OXYTOCIN AND ADDICTION: A REVIEW

doi:10.1016/S0306-4530(98)00064-X

Psychoneuroendocrinology

Volume 23, Issue 8, November 1998, Pages 945-962

https://doi.org/10.1016/S0306-4530(98)00064-X Get rights and content

Abstract

Neuropeptides affect adaptive central nervous system processes related to opiate ethanol and cocaine addiction. Oxytocin (OXT), a neurohypophyseal neuropeptide synthesized in the brain and released at the posterior pituitary, also is released in the central nervous system (CNS). OXT acts within the CNS and has been shown to inhibit the development of tolerance to morphine, and to attenuate various symptoms of morphine withdrawal in mice. In rats, intravenous self-administration of heroin was potently decreased by OXT treatment. In relation to cocaine abuse, OXT dose-dependently decreased cocaine-induced hyperlocomotion and stereotyped grooming behavior. Following chronic cocaine treatment, the behavioral tolerance to the sniffing-inducing effect of cocaine was markedly inhibited by OXT. Behavioral sensitization to cocaine, on the other hand, was facilitated by OXT. OXT receptors in the CNS—mainly those located in limbic and basal forebrain structures—are responsible for mediating various effects of OXT in the opiate- and cocaine-addicted organism. Dopaminergic neurotransmission—primarily in basal forebrain structures—is another important biochemical mediator of the central nervous system effects of OXT. Tolerance to ethanol (e.g. hypothermia-inducing effect of ethanol) also was inhibited by OXT. © 1998 Elsevier Science Ltd. All rights reserved.

Section snippets

INTRODUCTION

In the last 25 years there has been a great increase in interest in central nervous system (CNS) functions of neuroactive peptides (Hökfelt, 1991). Neuropeptides may function as neurotransmitters as well as neuromodulators. Neurotransmitters are localized in nerve terminals, preferentially in synaptic vesicles. They are released upon nerve stimulation, interact with receptor molecules on the postsynaptic cell membrane, and are subsequently inactivated by enzymatic degradation and re-uptake

The Effects of Oxytocin on Opiate Tolerance

In recent years it has become increasingly evident that neurohypophyseal neuropeptides (OXT and vasopressin, VP) might play a role in drug addiction processes (Kovács, 1986, Kovács and Telegdy, 1987b, Krivoy et al., 1974, Van Ree, 1983). For example, desglycinamide⁹-lysine⁸-vasopressin (DG-LVP) facilitated the rate at which tolerance to morphine-induced analgesia developed in mice (Krivoy et al., 1974, Van Ree and De Wied, 1977b). Van Ree and De Wied (1977a), Van Ree and De Wied (1977b)found

OXYTOCIN AND COCAINE ABUSE

Cocaine is a psychostimulant, which acts primarily through the brain dopaminergic system as an inhibitor of the dopamine transporter, thus resulting in an increase in synaptic dopamine content (Galloway, 1988, Koob et al., 1997). Locomotor hyperactivity, exploratory hyperactivity and stereotyped behavior were investigated as acute behavioral responses to cocaine. Two types of behavioral adaptation to repeated cocaine administration, sensitization and tolerance were chosen to study the

Oxytocin and Ethanol Tolerance

In the CNS, ethanol tolerance appears to be a combined process with both behavioral and cellular components. Tolerance to ethanol has been shown to involve learning. Some forms of tolerance are dependent on learning. The animals display tolerance only in the environment where ethanol was initially presented and not in a novel environment.

