Selective attenuation of cocaine-induced stereotyped behaviour by oxytocin: Putative role of basal forebrain target sites

doi:10.1016/0143-4179(91)90073-R

Neuropeptides

Volume 19, Issue 1, May 1991, Pages 51-56

https://doi.org/10.1016/0143-4179(91)90073-R Get rights and content

Abstract

The effects of oxytocin (OXT), arginine- and lysine-vasopressin (AVP and LVP) and an OXT-receptor antagonist on cocaine-induced sniffing behaviour were investigated in rats. OXT, but not AVP or LVP injected subcutaneously (s.c.) attenuated cocaine-induced sniffing. The effect of OXT (s.c.) was inhibited by an OXT-receptor antagonist administered intracerebroventricularly (i.c.v.). l.c.v. administration of different doses of OXT in nanogram quantities caused a dose-dependent attenuation of cocaine-induced sniffing. Local cerebral microinjection of OXT into the accumbens nucleus and olfactory tubercle but not into the olfactory nucleus, central amygdaloid nucleus or caudate nucleus, inhibited the cocaine-induced sniffing behaviour.

These results demonstrate that OXT selectively attenuates the cocaine-induced stereotyped behaviour through basal forebrain target sites.

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Neurohypophyseal peptides, motivated and drug-induced behaviour

