Oxytocin and Addiction: Potential Glutamatergic Mechanisms PMC

Microdialysis studies of endocannabinoids have demonstrated that they are released via dopaminergic signaling and are involved in regulating synaptic plasticity related to addiction development . It is essential to recognize the roles that these neurotransmitters and their interdependence have in addiction, even though the focus of this review will be on Glu, Da, and GABA. On January 17, FDA approved Vantrela ER (hydrocodone bitartrate extended-release tablets), an extended-release opioid analgesic to treat pain severe enough 10 most common reasons for addiction relapse to require daily, around-the-clock, long-term opioid treatment for which alternative treatment options are inadequate. Vantrela ER is the ninth ER opioid analgesic to be approved with labeling describing the product’s abuse-deterrent properties consistent with the FDA’s 2015 guidance for industry, Abuse-Deterrent Opioids – Evaluation and Labeling. The physical and chemical properties of Vantrela ER are expected to make intravenous abuse difficult and are expected to reduce, but not eliminate, abuse by nasal and oral routes.

November On November 18, FDA approved Narcan nasal spray, the first FDA-approved nasal spray version of naloxone hydrochloride, a life-saving medication that can temporarily stop or reverse the effects of an opioid overdose, including an overdose from heroin. On January 24, FDA and the Federal Trade Commission posted joint warning letters to the marketers and distributors of 12 opioid cessation products, for illegally marketing unapproved products with claims about their ability to help in the treatment alcohol, headaches and hangovers of opioid addiction and withdrawal. Examine the clinical use of different tools that can guide a clinician in prescribing opioids and reduce patient misuse, overuse, and abuse of opioids. They include 1) screening, brief intervention, and referral to treatment , 2) PDMPs, 3) REMS, 4) health insurer initiatives, and 5) treatment contracts. The study will survey approximately 1,300 prescribers to gain an understanding of the knowledge, use, and perceptions of utility of these strategies.

In the reproductive system, OXT is involved in processes such as giving birth or producing milk during lactation while, for social or emotional stress, it relieves anxiety by facilitating social interactions . The release of OXT into the peripheral system can be triggered by events such as labor, nipple stimulation, and psychosocial stress . Changes in endogenous OXT levels are also observed following the consumption of certain drugs of abuse. For instance, methamphetamine administration increases plasma OXT levels in juvenile rats .

Clinical trials with oxytocin

Qi J., Zhang S., Wang H.L., Barker D.J., Miranda-Barrientos J., Morales M. VTA glutamatergic inputs to nucleus accumbens drive aversion by acting on GABAergic interneurons. Fuchs R.A., Evans K.A., Parker M.C., See R.E. Differential involvement of the core and shell subregions of the nucleus accumbens in conditioned cue-induced reinstatement of cocaine seeking in rats. Qi J., Yang J.-Y., Wang F., Zhao Y.-N., Song M., Wu C.-F. Effects of oxytocin on methamphetamine-induced conditioned place preference and the possible role of glutamatergic neurotransmission in the medial prefrontal cortex of mice in reinstatement.

• Intranasal oxytocin is showing early promise as a treatment for cocaine dependence, new research suggests.
• Additionally, the infusion of an AMPA antagonist, and not an NMDA antagonist, into the medial NAc blocks reinstatement for cocaine .
• Previous research in cannabis users suggests it may have a role in treating addiction by reportedly reducing cravings.

Aim for a treatment plan that makes it possible to enjoy your life without opioids, if possible. Compared with men, women are also more likely to be prescribed opioid medications, to be given higher doses and to use opioids for longer periods of time. Women may also have biological tendencies to become dependent on prescription pain relievers more quickly than are men.

