Opioid peptides reduce synaptic transmission in the nucleus accumbens

doi:10.1016/0304-3940(92)90522-9

Neuroscience Letters

Volume 134, Issue 2, 6 January 1992, Pages 223-228

https://doi.org/10.1016/0304-3940(92)90522-9 Get rights and content

Abstract

Behavioral studies implicate the nucleus accumbens (NAcc) as a brain area pivotal for the rewarding effects of opiates like heroine and morphine. Therefore, we studied the effect of a variety of opioids on membrane properties and responses to synaptic stimulation in a slice preparation of the NAcc using intracellular recording. Superfusion of opioid peptides did not affect the membrane potential or input resistance of NAcc neurons, but significantly reduced both depolarizing and hyperpolarizing synaptic potentials. Naloxone superfusion significantly reversed the depressant effects of the μ and δ receptor agonists (but not those of the κ agonist) on synaptic transmission, suggesting involvement of opiate receptors. These results imply that the predominant effect of opiates in NAcc is a reduction of synaptic transmission.

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Interactions between the dopaminergic and glutamatergic systems may be a main component of neural circuitry of reward, including morphine-induced reward [1].
Neural circuitry comprising the ventral tegmental area, nucleus accumbens (NAc), prefrontal cortex (PFC) and hippocampus (HIP) has a main role in reward phenomena. Previous behavioral studies indicated that intracerebroventricular administration of AP5 (NMDA glutamate receptor antagonist) and CNQX (AMPA/kainate glutamate receptor antagonist) during the extinction and before reinstatement of morphine-induced conditioned place preference (CPP) reduced the extinction period and reinstatement of morphine-CPP. Therefore, in the present study, we tried to evaluate the effect of antagonism of NMDA glutamate receptors on the p-CREB/CREB ratio and c-fos expression in the NAc, PFC and HIP during these two phases of morphine-CPP in male adult albino Wistar rats. The p-CREB/CREB ratio and c-fos levels were estimated by Western blot analysis. The results revealed that these two factors decreased by antagonism of NMDA glutamate receptors (different doses of AP5) compared to saline-control group in aforementioned regions. The reduction of molecular markers, especially the p-CREB/CREB ratio, after AP5 administration was more during the extinction period. Therefore, it can be assumed that consolidation and reconsolidation of morphine memory via intra-PFC, −NAc and −HIP NMDA glutamate receptors are in accordance with changes in p-CREB/CREB ratio and c-fos levels.
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Unfortunately, in the present study, the time interval between the last morphine and the antagonist injections was not sufficient enough to avoid the residual effects on motor behaviour promoted by morphine itself in all behavioural tests used here; a condition also noted in other study [46]. This increase in motor activity promoted by morphine is possibly due to the activation of μ-opioid receptors in the dopaminergic neurons of the mesolimbic system [47,48]. This possibility is supported by the results obtained in the open-field, since the animals under morphine effect presented emphatic increases in the locomotor (travelled distance) and exploratory activity (number of rearings).
Withdrawal from morphine leads to the appearance of extreme anxiety accompanied of several physical disturbances, most of them linked to the activation of brainstem regions such as the locus coeruleus, ventral tegmental area, hypothalamic nuclei and periaqueductal grey (PAG). As anxiety remains one of the main components of morphine withdrawal the present study aimed to evaluating the influence of the dorsal aspects of the PAG on the production of this state, since this structure is well-known to be involved in defensive behaviour elicited by anxiety-evoking stimuli. Different groups of animals were submitted to 10 days of i.p. morphine injections, challenged 2 h after with an i.p. injection of naloxone (0.1 mg/kg), and submitted to the plus-maze, open-field and light–dark transition tests. The effects of morphine withdrawal on anxiety-induced Fos immunolabelling were evaluated in four animals that passed by the light–dark transition test randomly chosen for Fos-protein analysis. Besides the PAG, Fos neural expression was conducted in other brain regions involved in the expression of anxiety-related behaviours. Our results showed that morphine withdrawn rats presented enhanced anxiety accompanied of few somatic symptoms. Increased Fos immunolabelling was noted in brain regions well-known to modulate these states as the prelimbic cortex, nucleus accumbens, amygdala and paraventricular hypothalamus. Increased Fos labelling was also observed in the ventral and dorsal aspects of the PAG, a region involved in anxiety-related processes suggesting that this region could be a common neural substrate enlisted during anxiety evoked by dangerous stimuli as well as those elicited by opiate withdrawal.
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Drug addiction is a chronic relapsing disease in which drug administration becomes the primary stimulus that drives behavior regardless of the adverse consequence that may ensue. As drug use becomes more compulsive, motivation for natural rewards that normally drive behavior decreases. The discontinuation of drug use is associated with somatic signs of withdrawal, dysphoria, anxiety, and anhedonia. These consequences of drug use are thought to contribute to the maintenance of drug use and to the reinstatement of compulsive drug use that occurs during the early phase of abstinence. Even, however, after prolonged periods of abstinence, 80–90% of human addicts relapse to addiction, suggesting that repeated drug use produces enduring changes in brain circuits that subserve incentive motivation and stimulus–response (habit) learning. A major goal of addiction research is the identification of the neural mechanisms by which drugs of abuse produce these effects. This article will review data showing that the dynorphin/κ-opioid receptor (KOPr) system serves an essential function in opposing alterations in behavior and brain neurochemistry that occur as a consequence of repeated drug use and that aberrant activity of this system may not only contribute to the dysregulation of behavior that characterizes addiction but to individual differences in vulnerability to the pharmacological actions of cocaine and alcohol. We will provide evidence that the repeated administration of cocaine and alcohol up-regulates the dynorphin/KOPr system and that pharmacological treatments that target this system may prove effective in the treatment of drug addiction.
