The Combination of Marketed Antagonists of α1b-Adrenergic and 5-HT2A Receptors Inhibits Behavioral Sensitization and Preference to Alcohol in Mice: A Promising Approach for the Treatment of Alcohol Dependence

Abstract

Alcohol-dependence is a chronic disease with a dramatic and expensive social impact. Previous studies have indicated that the blockade of two monoaminergic receptors, α1b-adrenergic and 5-HT2A, could inhibit the development of behavioral sensitization to drugs of abuse, a hallmark of drug-seeking and drug-taking behaviors in rodents. Here, in order to develop a potential therapeutic treatment of alcohol dependence in humans, we have blocked these two monoaminergic receptors by a combination of antagonists already approved by Health Agencies. We show that the association of ifenprodil (1 mg/kg) and cyproheptadine (1 mg/kg) (α1-adrenergic and 5-HT2 receptor antagonists marketed as Vadilex ® and Periactine ® in France, respectively) blocks behavioral sensitization to amphetamine in C57Bl6 mice and to alcohol in DBA2 mice. Moreover, this combination of antagonists inhibits alcohol intake in mice habituated to alcohol (10% v/v) and reverses their alcohol preference. Finally, in order to verify that the effect of ifenprodil was not due to its anti-NMDA receptors property, we have shown that a combination of prazosin (0.5 mg/kg, an α1b-adrenergic antagonist, Mini-Press ® in France) and cyproheptadine (1 mg/kg) could also reverse alcohol preference. Altogether these findings strongly suggest that combined prazosin and cyproheptadine could be efficient as a therapy to treat alcoholism in humans. Finally, because α1b-adrenergic and 5-HT2A receptors blockade also inhibits behavioral sensitization to psychostimulants, opioids and tobacco, it cannot be excluded that this combination will exhibit some efficacy in the treatment of addiction to other abused drugs.

Do specific NMDA receptor subunits act as gateways for addictive behaviors?

“…GluN2B subunits are interesting in that there can be a sizable population of extrasynaptic receptors, which can be rapidly trafficked into the synapse, and can produce differential regulation of plasticity induction relative to synaptic NMDARs (deBacker et al ; Newpher & Ehlers ; Traynelis et al ). There are also relatively selective antagonists for GluN2B subunits (ifenprodil, Ro 04‐5595, deBacker et al , but see Trovero et al ). The increasing evidence for a central role for GluN2B might, in part, reflect the presence of selective tools to interrogate GluN2B subunits, and subunits other than GluN2B may be assessed as more selective antagonists for other subunits are developed.…”

Anticraving therapy for alcohol use disorder: A clinical review

“…Furthermore, they also showed the combination of cyproheptadine and prazosin (antagonist of α‐1 adrenergic receptor) also decreases alcohol preference, but separation of administration of these drugs has not found to be effective for alcohol preference. In addition, the antagonist studies show that concurrently activated NMDA and GABA channels each tend to limit the responses of the other . These studies suggest that GIRK channel may have a key molecule in alcohol dependence and ifenprodil is one of a candidate drug in medical treatment.…”

“…A recent study showed that combination of pretreated with ifenprodil and cyproheptadine (antagonist of 5‐HT 2 receptor) in the mice inhibits alcohol intake and decreases alcohol preference compared to the mice pretreated with saline . Furthermore, they also showed the combination of cyproheptadine and prazosin (antagonist of α‐1 adrenergic receptor) also decreases alcohol preference, but separation of administration of these drugs has not found to be effective for alcohol preference.…”

Study of effects of ifenprodil in patients with methamphetamine dependence: Protocol for an exploratory, randomized, double‐blind, placebo‐controlled trial

“…Pretreatment with ifenprodil dose‐dependently suppressed morphine‐induced conditioned place preference . Mice that were pretreated with ifenprodil and cyproheptadine did not exhibit locomotor sensitization to d ‐amphetamine, whereas mice that were pretreated with saline did . Ifenprodil is not a specific blocker of GIRK channels and does not produce serious side effects .…”

“…33 Mice that were pretreated with ifenprodil and cyproheptadine did not exhibit locomotor sensitization to D-amphetamine, whereas mice that were pretreated with saline did. 34 Ifenprodil is not a specific blocker of GIRK channels and does not produce serious side effects. 35 Paroxetine has been reported to have several adverse effects, including serotonin syndrome, neuroleptic malignant syndrome, convulsions, toxic epidermal necrosis, antidiuretic hormone incompatible secretion syndrome, severe liver dysfunction, rhabdomyolysis, lower white blood cell counts, and anaphylaxis.…”