Development of rapid tolerance to the hypothermic effect of ethanol has been proposed as a reliable model for investigating the above phenomenon. Peripheral

CONCLUSIONS

Recent results from our laboratories (Kovács, 1986Sarnyai and Kovács 1994), and other laboratories (Krivoy et al., 1974, Van Ree, 1983, Van Ree and De Wied, 1977a, Van Ree and De Wied, 1977b) suggest that neurohypophyseal neuropeptides modulate the response to drugs of abuse. In the case of OXT, adaptive components of drug addiction are affected primarily: the neuropeptide inhibits the development of tolerance to, and physical dependence on, morphine and reduces the self-administration of

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Glutamate plays a crucial role in cognitive impairments after ischemic stroke. There is a scarcity of information about how glutamate-induced activation of cAMP-response element binding (CREB) signaling pathway regulates both the negative and positive regulators of synaptic plasticity. Recent studies have demonstrated the involvement of prominent epigenetic repressors, such as MeCP2 and DNMTs, in stroke. Neuroprotective effects of oxytocin against ischemia have been previously reported, while the underlying mechanism is still elusive. In this research, the possible role of CREB-mediated DNA hypermethylation and the potential mechanism of oxytocin in a rat model of permanent middle cerebral artery occlusion (pMCAO) were assessed. Adult male Sprague-Dawley rats were pretreated with intraperitoneal injection of oxytocin at the onset of pMCAO. The effects of oxytocin on spines and the expression levels of synaptic genes were determined. The regulatory effects of oxytocin on glutamate level, N-methyl-D-aspartate receptors (NMDARs), its downstream CREB pathway, and global or gene-specific DNA methylation status were evaluated by immunofluorescence, co-immunoprecipitation, and chromatin immunoprecipitation, respectively. We found that CREB could act as a common transcription factor for MeCP2 and DNMT3B after ischemic stroke. Oxytocin dose-dependently deactivated NR2B-related CaM-CREB pathway and inhibited DNA hypermethylation at the CpG islands of Ngf gene in pMCAO-operated rats. Moreover, oxytocin prevented pMCAO-induced reduction in the number of spines and neural cells. DNA hypermethylation in Ngf gene contributed to the cognitive deficits post-stroke. The neuroprotective effects of oxytocin against ischemia could be attributed to inhibiting glutamate release, providing additional evidence on the mechanism of oxytocin against ischemic stroke.
Food addiction, hormones and blood biomarkers in humans: A systematic literature review
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Food addiction may play a role in rising obesity rates in connection with obesogenic environments and processed food availability, however the concept of food addiction remains controversial. While animal studies show evidence for addictive processes in relation to processed foods, most human studies are psychologically focussed and there is a need to better understand evidence for biological mechanisms of food addiction in humans. Several key hormones are implicated in models of food addiction, due to their key roles in feeding, energy metabolism, stress and addictive behaviours. This systematic literature review examines evidence for relationships between food addiction, hormones and other blood biomarkers.
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Sex matters: The impact of oxytocin on healthy conditions and psychiatric disorders
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Oxytocin (OT) is involved in the regulation of physiological processes and emotional states, with increasing evidence for its beneficial actions being mediated by the autonomic and immune systems. Growing evidence suggests that OT plays a role in the pathophysiology of different psychiatric disorders. Given the limited information in humans the aim of this study was to retrospectively explore plasma OT levels in psychiatric patients, particularly focusing on sex-related differences, as compared with healthy controls. The patients studied here were divided into three groups diagnosed with obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD) or major depressive disorder (MDD). Plasma OT levels were significantly different between healthy men and women, with the latter showing higher values, while none of the three psychiatric groups showed sex-related differences in the parameters measured here. The intergroup analyses showed that the OT levels were significantly higher in OCD, lower in PTSD and even more reduced in MDD patients than in healthy subjects. These differences were also confirmed when gender was considered, with the exception of PTSD men, in whom OT levels were similar to those of healthy men. The present results indicated that OT levels were higher amongst healthy women than men, while a sex difference was less apparent or reversed in psychiatric patients. Reductions in sex differences in psychopathologies may be related to differential vulnerabilities in processes associated with basic adaptive and social functions.
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The prefrontal cortex plays a critical role in regulating substance use disorder and is strongly implicated in inhibition of and relapse to drug-seeking. Within the prefrontal cortex, inhibitory interneurons make up tightly regulated microcircuits that moderate activity of pyramidal neurons and hence control output to downstream circuits including those important for addiction-related behaviours. These interneurons can be classed into subpopulations based on peptide expression, however the complexity of these subclasses is only beginning to be understood. In this review we focus on four peptides that have receptor expression on interneurons and pyramidal neurons in the PFC. All four peptides have well-known roles in mediating drug-seeking behaviours, however their function within the prefrontal cortex is less well defined. We will review evidence from preclinical animal models that cells expressing these receptors are recruited during addiction-related behaviours, and that direct pharmacological manipulation of these systems within the prefrontal cortex may lead to altered drug-seeking behaviours. In our view, a deeper understanding of activity of specific microcircuits within this region, and their effect on pyramidal neuronal output are critical for understanding and remediating specific behaviours relevant to substance use disorder. Uncovering function of cells populations that express these neuropeptides and their receptors may help to define these microcircuits, and hence to understand how and why these behaviours are altered following drug exposure.
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It is well established that the damaging effects of drugs of abuse, such as cocaine, can extend beyond the user to their offspring. While most preclinical models of the generational effects of cocaine abuse have focused on maternal effects, we, and others, report distinct effects on offspring sired by fathers treated with cocaine prior to breeding. However, little is known about the effects of paternal cocaine use on first generation (F1) offspring’s social behaviors. Here, we expand upon our model of oral self-administered paternal cocaine use to address the idea that paternal cocaine alters first generation offspring social behaviors through modulation of the oxytocin system. F1 cocaine-sired males displayed unaltered social recognition vs. non-cocaine sired controls but showed increased investigation times that were not related to altered olfaction. Paternal cocaine did not alter F1 male-aggression behavior or depression-like behaviors, but cocaine-sired males did display decreased anxiety-like behaviors. Female F1 behavior was similarly examined, but there were no effects of paternal cocaine. Cocaine-sired male mice also exhibited localized oxytocin receptor expression differences vs. controls in several brain regions regulating social behavior. These results provide evidence for effects of paternal cocaine exposure on social behaviors in male offspring with associated alterations in central oxytocin transmission.
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OXYTOCIN AND ADDICTION: A REVIEW