Dopamine

It is possible that OXT attenuates abnormal Glu transmission by modifying the activity of Glu receptors. In examining its interactions with ionotropic receptors, OXTRs were found to reduce methamphetamine-induced increases in the NMDA NR1 subunit in the PFC . OXT administration also opposed cocaine-induced decreases in the phosphorylation of the GluR1 AMPA subunit in the PFC, amygdala, dorsal hippocampus, and bed nucleus of the stria terminalis inpatient rehab for alcoholism . Interestingly, GluR1 phosphorylation increases the trafficking of the subunit to the cell surface, suggesting that cocaine may selectively decrease the excitatory current induced by AMPA in some regions, and OXT is able to correct this abnormality. Thus, while OXT seems to have differential effects on NMDA and AMPA surface expression in certain brain regions, the neuropeptide ultimately opposes drug-induced alterations of ionotropic receptors.

With cases of substance-abuse disorders growing each year, there is a dire need for effective pharmacotherapeutics for addiction. However, some have questioned whether the systemic administration of OXT actually allows for the compound to reach the brain in sufficient amounts, due to the challenge posed by the blood–brain barrier . We maintain that OXT is still highly effective when given peripherally, as demonstrated by numerous studies which have used peripheral injections on rodents to produce an OXT-based effect . Further, central administration of an OXT or OXTR antagonist inhibits the effects of peripherally injected OXT . Peripherally circulating OXT could be crossing the BBB through carrier-mediated transport or transcellular passage across the endothelial cells that compose the BBB .

On the street, the high content of the narcotic oxycodone in OxyContin is what makes the drug popular. Until September of 2013, OxyContin was available in a form allowing addicts to chew the tablet, crush it and snort the tablet, or dilute the powdered form in water before injecting it. This process allowed for the disabling of the time-release mechanism to allow for the full euphoric effects of the drug. In 2013, the manufacturers of OxyContin developed a crush-resistant formulation of Oxy to discourage abuse among addicts.

The present study investigated and compared the impact of nandrolone decanoate and testosterone undecanoate on body weight gain, levels of stress hormones, brain gene expression, and behavioral profiles in the male rat. The behavioral profile was determined using the multivariate concentric squared field test (MCSF-test). Nandrolone decanoate caused a reduction in body weight gain in comparison with both testosterone undecanoate and control. Rats receiving nandrolone decanoate also demonstrated decreased general activity in the MCSF.

Region-specific up-regulation of oxytocin receptor binding in the brain of mice following chronic nicotine administration

The modulation of Glu transmission by dopaminergic projections is often exhibited by the effects of psychostimulants. This increases synaptic DA levels, which activates D1 receptors and enhances Glu transmission . In addition, D1 receptor stimulation increases the surface expression of the GluR1 subunit of the AMPA receptor on NAc neurons; this subunit is essential for LTP . Another study found that D1 receptors and NMDA receptors interact with each other to retain a sufficient concentration of D1 receptors in the Glu synapses of the hippocampus .

If you need opioids for acute pain, work with your doctor to take the lowest dose possible, for the shortest time needed, exactly as prescribed. Opioids are most addictive when you take them using methods different from what was prescribed, such as crushing a pill so that it can be snorted or injected. This life-threatening practice is even more dangerous if the pill is a long- or extended-acting formulation. Taking more than your prescribed dose of opioid medication, or more often than prescribed, also increases your risk of addiction.

Complexity of oxytocins effects in a chronic cocaine dependent population

OXT has a greater gating effect on Glu neurons that fire only occasionally compared to those that fire repeatedly. These mechanisms lead to a decrease in Glu release in VTA DA neurons in the presence of OXT . Glu-mediated DA release is also relevant to processes such as tonic-phasic DA activity; OXT suppression of Glu would allow for less modulation of tonic and phasic firing of DA neurons, which is a key component of reward processing. Similarly, glutamatergic synaptic transmission in the NAc was dampened in the presence of OXT through a presynaptic mechanism involving serotonergic inputs . This modulatory interaction of OXT on Glu transmission in the VTA allows for regulation of both Glu and DA levels through their interactions .