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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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Citation Excerpt :
Additionally, OXT pre-treatment inhibited the development of tolerance to morphine-induced hyper-locomotion (Kovacs et al., 1987) and anti-nociceptive effects (Kovacs et al., 1985) in mice. With regards to psychostimulants, higher doses of OXT have been shown to reduce locomotor hyperactivity and stereotyped behaviors induced by cocaine (Kovacs et al., 1990, Sarnyai et al., 1991, Sarnyai et al., 1992) and methamphetamine (Carson et al., 2010a, Qi et al., 2008), but not amphetamine (Sarnyai and Kovacs, 1994, Kovacs et al., 1985). Interestingly, lower doses of OXT were unable to prevent the development of tolerance or sensitization in rodents (Sarnyai et al., 1992).
The neuropeptide oxytocin (OXT) plays a key role in adaptive processes associated with reward, tolerance, memory and stress responses. Through interactions with brain reward and stress systems, OXT is known to play a role in several neuropsychiatric disorders, particularly those that involve altered social integration, such as alcohol and drug addiction (Heilig et al., 2016). As such, there is growing interest in the oxytocin system as a potential therapeutic target for the treatment of alcohol and substance use disorders. Accumulating preclinical evidence suggests that administration of OXT influences the development of tolerance, sensitization and withdrawal symptoms, and modulates numerous alcohol/drug-seeking and alcohol/drug-taking behaviors. Further, there is some evidence to suggest that OXT may help to reverse neuroadaptations that occur as a result of chronic alcohol or drug exposure. To date, there have been only a handful of clinical studies conducted in alcohol and drug dependent populations. This review summarizes the preclinical and clinical literature on the effects of OXT administration on alcohol- and drug-related behaviors. In addition, we discuss OXT interactions with the hypothalamic-pituitaryadrenal axis and multiple neurotransmitter systems within addiction circuitry.
The impact of early life stress on the central oxytocin system and susceptibility for drug addiction: Applicability of oxytocin as a pharmacotherapy
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The majority of this work has thus far been conducted for psychostimulant or alcohol use, with limited research in the space of opiates, nicotine or cannabis use. In relation to psychostimulants, peripheral oxytocin injections administered acutely prior to testing attenuated cocaine-induced stereotypy (Sarnyai et al., 1991), tolerance (Sarnyai et al., 1992a) and drug-primed relapse to cocaine seeking behaviour in male rats (Zhou et al., 2014). In male and female rats, systemic oxytocin administration decreased intravenous self-administration of cocaine as well as cue-induced relapse to cocaine-seeking behaviour (Leong et al., 2016; Sarnyai and Kovacs, 1994; Zhou et al., 2014; Weber et al., 2018; Kohtz et al., 2018).
Early life trauma is strongly associated with an increased vulnerability to abuse illicit drugs and the impairment of neural development. This includes alterations to the development of the oxytocin system, which plays a pivotal role in the regulation of social behaviours and emotion. Dysregulation of this important system also contributes to increased susceptibility to develop drug addiction. In this review, we provide an overview of the animal models of early life stress that are widely used, and discuss the impact that early life stress has on drug-taking behaviour in adolescence and adulthood in both sexes. We link this to the changes that early life stress has on the endogenous oxytocin system, and how exogenously administered oxytocin may help to re-establish functioning of the system, and in turn, reduce drug-taking behaviour.
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Repeated exposure to the opioid agonist, oxycodone, can lead to addiction. Accumulating evidence has shown that oxytocin (OT), a neurohypophyseal neuropeptide, could reduce the abuse potential of drugs. Recent studies suggest that epigenetic regulation through DNA methylation are involved in neuroadaptations. The current study was conducted to investigate the effects of OT on oxycodone conditioned place preference (CPP) and the epigenetic mechanism of OT in the hippocampus. For induction of CPP, oxycodone (3.0 mg/kg, i. p.) was administrated to male Sprague-Dawley rats once every other day during an eight-day conditioning phase. Global 5-methylcytosine (5-mC) level was determined based on CPP procedure, including acquisition, expression, extinction and reinstatement. We also measured mRNA levels of DNA methyltransferases (Dnmts), ten-eleven translocations (Tets) and synaptic genes (Psd95, Shank2, Gap43, etc.), and determined synaptic density after restraint stress-induced reinstatement of oxycodone CPP. The results showed that OT (2.5 μg, i. c.v.) pretreatment specifically inhibited the CPP acquisition and expression, facilitated the CPP extinction, and abolished restraint stress-induced reinstatement of oxycodone CPP. OT markedly inhibited global 5-mC changes induced by oxycodone CPP in the four phases. Following restraint stress-induced reinstatement of oxycodone CPP, OT significantly increased mRNA levels of Dnmt1, decreased Tet1 mRNA, synaptic proteins and synaptic density in the hippocampus. Our study indicated that reversal of global DNA hypomethylation through OT could significantly attenuate the rewarding effects induced by oxycodone. Our results suggested that OT could be specific manipulation on oxycodone addiction.
Oxytocin prevents the increase of cocaine-related responses produced by social defeat
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The neuropeptide oxytocin (OXT) plays a critical role in the regulation of social and emotional behaviors. OXT plays a role in stress response and in drug reward, but to date no studies have evaluated its implication in the long-lasting increase of the motivational effects of cocaine induced by repeated social defeat (RSD). During the social defeat procedure, 1 mg/kg of OXT was administered 30 min before each episode of RSD. Three weeks after the last defeat, the effects of cocaine on the conditioned place preference (CPP), locomotor sensitization and the self-administration (SA) paradigms were evaluated. The influence of OXT on the levels of BDNF in the prefrontal cortex (PFC), striatum and hippocampus was also measured. Our results confirm that raising the levels of OXT during social defeat stress can block the long-lasting effects of this type of stress. OXT counteracts the anxiety induced by social defeat and modifies BDNF levels in all the structures we have studied. Moreover, OXT prevents RSD-induced increases in the motivational effects of cocaine. Administration of OXT before each social defeat blocked the social defeat-induced increment in the conditioned rewarding effects of cocaine in the CPP, favored the extinction of cocaine-associated memories in both the CPP and SA, and decreased reinstatement of cocaine-seeking behavior in the SA. In conclusion, the long-lasting effects of RSD are counteracted by administering OXT prior to stress, and changes in BDNF expression may underlie these protective effects.
Antagonism of mGlu2/3 receptors in the nucleus accumbens prevents oxytocin from reducing cued methamphetamine seeking in male and female rats
2017, Pharmacology Biochemistry and Behavior
Methamphetamine (meth) addiction is a prevalent health concern worldwide, yet remains without approved pharmacological treatments. Preclinical evidence suggests that oxytocin may decrease relapse, but the neuronal underpinnings driving this effect remain unknown. Here we investigate whether oxytocin's effect is dependent on presynaptic glutamatergic regulation in the nucleus accumbens core (NAcore) by blocking metabotropic glutamate receptors 2/3 (mGluR2/3). Male and female Sprague-Dawley rats self-administered meth or sucrose on an escalating fixed ratio, followed by extinction and cue-induced reinstatement sessions. Reinstatement tests consisted of systemic (Experiment 1) or site-specific application of the drugs into the NAcore (Experiments 2 and 3). Before reinstatement sessions, rats received LY341495, an mGluR2/3 antagonist, or its vehicle followed by a second infusion/injection of oxytocin or saline. As expected, both males and females reinstated lever pressing to meth associated cues, and LY341495 alone did not impact this behavior. Oxytocin injected systemically or infused into the NAcore decreased cued meth seeking. Importantly, combined LY341495 and oxytocin administration restored meth cued reinstatement. Interestingly, neither oxytocin nor LY341495 impacted sucrose-cued reinstatement, suggesting distinct mechanisms between meth and sucrose. These findings were consistent between males and females. Overall, we report that oxytocin reduced responding to meth-associated cues and blocking presynaptic mGluR2/3 reversed this effect. Further, oxytocin's effects were specific to meth cues as NAcore oxytocin was without an effect on sucrose cued reinstatement. Results are discussed in terms of oxytocin receptor localization in the NAcore and modulation of presynaptic regulation of glutamate in response to drug associated cues.

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^∗: Present address: Central Laboratory, Markusovszky Teaching Hospital, Szombathely, Hungary

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Selective attenuation of cocaine-induced stereotyped behaviour by oxytocin: Putative role of basal forebrain target sites

Abstract

Neuropharmacology

Life Science

Drug and Alcohol Dependence

Brain Research

Life Science

Brain Research

Neurochemistry International

Neuropharmacology

Pharmacology, Biochemistry and Behaviour

Life Science

Neuropharmacology

Psychoneuroendocrinology

Neuropharmacology

Oxytocin and behaviour

Neurohypophyseal peptides, motivated and drug-induced behaviour