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INNOSC Theranostics and
Pharmacological Sciences Alpha-2A receptor agonist and addiction

Emerging evidence suggests the possibility of minimally laboratory clearly pointed out that a reduction in serotonin
invasive procedures for manipulating the LC, such as levels in the brains of rodents resulted in an enhanced fear
regulating the circuit from the suprachiasmatic nucleus to reaction, potentially implicating clonidine in serotonergic
the LC through a relay in the dorsomedial hypothalamus. transmission. 168
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Another potential method is transcutaneous vagus nerve Some researchers consider smoking behavior, not
stimulation, a non-invasive procedure reported to possess just nicotine dependence, to be related to oral fixation
positive effects on psychiatric and neurological disorders, and potentially a behavioral addiction. Moreover,
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such as depression. 162 combined data from nine double-blind placebo-controlled
Despite the potential benefits, noradrenergic trials (N = 813) revealed that the smoking quit rate with
compounds are not frequently administered as a frontline clonidine was significantly greater than with placebo.
therapeutic modality. NA dysfunction contributes to many Moreover, the in-depth analysis suggested that clonidine
aspects of brain disorders, but many human clinical trials potentiates the effect of individual behavior therapy and
have not distinguished specific NA effects from dopamine may be more beneficial for female smokers compared to
effects. Indeed, more is known about the specific effects of male smokers. Current standards of care for medically
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dopamine and associated neuron degeneration and other supervised withdrawal include treatments with mu-opioid
physiological and psychiatric effects. 163 receptor agonists such as methadone, partial agonists like
To investigate the involvement of the noradrenergic buprenorphine, and alpha-2 adrenergic receptor agonists
system in pathological gambling (PG), Pallanti et al. such as clonidine and lofexidine. Newer agents also utilize
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measured the neuroendocrine growth hormone (GH) these pharmacological mechanisms, including tramadol
response to the alpha-2 adrenergic receptor agonist for mu-opioid receptor agonism and tizanidine for alpha-2
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clonidine and placebo in PG individuals and controls. One agonism. To explore the initiation of detoxification
hypothesized mechanism, as proposed by these authors, is in individuals addicted to opioids/opioids, Blum’s
that clonidine’s net effects entail reducing neurotransmission laboratory developed a protocol for use in treatment
by suppressing LC activity and stimulating GH secretion centers, particularly for heavily dependent opioid/
through activation of post-synaptic alpha-2 adrenergic opioid subjects. 171,172 Moreover, future research endeavors
receptors in the hypothalamus. The area under the curve encompass managing withdrawal while stabilizing patients
for GH response to clonidine was found to be significantly with OUD on extended-release naltrexone, transitioning
lower in the PG group compared to controls. Notably, patients from methadone to buprenorphine for OUD
individuals with PG exhibited significantly blunted GH treatment, and tapering opioids in patients with chronic,
responses relative to controls at 120 and 150 min post- non-cancer pain. However, compliance remains a challenge
clonidine administration. These findings support the that could potentially be addressed through the addition of
notion that the diminished sensitivity of post-synaptic a pro-dopamine regulator. 173
alpha-2 receptors may be linked to elevated noradrenergic 6. Limitations
secretion in PG. This peripheral noradrenergic dysfunction
aligns with attenuated corticofrontal noradrenergic While this article takes a narrative approach rather than a
function observed in positron emission tomography (PET) systematic review, we acknowledge the potential for bias
studies of PG. 17 in our overall perspective on this topic. It is important
to recognize that some studies present alternative views,
In an interesting study, Saddichha et al. demonstrated
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that clonidine was effective in reducing compulsive soap suggesting that regions proximal to the LC, such as the
eating, known as sapophagia, but not feeding behavior, periaqueductal gray, as well as other brain structures
suggesting an effect on compulsive behavior rather than on independent of the LC noradrenergic system, may play
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eating disorders. Another study by Cazala demonstrated a more significant role in the manifestation of opioid
withdrawal syndrome.
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that clonidine specifically stimulates alpha-noradrenergic
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receptors and has two distinct effects on intracranial self- In a study by Christie, intracellular recordings of
stimulation (ICSS) behavior: it acutely depresses ventral membrane potassium current were conducted from rat LC
hypothalamic ICSS at low doses, while it causes a discrete in vitro. The researchers observed tolerance to the opioid-
increase in dorsal ICSS. In addition, evidence indicates that induced increase in potassium conductance, with a more
chronic clonidine administration affects conflict behavior pronounced effect observed for normorphine compared to
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4
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in rats, increasing punished responding in the conflict [Met ]enkephalin and [D-Ala ,MePhe ,Gly -ol]enkephalin.
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test. The authors suggest that clonidine may have some Experiments using the irreversible receptor blocker beta-
potential as an anti-panic drug. Experiments in Blum’s chlornaltrexamine indicated that normorphine exhibited
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Volume 7 Issue 3 (2024) 11 doi: 10.36922/itps.1918