Abstract

Section snippets

INTRODUCTION

The Effects of Oxytocin on Opiate Tolerance

OXYTOCIN AND COCAINE ABUSE

Oxytocin and Ethanol Tolerance

CONCLUSIONS

Pharmacological Therapy

Neuropeptides

European Journal of Pharmacology

Physiology and Behavior

Trends in Pharmacological Science

Behavioral Brain Research

Neuron

Pharmacology and Biochemical Behavior

Life Sciences

Neurochemical International

Behavioral Brain Research

Neuropharmacology

Drug and Alcohol Dependence

Neuropharmacology

Brain Research

Pharmacology and Biochemical Behavior

Life Sciences

Trends in Neuroscience

Neuropeptides

Psychoneuroendocrinology

Pharmacology and Biochemical Behavior

Brain Research

Brain Research

Neuropharmacology

Psychoneuroendocrinology

Depression of mesolimbic dopamine transmission and sensitization to morphine during opiate abstinence

Journal of Neurochemistry

Neurohypophyseal peptides in tolerance and dependence

[3H]-[Thr4,Gly7]OT: a highly selective ligand for central and peripheral OT receptors

American Journal of Physiology

Specific binding of [3H]oxytocin in female rat brain

Canadian Journal of Physiology and Pharmacology

Arginine vasopressin maintains ethanol tolerance

Nature

Microinjection of oxytocin into limbic–mesolimbic brain structures disrupts heroin self-administration behavior: a receptor mediated event?

Life Sciences

[³H]-[Thr⁴,Gly⁷]OT: a highly selective ligand for central and peripheral OT receptors

Specific binding of [³H]oxytocin in female rat brain