MC Vol. 18 - No.4 - 2012 ( 5-6 ) Akram. H.
et al
1 HUMA IKRAM
PH.D
2 ADNAN MAQSOOD
CHOUDHRY
B.A, M.D.
3 DARAKHSHAN JABEEN
HALEEM
PH.D
1 Neurochemistry and Biochemical
Neuropharmacology Research
Unit, Department of Biochemistry,
University of Karachi,
Karachi-75270, Pakistan;
2 Dalhousie University, Halifax,
Nova Scotia, Canada B3H 4R2;
3. Neuroscience Research
Laboratory, Dr. Panjwani Center
for Molecular Medicine and Drug
Research, University of Karachi,
Karachi-75270, Pakistan
Corresponding To:
HUMA IKRAM,
PH.D.
Neurochemistry and Biochemical
Neuropharmacology Research Unit,
Department of Biochemistry, University
of Karachi, Karachi-75270, Pakistan
E-mail: huma_biochemist@yahoo.com
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OCTOBER-DECEMBER 2012
M E D I C A L
CHANNEL
EDITORIAL
EXTENDING THERAPEUTIC UTILITY OF
PSYCHOSTIMULANTS
O)CNS stimulants (Psychostimulants) are psychoactive drugs which induce temporary
improvements in either mental or physical function or both. Although considered as
drugs of abuse, psychostimulants could also be used for the pharmacotherapy of
various pathological conditions. They are considered as drugs of choice especially in
cases where resistance to primary treatment develops and patients stop responding to
those pharmacotherapeutic agents [1]. Psychostimulants, have the edge in this regard as
few of them (like apomorphine) produce sensitization (a potentiation of behavior)
rather than tolerance [2]. This makes them potential candidates for the treatment of
various disorders like use of apomorphine for the treatment of Parkinson’s/ related
motor disorders [3], methylphenidate for the treatment of attention-deficit hyperactivity
disorder (ADHD), depressive symptoms, narcolepsy, obesity and postural orthostatic
tachycardia syndrome [4].
Depression is one of the largest health issues worldwide. In many of the physical and
psychological disorders, depression is an underlying cause and treatment of depression
in these individuals is very necessary for the recovery. A wide variety of drugs has
been implicated lately for the treatment of depression, like tricyclic antidepressants
(TCAs), selective serotonin reuptake inhibitors (SSRIs) and others. However, these
antidepressant therapies do not work in around 30% of patients with clinical depression
[5]
. This resistance to antidepressant therapies may result due to inappropriate dose/
treatment duration as well as loss of potency or efficacy over the period of time [6].
However, psychostimulants could be the drugs of choice in these patients and patients
with treatment-resistant depression, respond to psychostimulants. Since monoaminergic
hypothesis of depression suggests the prognosis of depression due to the deficits of
monoamines in synapse, an increased availability of monoamines in synapse, could
prevent depression. Psychostimulants although are supposed to increased dopaminergic
release in synapse, some other mechanisms might also be involved. Pae et al (2007)
have suggested an important role of CART (cocaine- and amphetamine-regulated transcript);
a brain-enriched mRNA with a protein product(s) in the treatment of treatment-
resistant depression [7].
A role of psychostimulant, for the treatment of fatigue is also suggested by the
researchers. Hardy (2009) has reported that methylphenidate at low doses, could be
safely used for the treatment of adults with depression, fatigue or apathy [8]. Minton
et al (2011) have also reported use of methylphenidate for the management of cancer-
related fatigue [9]. However, they have recommended expert supervision and active
monitoring of these patients, due to the likelihood of the development of addiction, in
the long run. For the treatment of excessive sleepiness, as in case of narcolepsy,
amphetamine could be the drug of choice [10].
However, a major limitation associated with pharmacotherapeutic use of psychostimulants,
is their high abuse potential and their self-administration could not be recommended.
A safer strategy, therefore, could be, to implant infusion pumps, to supply
psychostimulant at a constant rate, without allowing patients to control it. However,
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 MC Vol. 18 - No.4 - 2012 ( 5-6 ) Akram. H. et al
OCTOBER-DECEMBER 2012
when apomorphine infusion pumps were implanted in patients
with Parkinson’s disease [11], this resulted in problematic skin
reactions and multiple subcutaneous abscesses and necroses resulted
due to the multiple apomorphine pump infusions [12]. Therefore,
future research in this area should focus on lowering the reinforcing
effects of psychostimulants, while keeping their therapeutic profiles
unaffected. So that these psychostimulants could be administrated
safely, in combination with other adjuvant therapies, to increase
the quality of life in patients with conditions treatable with
psychostimulants only.
Dopamine is the primary neurotransmitter involved in the
pathophysiology of addiction, and drugs of abuse increase
dopaminergic neurotransmission mainly in the Nucleus Accumbens,
irrespective of their initial targets. However, 5-Hydroxytryptamine
(5-HT; serotonin) could also play an important role in the
attenuation/ normalization of reinforcing effects of drugs of abuse.
We also have proposed an involvement of somatodendritic 5-
HT1A receptors in the pathophysiology of addiction [2]. Since
somatodendritic 5-HT1A receptors are found to be supersensitized
in drug addicts and psychostimulant addiction is more common
in depressed individuals; a desensitization of somatodendritic 5-
HT1A receptors, could lead to the attenuation of psychostimulant
addiction. So, desensitization of these somatodendritic 5-HT1A
receptors seems to be one of the common mechanisms underlying
the pathophysiology of both addiction and depression. This idea
is further strengthen by the fact that prevalence of depression
is high in addicts.
In line with this hypothesis, we administered buspirone at the
dose of 1.0 mg/kg, along with the apomorphine, to monitor its
effects on apomorphine-induced sensitization [2]. Repeated
administration of buspirone at this dose produces a desensitization
of somatodendritic 5-HT1A receptors. We have observed that a
desensitization of these receptors by the repeated co-administration
of buspirone could attenuate apomorphine-induced sensitization
(a component of addiction). So a formulation containing apomorphine
and buspirone could safely be prescribed for the self-administration
in individuals with Parkinson’s and related disorders. Another
advantage of using buspirone as adjuvant therapy is, that it is
clinically prescribed anxiolytic and could be used safely in the
human subjects. Further validation of these results and clinical
trials are required to implicate these results in humans.
CORREGENDUM
This office issue the Corregandum that July - September
2012 Due to misprint title bear publishing
MC Vol. 19, No. 3 - 2012, The correct Bar read as under
MC Vol. 18, No. 3 - 2012. This office apolize on this
mistake editor.
Quarterly Medical Channel
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