On the other hand, several new studies continue to support the OXT system’s potential for such treatment. In this review, we thoroughly analyze existing literature assessing both alcohol’s effects on the OXT system and OXT’s effects on alcohol-related behaviors. We identify areas that have been studied extensively and those that have been undeservingly understudied. OXT’s potential effects on tolerance, withdrawal, craving, anxiety and social behaviors, and how these processes ultimately affect alcohol consumption, are critically explored.

A previous trial of INOT showed it decreased cocaine craving, and additional research has revealed recurrent cocaine use results in lower endogenous oxytocin levels and depleted oxytocin in the hypothalamus and amygdala. Intranasal oxytocin is showing early promise as a treatment for cocaine dependence, new research suggests. A number of additional factors — genetic, psychological and environmental — play a role in addiction, which can happen quickly or after many years of opioid use. Loup F., Tribollet E., Dubois-Dauphin M., Dreifuss J.J. Localization of high-affinity binding sites for oxytocin and vasopressin in the human brain.

Oxytocin and Glutamate

Additionally, OXT has been shown to decrease alcohol-induced GABAergic signaling in the CeA, and to reduce GABA receptor function in both alcohol-dependent and alcohol-naïve rats . GABAergic neurons innervating the VTA inhibit glutamatergic and dopaminergic neurons and their respective neurotransmitter release . Therefore, a plausible mechanism is that OXT enhances GABA’s inhibitory effects on glutamatergic 10 most common reasons for addiction relapse and dopaminergic VTA neurons, which can then dampen the signaling of these cells and decrease mesocorticolimbic Glu and DA levels. In fact, Qi et al. demonstrated that OXT increased extracellular GABA levels in the mPFC following methamphetamine administration . Thus, OXT may be acting as an activating neuromodulator in regions where drugs cause an inability to control behavior and impulses.

Carter R.M., Macinnes J.J., Huettel S.A., Adcock R.A. Activation in the VTA and nucleus accumbens increases in anticipation of both gains and losses. 2012.FDA implemented the ER/LA opioids REMS program, which includes voluntary training for prescribers. Substance Abuse and Mental Health Services Administration to launch an initiative to help ensure the safe use of the opioid methadone.

Tunstall B.J., Kirson D., Zallar L.J., McConnell S.A., Vendruscolo J.C.M., Ho C.P., Oleata C.S., Khom S., Manning M., Lee M.R., et al. Oxytocin blocks enhanced motivation for alcohol in alcohol dependence and blocks alcohol effects on GABAergic transmission in the central amygdala. Ladepeche L., Yang L., Bouchet D., Groc L. Regulation of dopamine D1 receptor dynamics facts and laws about drinking and driving within the postsynaptic density of hippocampal glutamate synapses. Pierce R.C., Born B., Adams M., Kalivas P.W. Repeated intra-ventral tegmental area administration of SKF-38393,induces behavioral and neurochemical sensitization to a subsequent cocaine challenge. Geisler S., Wise R.A. Functional implications of glutamatergic projections to the ventral tegmental area.

Neurobiology of addiction: a neurocircuitry analysis

Reports of overdose and death from prescription drug products, especially opioids, began to rise sharply, with OxyContin at the center of the problem. For instance, the number of people who admitted to using OxyContin for non-medical purposes increased dramatically from approximately 400,000 in 1999 to 1.9 million in 2002 and to 2.8 million in 2003. Physical examinations are completed by Wakebrook physicians within 24 hours after patients are admitted. Findings on physical examinations will not be available until later the day of admission or the following day, which will be after initiation of intranasal doses. If significant physical exam abnormalities are identified, treatments and further subject participation in the study will be stopped immediately.

On August 22, FDA awarded a contract to the National Academies of Sciences, Engineering, and Medicine to help advance the development of evidence-based guidelines for appropriate opioid analgesic prescribing for acute pain resulting from specific conditions or procedures. On May 26, FDA approved Probuphine, the first buprenorphine implant for the maintenance treatment of opioid dependence. At the time of approval, FDA believed the controlled-release formulation of OxyContin would result in less abuse potential, since the drug would be absorbed slowly and there would not be an immediate “rush” or high that would promote abuse. In part, FDA based its judgment on the prior marketing history of a similar product, MS Contin, a controlled-release formulation of morphine approved by FDA and used in the medical community since 1987 without significant reports of abuse and misuse. Recognize that no one is safe, and we all play a role in tackling the grip these drugs currently hold on our loved ones and communities. One reason opioid addiction is so common is that people who develop tolerance may feel driven to increase their doses so they can keep feeling good.

