There is evidence that a positive social environment plus a well-developed endogenous OXT system is a protective factor that diminishes an individual’s vulnerability to become initiated in the addictive cycle [29]. One of the mechanisms put forward to explain this effect is that OXT decreases novelty seeking and the initial response to drug reward [29,30]. Novelty seekers display a preference reminding yourself that a sober life is a better life for novel environments and stimuli over familiar ones [31], and this behavioral trait has been linked to an increased risk of drug abuse in both humans and animal models [29,32]. For instance, rodent studies show that rats that display an enhanced locomotor response to a novel context also display an enhanced response to psychostimulant drugs and a faster acquisition of SA behavior [33].
- This increases synaptic DA levels, which activates D1 receptors and enhances Glu transmission [108].
- In addition, exposure to SD augments the permeability of the blood-brain barrier, allowing immune cells to cross into the CNS [183].
- The possible mechanisms of methamphetamine-induced brain changes are neurotoxicity and inflammation [25].
- The catheter was flushed daily with a 0.2 ml saline solution containing heparin (60 IU) and cephazolin (20 mg).
- However, McGregor and Bowen (85) found a long lasting effect of OT
administration on ethanol preference in rats.
Percentage of time spent in the closed arms relative to the total 5-min was analysed using CleverSys software (USA). It consists mostly of DA neurons and receives glutamatergic inputs from the medial prefrontal cortex (mPFC), lateral habenula (LHb), lateral hypothalamus (LH), and laterodorsal tegmentum [21]. Within the VTA, there are GABAergic interneurons which project to VTA DA neurons to regulate DA release [21]. A population of Glu neurons also resides in the VTA, as discovered by expression of the vesicular glutamate transporter 2 (VGLUT2) [22].
Methamphetamine also has been shown to deplete dopamine, serotonin, and their metabolites in several brain regions [24]. The possible mechanisms of methamphetamine-induced brain changes are neurotoxicity and inflammation [25]. Excess dopamine auto-oxidizes in the cytoplasm of neurons, enabling significant production of reactive oxygen species [26]. Subsequent oxidative stress leads to significant dysfunction of neurons, terminal degeneration, and apoptosis [27]. Due to recent developments in the understanding of oxytocin neurophysiology, targeting the central neuromodulation of oxytocin may induce improved symptomatic effects in treating methamphetamine use disorder. Due to the current advancements in oxytocin neurophysiology and modulation of behavior in the setting of chronic drug abuse, the medical community has brought further attention to oxytocin as a possible pharmacotherapy, which warrants further clinical investigations [7].
Restoring the endogenous oxytocin system with exogenous oxytocin
However, the effect of OT on
heroin self-administration was tested with only one dose of heroin (63), therefore, without dose –
response information, it is not possible to determine whether OT was inhibiting
or potentiating the effects of heroin. Overall, OT administered peripherally,
appears to inhibit the development of tolerance and withdrawal to opioids and
this effect seems to be centrally mediated. Although there has been no research that looks directly at the interactions between OXT, GABA, and DA levels, it is possible that OXT interacts with GABA neurons that project onto glutamatergic and dopaminergic neurons in the VTA.
The OT receptor belongs to the rhodopsin-type (class1) G protein-coupled receptor family and was cloned in 1992 (Kimura et al. 1992). 1) There is dendritic release from the PVN and SON in the hypothalamus (Ludwig and Leng 2006) with passive diffusion to OT receptors, which are located throughout the brain (Gimpl and Fahrenholz 2001). 2) More targeted direct release of OT occurs from nerve terminals of parvocellular neurons of the PVN, which project centrally to diverse regions including, among others, the olfactory bulb, tubercule, medial and central amygdala, lateral septum, hippocampus(HC), brainstem and spinal cord (Stoop 2014). The primary aim of the present study was to determine whether adolescent oxytocin treatment prevents ELS-induced vulnerability to METH-taking and reinstatement, anxiety, and social deficits.
OXT also has the potential to prevent the progression of the addictive cycle by stemming the development of dependence and the appearance of behavioral alterations after continuous contact with the drug [6,20]. The initial motivation to consume a drug is first driven by positive reward experiences; however, after repeated drug consumption, there is a shift of motivation to avoid the negative emotional state that emerges during abstinence [22]. During early adulthood (PND 54–55), anxiety-like behaviour was measured using the elevated plus maze [14]. Briefly, the elevated plus maze was elevated 50 cm off the floor in a dark room, with open and closed arms measuring 50 cm long × 10 cm wide, and the closed arms having 40 cm high walls. The arena was illuminated from above with a white light (40 lux), and video recording was conducted with an infrared camera.
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 [29,134]. 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 [9]. OXT has a greater gating effect on Glu neurons that fire only occasionally compared to those that fire repeatedly. 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 [9].
How is oxytocin given?
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. Overall, drug and alcohol exposure appear to produce compensatory neuroadaptive changes in the endogenous OXT system in brain regions specifically involved in the addiction process, though these changes appear to be drug- and possibly species-specific. Impaired functioning of the brain OXT system is likely to contribute to dysfunctional social-, reward-, and stress-related behaviors (Bowen and Neumann, 2017).
