that both inhibition of 5-hydroxytryptamine synthesis and selective lesions of 5-hydroxytryptamine neurons are associated with decreases in the number of newly generated cells in the dentate gyrus, as well as in the subventricular zone.
The action of antidepressants on cell proliferation (bromodeoxyuridine (BrdU) or [3H]thymidine incorporation) was studied in the adult rat hippocampus in vivo and in neural precursors (immature rat cerebellar granule cells) in vitro. In vivo, prolonged (21 days) but not acute (single) intraperitoneal treatment with fluoxetine (5 mg/kg) resulted in a 3.4-fold increase of bromodeoxyuridine-positive cells in the subgranular zone of the dentate gyrus. In cell cultures, at 1 and 10 days in vitro, 48-h fluoxetine exposure (1 microM, which is comparable to therapeutic plasma concentrations) reduced thymidine incorporation when initiated at 1 day in vitro, but increased cell proliferation when initiated at 10 days in vitro. Clomipramine and imipramine produced similar action in vitro; desipramine was ineffective.
Knowing the rate of addition of new granule cells to the adult dentate gyrus is critical to understanding the function of adult neurogenesis. Despite the large number of studies of neurogenesis in the adult dentate gyrus, basic questions about the magnitude of this phenomenon have never been addressed. The S-phase marker bromodeoxyuridine (BrdU) has been extensively used in recent studies of adult neurogenesis, but it has been carefully tested only in the embryonic brain. Here, we show that a high dose of BrdU (300 mg/kg) is a specific, quantitative, and nontoxic marker of dividing cells in the adult rat dentate gyrus, whereas lower doses label only a fraction of the S-phase cells. By using this high dose of BrdU along with a second S-phase marker, [(3)H]thymidine, we found that young adult rats have 9,400 dividing cells proliferating with a cell cycle time of 25 hours, which would generate 9,000 new cells each day, or more than 250,000 per month. Within 5-12 days of BrdU injection, a substantial pool of immature granule neurons, 50% of all BrdU-labeled cells in the dentate gyrus, could be identified with neuron-specific antibodies TuJ1 and TUC-4. This number of new granule neurons generated each month is 6% of the total size of the granule cell population and 30-60% of the size of the afferent and efferent populations (West et al. [1991] Anat Rec 231:482-497; Mulders et al. [1997] J Comp Neurol 385:83-94). The large number of the adult-generated granule cells supports the idea that these new neurons play an important role in hippocampal function.