Does endogenous cholecystokinin modulate alcohol intake?

The acute intracerebroventricular administration of OXT (1 µg/5 µL) reduced alcohol self-administration and prevented the ethanol-induced release of DA in the NAc in rats both chronically exposed and naive to ethanol . Behavioral and neuroplastic changes occurring in the development of addiction parallel those that occur in social bonding. This has led to speculation that drugs of abuse co-opt systems that subserve social attachment to shift attachment to drugs of abuse. Oxytocin, a neuropeptide that is important in social bonding, has been shown in rodents to decrease psychostimulant self-administration, locomotor activity, and conditioned place preference, it is unclear what role it may play in human drug addiction. In this double-blind, placebo-controlled crossover study, 23 cocaine-dependent inpatients in court-ordered treatment completed 4 task sessions measuring desire to use cocaine, cue-induced craving, monetary reward decisions and social cognition. Oxytocin increased desire to use cocaine and cue-induced excitability with no effect on cue-induced desire to use.

Floresco S.B., Todd C.L., Grace A.A. Glutamatergic afferents from the hippocampus to the nucleus accumbens regulate activity of ventral tegmental area dopamine neurons. Ford C.P. The role of D2-autoreceptors in regulating dopamine neuron activity and transmission. Cartmell J., Schoepp D.D. Regulation of neurotransmitter release by metabotropic glutamate receptors. Niciu M.J., Kelmendi B., Sanacora G. Overview of glutamatergic neurotransmission in the nervous system. Baracz S.J., Rourke P.I., Pardey M.C., Hunt G.E., McGregor I.S., Cornish J.L. Oxytocin directly administered into the nucleus accumbens core or subthalamic nucleus attenuates methamphetamine-induced conditioned place preference. Ritz M.C., Lamb R.J., Goldberg S.R., Kuhar M.J. Cocaine receptors on dopamine transporters are related to self-administration of cocaine.

• Excitatory amino acid transporters , VGLUTs, and cystine-glutamate exchangers are components that are critical for maintaining homeostasis.
• Further, central administration of an OXT or OXTR antagonist inhibits the effects of peripherally injected OXT .
• Heroin can also increase Glu signaling via dopaminergic interactions and the inhibition of GABA neurons, similarly to alcohol .
• Rats have OXTRs in the ventral tegmental area , nucleus accumbens , prefrontal cortex , bed nucleus of the stria terminalis, PVN, SON, ventromedial hypothalamus, and hippocampus .
• Among the changes, the FDA is requiring a new boxed warning about the serious risks of misuse and abuse, which can lead to addiction, overdose and death.

The risk for life-threatening side effects of “Hillbilly Heroin” only compounds when used with benzodiazepines and alcohol – two other substances which are a major cause of respiratory depression. Some individuals use Oxy as a way to mellow out the high from stimulants, such as crystal meth and cocaine, which can cause other life-threatening consequences. If you’re living with chronic pain, opioids are not likely to be a safe and effective long-term treatment option. Many other treatments are available, including less-addictive pain medications and nonpharmacological therapies.

Behaviorally active oxytocin fragments simultaneously attenuate heroin self-administration and tolerance in rats

At each visit, they completed the cocaine craving scale, the Perceived Stress Scale, and the Clinician Global Inventory (all self-reports), as well as the Time Line Follow Back to document cocaine use. At a baseline, the researchers collected participants’ medical history and conducted a physical examination, urine toxicology, electrocardiogram, comprehensive metabolic panel, and complete blood count. They used the MINI International Neuropsychiatric Interview to confirm the diagnosis of cocaine dependence. Mayo Clinic is a nonprofit organization and proceeds from Web advertising help support our mission. Sign up for free, and stay up to date on research advancements, health tips and current health topics, like COVID-19, plus expertise on managing health.

Thus, it is possible that OXT stimulates Group 2 mGluRs to reduce the excitatory effects of Glu in the NAc, subsequently reducing activation in other regions like the mPFC and hippocampus and preventing the initiation of drug-seeking behaviors. Context-specific aspects of reward seeking appear to be more dependent on glutamatergic transmission . Studies indicate that ionotropic Glu receptors are especially involved in drug-seeking behaviors mediated by drug-seeking cues. For instance, the microinfusion of an AMPA/kainate receptor antagonist into the NAc core, but not the shell, dose-dependently reduced lever presses for cocaine . It is noteworthy that an NMDA receptor antagonist decreased cocaine-seeking behavior when infused into the NAc shell . There is strong evidence that that Glu transmission in the NAc is a primary determinant of relapse .