Total METH intake
Largely from preclinical literature, the
overall pattern of changes appears to be a decrease in peptide expression with
chronic use and an upregulation of the OT receptor. Accumulating evidence suggests a clear role for the oxytocinergic system in the acute reinforcing effects of drugs and alcohol (Lee et al., 2016, Lee and Weerts, 2016, Leong et al., 2018). However, the specific effect of OXT on drug-taking behavior appears to be dose-, drug-, use history-, and possibly species-dependent. For example, early studies showed that peripherally administered OXT slightly sobriety strategies increased heroin self-administration in rats (Ree and Wied, 1977). In support of this finding, central OXT administration did not prevent the acquisition of morphine-conditioned place preference (CPP), and instead, increased the expression of CPP in rats (Moaddab et al., 2015). In contrast, systemically administered OXT decreased both the acquisition and maintenance of heroin self-administration (Kovacs et al., 1985), and inhibited heroin self-administration in heroin-tolerant, but not heroin-naïve rats and mice (Kovacs et al., 1985, Kovács and Van Ree, 1985).
Furthermore, an mGluR2/3 antagonist inhibited the effects of intra-accumbal OXT on cued reinstatement of cocaine seeking [30]. 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. Administration of OXT can influence Glu levels in the reward circuit, suggesting that the neuropeptide may attenuate addictive behaviors by acting on the glutamatergic system. Thus, the medial projections from the VTA to NAc, which are likely to be glutamatergic are also likely to be involved in oxytocinergic mechanisms.
Tops et al. [29] posited that an increased tone of endogenous OXT alters DA, serotonin, and endogenous opioid neurotransmission, thus promoting a shift in novelty processing from ventral to dorsal striatal structures and a subsequent decrease of preference and emotional reactivity to these contexts. Endogenous oxytocin is a nine amino acid peptide that is produced by the hypothalamus and enters the peripheral circulation [6]. Peripherally, oxytocin promotes uterine contraction and lactation, during the intrapartum and postpartum period but additional receptors are located in the kidneys, pancreas, and heart. Modifying central neurotransmitter function in these regions is understood to attenuate neurobehavioral manifestations, including bonding, maternal, and stress-reducing behaviors, and contributes to the sensation of reward, stress, social affiliation, learning, and processing memories. First, the behavioral measures may not have been obtained at optimal times to detect oxytocin effects.
Alcohol
In this domain, previous studies have demonstrated positive correlations between cocaine or heroin EV and drug choice, and negative correlations between food or saccharin EV and drug choice [59, 62]. In the present study, heroin choice did not correlate with any behavioral economics variables, indicating that these are fundamentally separate metrics of OUD severity. Furthermore, heroin EV was higher than food EV, whereas previous studies have found food or saccharin EV to be higher than drug (cocaine or heroin) EV [59, 62]. Consistent with our prior work [6], food α was higher than heroin α, again pointing to a higher motivational state for heroin than food, contrary to other reports [59, 72, 73]. Nonetheless, this underscores the enhanced face validity of this behavioral economics choice model for OUD.
Likewise, through functional magnetic resonance imaging (fMRI), an increase in neural responses was observed in the striatum, dorsal anterior cingulate cortex [147], and insula [147,148] with respect to patients treated with a placebo. Several studies by Koch and co-workers suggest that OXT acts as a cognitive regulator of emotions and anxiety; for instance, it decreased anxiety before an emotional faces recognition task and lowered the reactivity of the amygdala during the task [149]. In an extension of the study in question, an increase in connectivity between the left thalamus and amygdala was observed during a distraction task in male patients [150]. Here we describe several instances of adolescent oxytocin treatment preventing the emergence of ELS-induced addiction vulnerability differentially between the sexes. Sex differences in oxytocin effects have been reported in various rodent models, including self-administration studies [65,66,67]. The underlying mechanisms are unclear with sex-dependent neurobiological effects of oxytocin only starting to be described in the literature.
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Future studies might directly compare acute MDMA-related effects in a social vs an isolated context. Further, administration of an OT receptor antagonist inhibits this effect on tolerance, suggesting that how long alcohol stays your system urine and blood test the endogenous OT system opposes the development of acute tolerance (Kovacs et al. 1987). OT also delays naloxone-induced withdrawal symptoms in a dose dependent manner (Kovacs et al. 1984, 1985b).
Brain penetrance of exogenously administered oxytocin and dosing
Following five days of either oxytocin or saline administration, the rats were left in their cages for ten days to allow for the extinction of the conditioned response [49]. The extinction phase is where the place preference is unpaired from the conditioned stimulus (i.e., administration of methamphetamine). The subjects were evenly distributed into groups sequentially exposed to saline and either oxytocin or vasopressin after this initial place preference test. After conditioning and the initial preferential placement, from Days 10 to 17, saline was alternately paired four times with each of the chambers once per day over eight days.
Larger doses of OT reduced
locomotor hyperactivity and stereotyped behaviors induced by both cocaine (69–71) and METH(50, 51), but not amphetamine(32, 60). Of
note for these experiments is the long duration of action of a single dose of OT
administered subcutaneously on locomotor hyperactivity, i.e. up to 2 hours(69). This pharmacodynamic effect is not
understood as this duration of effect is considerably longer than one would
expect from a peptide with a half- life of minutes in the plasma (72) and ~20 minutes in the cerebrospinal
fluid(73). Pedersen and colleagues (2013) 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.