The committees were asked to discuss whether the applicant has demonstrated abuse-deterrent properties for their product that would support labeling, as well as the overall risk-benefit profile of the product. Another matter to consider for exploring OXT as a therapeutic for addiction is that studies have not yet shown the localization of OXTRs in the human VTA. There is, however, strong evidence that OXT enhances the activation of the VTA in humans in response to rewarding social stimuli . Knowing how central the role of the VTA is in reward processing and addictive behaviors, all of the findings that demonstrate that OXT reduces drug-seeking in humans implies that there must be OXT binding sites on the VTA.

There are eight different subtypes and three different groups of metabotropic Glu receptors that are separated by their signal transduction pathways and homology sequence. Typically, group 1 receptors are stimulatory, whereas Group 2 and Group 3 are inhibitory . Group 1 receptors are predominantly postsynaptic receptors, Group 2 are both pre- and postsynaptic, and Group 3 are presynaptic autoreceptors . These different groups of receptors are implicated in different parts of the addictive cycle. Group 1 receptors are important in drug reinforcement and Group 2 receptors are involved in neuroplasticity induced by chronic drug use or aversion during withdrawal; it is unclear how Group 3 receptors are involved in similar behaviors . For the purposes of this paper, we will discuss OXT’s effect on Group 1 and Group 2 receptors.

The subjects who received OXT demonstrated fewer withdrawal symptoms and used less lorazepam than the control group . Another clinical trial found that a single intranasal OXT administration reduced drug cravings, stress, and anxiety in cannabis-dependent individuals . The reward circuit, or the mesocorticolimbic system, is responsible for regulating the association between substances and reward.

However, data demonstrated that these programs did not adequately manage the risks of misuse, abuse, addiction, and overdose. Your personal history and the length of time you use opioids play a role, but it’s impossible to predict who’s vulnerable to eventual dependence on and abuse of these drugs. Legal or illegal, stolen and shared, these drugs are responsible for the majority of overdose deaths in the U.S. today. McFarland K., Lapish C.C., Kalivas P.W. Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. Several clinical trials have been initiated to test whether OXT curbs drug-seeking in humans. Pedersen and colleagues had alcohol-dependent subjects undergo alcohol detoxification with the treatment of lorazepam, as needed, and were to either receive intranasal OXT (24 IU; twice daily for three days) or a placebo.

It is this feeling of euphoria and happiness which can lead an individual to continue taking OxyContin far after the pain has subsided. Many use Oxy and other narcotic painkillers in order to experience emotional numbing and to relieve emotional pain. Withdrawal from opiates such as OxyContin also known as “OC,” “Oxycotton,” “Kicker,” and “Hillbilly Heroin,” does lead to depression in chronic users, which in turn leads to more abuse of the drug. Joseph, who was not involved with the study, said her group’s research showed oxytocin to be the most helpful for men with cocaine use disorder who reported childhood trauma, while for women, oxytocin “seemed to worsen their reactivity to cocaine cues.”

The oxytocin receptor impairs ethanol reward in mice

Another factor to consider is the ramifications of OXT administration on the peripheral system, specifically on the reproductive system, where it has a substantial role. Thus, there is still a need to examine certain aspects of OXT being a treatment for addiction. Nonetheless, this is an exciting and novel direction towards pharmacologically disrupting the addiction cycle and the behaviors it induces.

It may just be that very few studies have even attempted to localize OXTRs in the human brain that this discovery has not been made. Additionally, it is well-established that OXTRs are found in the VTA of rodents , and given the high similarity between the rodent and human brain, it is not unreasonable to assume that OXTRs exist in the human VTA. The human brain has displayed dense OXTR binding sites in other regions, such as the substantia nigra pars compacta, so this may be a potential target for OXT as well . It is possible that OXT’s impact on addictive behaviors occurs due to interference with the DA and Glu interactions that occur in the reward circuit during the addiction cycle. This is supported by the fact that OXTRs are on both dopaminergic and glutamatergic neurons in the VTA . At specific glutamatergic inputs to VTA dopamine neurons, OXT acts as a filter by selectively inhibiting excitatory synaptic transmission to the VTA through OXTRs alongside endocannabinoid signaling .