Drugs of abuse greatly increase Glu and DA levels in the synapse and alter the transmission of these neurotransmitters using various mechanisms. As described previously, psychostimulants increase Glu transmission indirectly through interactions with DA . Some studies show that alcohol can inhibit presynaptic Glu release and postsynaptic NMDA-mediated Glu transmission. However, other studies found Glu levels to increase after alcohol administration, possibly due to the activation of D1 receptors or inhibition of GABAergic interneurons that project to presynaptic Glu neurons . Meanwhile, heroin activates mu-opioid receptors to enhance postsynaptic NMDA-mediated Glu transmission . Heroin can also increase Glu signaling via dopaminergic interactions and the inhibition of GABA neurons, similarly to alcohol .

The committee also discussed the efficacy and safety data and benefit-risk considerations. The agency is also requiring the addition of safety information about the risks of misuse, abuse, addiction, overdose, death, and slowed or difficult breathing to the Boxed Warning of the drug labels for prescription cough and cold medicines containing codeine or hydrocodone. Many erroneously believe abusing prescription narcotics is far safer than using its illegal street version – heroin. This could not be farther than the truth as overdoses from the usage of OxyContin are on the rise. One of the things making Oxy so dangerous is not only its addiction potential, but its lethality. The drug allows you to feel as though you can take more and more of the substance, but it can lead to respiratory failure and death.

The role of oxytocin in attenuating the abuse of licit and illicit drugs, including the psychostimulant methamphetamine, has been examined with increased ferocity in recent years. However, the neural mechanisms by which oxytocin modulates methamphetamine abuse are not well understood. Recent research identified an important role for the accumbens core and subthalamic nucleus in this process, which likely involves an interaction with dopamine, glutamate, GABA, and vasopressin. A growing understanding of exogenous oxytocin effects at a neurochemical and neurobiological level will assist in its evaluation as a pharmacotherapy for drug addiction. The product has been formulated with properties intended to deter abuse, and the applicant has submitted data to support these abuse-deterrent properties for this product.

1. Ionotropic and Metabotropic Glutamate Receptors

Studies have shown that giving oxytocin to opioid-addicted animals diminished opioid use after they had been denied access to opioids for a while and reduced symptoms when they were put into opioid withdrawal. Di Ciano P., Everitt B.J. Dissociable effects of antagonism of NMDA and AMPA/KA receptors in the nucleus accumbens core and shell on cocaine-seeking behavior. After withdrawal from alcohol, cocaine, nicotine, and heroin, NAc core astrocytes exhibit a decrease in glutamate transporter 1 (GLT-1) levels . Additionally, there is an increase in postsynaptic AMPA receptor function, a downregulation of inhibitory Group 2 mGluRs, and/or upregulation of the activator of G-protein signaling 3 after withdrawal from alcohol, cocaine, heroin, or methamphetamine . Cocaine alters AMPA receptor function in the NAc by upregulating its surface and synaptic receptor levels; it also decreases the surface expression of mGluR2 . However, it should be noted that the effects that drugs have on corticostriatal Glu neuroplasticity can be dependent on various facets of the experimental paradigms used, such as contingency and duration .

Previous research has given thought to how dopamine may be involved in oxytocinergic mechanisms, but there has not been as strong of a focus on the role that glutamate has. The glutamatergic system is critical for the processing of rewards and the disruption of glutamatergic projections produces the behaviors seen in drug addicts. We introduce the idea that OXT has direct effects on Glu transmission within the reward processing pathway. Thus, OXT may reduce addictive behaviors by restoring abnormal drug-induced changes in the glutamatergic system and in its interactions with other neurotransmitters.

A unique population of ventral tegmental area neurons inhibits the lateral habenula to promote reward. Arletti R., Benelli A., Bertolini A. Influence of oxytocin on feeding behavior in the rat. Zhou L., Ghee S.M., See R.E., Reichel C.M. Oxytocin differentially can alcohol abuse cause premature aging? affects sucrose taking and seeking in male and female rats. Bimpisidis Z., De Luca M.A., Pisanu A., Di Chiara G. Lesion of medial prefrontal dopamine terminals abolishes habituation of accumbens shell dopamine responsiveness to taste stimuli.