The role of oxytocin in alcohol and drug abuse

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 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.

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.

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.

OxyContin addiction & co-occurring disorders

At Mount Regis Center, we offer an intensive, evidence-based approach to OxyContin abuse and addiction treatment. We offer a variety of therapeutic interventions that help our clients build a strong foundation for long-term recovery. Qi J., Han W.-Y., Yang J.-Y., Wang L.-H., Dong Y.-X., Wang F., Song M., Wu C.-F. Oxytocin regulates changes of extracellular glutamate and GABA levels induced by methamphetamine in the mouse brain. Wolf M.E., Ferrario C.R. AMPA receptor plasticity in the nucleus accumbens after repeated exposure to cocaine. Spencer S., Scofield M., Kalivas P.W. The good and bad news about glutamate in drug addiction. Borland L.M., Michael A.C. Voltammetric study of the control of striatal dopamine release by glutamate.

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.

3. Glutamate-GABA Interactions

Chronic nicotine administration induced a marked region-specific upregulation of the oxytocin receptor binding in the amygdala, a brain region involved in stress and emotional regulation. These results provide direct evidence for nicotine-induced neuroadaptations in the oxytocinergic system, which may be involved in the modulation of nicotine-seeking as well as emotional consequence of chronic drug use. The committee also discussed risk-benefit considerations and whether this product should be approved. The meeting was intended to give FDA the opportunity to discuss, and seek public input from stakeholders on, the approach to testing FDA recommended in its draft guidance General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products. The meeting also provided an opportunity to discuss FDA’s efforts to develop standardized in vitro testing methodologies for evaluating the abuse deterrence of opioid drug products. OXT is a neurohormone consisting of nine peptides and is synthesized in the paraventricular nucleus and supraoptic nucleus of the hypothalamus.

This review offers insight into the mechanisms through which a potentially viable therapeutic target, OXT, could be used to reduce addiction-related behaviors. Although DA is a prominent focus in studies of addiction, research into Glu’s role in addiction is growing. It appears that DA has a primary role most common house rules in sober livings in the beginning of the addictive cycle, while Glu is a greater factor in the later parts of the cycle . This section will discuss the endogenous glutamatergic system, the role of Glu in addiction, interactions between DA and Glu in the reward circuit, and how drugs of abuse impact Glu transmission.

The Action Radius of Oxytocin Release in the Mammalian CNS: From Single Vesicles to Behavior

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.

Meets DSM-IV criteria for dependence on psychoactive substances other than opioids, caffeine or nicotine within 6 months prior to screening. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Most addictions do not have a clear-cut reason for the development of an addiction to a substance such as OxyContin. Oxy addiction can be treated and managed with the right therapies and proper medication management. Of the 11 who dropped out from the treatment group, seven were abstinent at the time of discontinuation for ≥1 week.

Data Availability Statement

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 how drugs affect the brain 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.

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 .

Drugs of abuse interact with the reward circuit in various ways, causing severe maladaptations to its reward processing function. This dysfunction induces abnormally strong cravings and drug-seeking behaviors, thus initiating the cycle of addiction. Most drugs cause maladaptations to the mesolimbic system by substantially increasing extracellular DA, which encodes the substance with a highly rewarding value, and/or they influence changes in Glu and GABA transmission to prompt drug-seeking.

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 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.

DA transmission can be regulated by glutamatergic afferents and, conversely, DA can influence Glu transmission via inputs to glutamatergic neurons. This interdependence of Glu and DA transmission is critical for regulating various aspects of reward processing and addictive behaviors. Many glutamatergic projections originating in limbic, cortical, and subcortical structures innervate DA neurons in the VTA and the NAc. Glutamatergic projections to the VTA come primarily from the PFC, but some stem from the amygdala, hippocampus, LHb, LH, or ventral pallidum . These glutamatergic inputs to the VTA help to modulate the phasic firing of the dopaminergic neurons directly or indirectly . For instance, glutamatergic projections from the LHb to GABAergic neurons in the VTA inhibit the firing of VTA DA neurons .

As previously discussed, OXTRs are found on glutamatergic neurons within the VTA, suggesting that OXT directly modulates Glu release in VTA neurons . Furthermore, OXTR-expressing projections have shown that they target the LHb , a region that receives Glu input from the VTA and is primarily involved in aversive conditioning , which may provide another mechanism through which OXT provides a neuromodulatory role in reward processing. Finally, VTA antidepressants and alcohol glutamatergic neurons have been shown to promote aversion behavior via projections to GABAergic interneurons within the NAc that subsequently inhibited NAc medium spiny neurons . While it is not yet known which specific VTA subpopulations of glutamatergic neurons express OXTRs, there are a number of possible mechanisms through which OXT could provide a neuromodulatory effect on reward-processes via its effect on Glu transmission within the VTA.

• Opioids are highly addictive, in large part because they activate powerful reward centers in your brain.
• For instance, glutamatergic projections from the LHb to GABAergic neurons in the VTA inhibit the firing of VTA DA neurons .
• Reports of overdose and death from prescription drug products, especially opioids, began to rise sharply, with OxyContin at the center of the problem.
• Recent evidence has suggested that natural rewards, such as food, sexual behavior, and social interactions, can also affect the reward circuit to elicit cravings, the impairment of control, and substance-seeking .

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.

Timeline of Selected FDA Activities and Significant Events Addressing Substance Use and Overdose Prevention

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.

Groppe S.E., Gossen A., Rademacher L., Hahn A., Westphal L., Gründer G., Spreckelmeyer K.N. Oxytocin influences processing of socially relevant cues in the ventral tegmental area of the human brain. Rothstein J.D., Martin L., Levey A.I., Dykes-Hoberg M., Jin L., Wu D., Nash N., Kuncl R.W. Localization of neuronal and glial glutamate transporters. Wolf M.E. The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Stamatakis A.M., Jennings J.H., Ung R.L., Blair G.A., Weinberg R.J., Neve R.L., Boyce F., Mattis J., Ramakrishnan C., Deisseroth K., et al.

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.

However, the NAc core and shell subregions have different roles in the mediation of relapse. The shell seems to be responsible for context-induced relapse, whereas the core is essential for cue-induced and drug-primed reinstatement . Additionally, the infusion of an AMPA antagonist, and not an NMDA antagonist, into the medial NAc blocks reinstatement for cocaine . While growing evidence indicates that the neurohypophysial peptide oxytocin can modulate the addictive properties of several abused drugs, the regulation of the oxytocinergic system following nicotine administration has so far received little attention. Here, we examined the effects of long-term nicotine or saline administration on the central oxytocinergic system using OVTA autoradiographic binding in mouse brain. Male, 7-week old C57BL6J mice were treated with either nicotine (7.8mg/kg daily; rate of 0.5μl per hour) or saline for a period of 14-days via osmotic minipumps.

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 .

Another possibility is that the drug reaches the brain through leakages into the cerebral spinal fluid, which occurs when the permeability of the BBB is compromised by addiction, hypertension, stress, or disease . Intranasal administration of OXT also seems to effectively deliver the drug to the brain, as this method allows for bypassing the BBB . Being able to avoid the limitations set by the BBB through intranasal administration opens up new opportunities for pharmaceutical treatments of disease. The initial enthusiasm towards oxytocin as a potential treatment for alcohol use disorder has been recently tempered by recognizing existing gaps in literature and the recent appearance of a relatively small number of clinical studies with negative outcomes.