Nucleus accumbens opioid signaling conditions short-term flavor preferences
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Differences in receptor distribution patterns, local microcircuit anatomy or cellular physiological effects must account for these differences between DAMGO and muscimol. One possible explanation for the difference is that in the NAcc, GABA agonists directly and non-selectively inhibit all medium spiny neurons by a postsynaptic mechanism, whereas opioid peptides presynaptically inhibit GABAergic release (Yuan et al., 1992). Thus opioids have the potential to selectively control specific inputs, perhaps those that relay taste information.
Opioid signaling in the nucleus accumbens (NAcc) strongly modulates flavor-based food choice. To further investigate the role of opioid signaling in taste reward, we used a sensory specific satiety (SSS) paradigm to devalue specific flavors of nutritionally identical food pellets in rats. In the NAcc, infusion of a μ opioid (MOP) receptor selective agonist selectively increased consumption of a pre-fed flavor, thus reversing the SSS effect. Conversely, blockade of endogenous opioid signaling with the opioid antagonist naltrexone selectively decreased consumption of a recently consumed flavor, potentiating the SSS effect. No enhancement of consumption was observed if a delay of 3 h was imposed following the intra-NAcc MOP agonist indicating that there were no long-term changes in flavor preference. If a delay was introduced between the initial flavor exposure and the intra-NAcc MOP agonist infusion, pellet consumption was increased non-selectively (irrespective of flavor) suggesting that close temporal contiguity between flavor experience and NAcc opioid action is critical for the opioid effect on flavor preference. In contrast to opioid effects, inactivating NAcc neurons by local microinjection of muscimol (a GABA_A agonist) increased consumption of both the pre-fed and non-pre-fed flavors equally. These results demonstrate that opioids released in the NAcc during consumption of palatable foods produce a selective and transient increase in preference for a recently sampled flavor.
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It is well documented that stressful life experiences contribute to the etiology of human mood disorders. Cholecystokinin (CCK) is a neuropeptide found in high concentrations throughout the central nervous system, where it is involved in numerous physiological functions. A role for CCK in the induction and persistence of anxiety and major depression appears to be conspicuous. While increased CCK has been associated with motivational loss, anxiety and panic attacks, an increase in mesocorticolimbic opioid availability has been associated with coping and mood elevation. The close neuroanatomical distribution of CCK with opioid peptides in the limbic system suggests that there may be an opioid-CCK link in the modulation and expression of anxiety or stressor-related behaviors. In effect, while CCK induces relatively protracted behavioral disturbances in both animal and human subjects following stressor applications, opioid receptor activation may change the course of psychopathology. The antagonistic interaction of CCK and opioid peptides is evident in psychological disturbances as well as stress-induced analgesia. There appears to be an intricate balance between the memory-enhancing and anxiety-provoking effects of CCK on one hand, and the amnesic and anxiolytic effects of opioid peptides on the other hand. Potential anxiogenic and mnemonic influences of site-specific mesocorticolimbic CCK and opioid peptide availability, the relative contributions of specific CCK and opioid receptors, as well as the time course underlying neuronal substrates of long-term behavioral disturbances as a result of stressor manipulations, are discussed.
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Mice lacking the D₂ dopamine receptor (D₂^−/−) and congenic to the C57BL/6J background were tested for opioid-mediated locomotor activity to examine the involvement of the D₂ dopamine receptor in opioid pharmacology. Morphine-stimulated locomotor activity did not significantly differ between the two genotypes. The opioid antagonist naloxone dose-dependently decreased spontaneous motor activity in wild-type mice but was without significant effect in D₂^−/− mice. The magnitude of food-conditioned increases in locomotor activity in wild-type mice and D₂^−/− mice was similar but naloxone did not decrease conditioned motor activity in D₂^−/− mice. Spontaneous locomotor activity of mice lacking the endogenous opioids β-endorphin and/or enkephalin was also tested and we found that naloxone did not reduce activity in mice specifically lacking enkephalin. We suggest that the D₂ dopamine receptor is necessary for modulation of spontaneous locomotor activity stimulated by the endogenous opioid enkephalin.

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^∗: Current address: Department of Physiology, Nanjing Medical College, 140 Hanzhong Rd., Nanjing, Jiangsu 210029, People's Republic of China.

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Opioid peptides reduce synaptic transmission in the nucleus accumbens

Abstract

Neurosci. Lett.

Neuroscience

Trends Neurosci.

Eur. J. Pharmacol.

Life Sci.

Neurosci. Lett.

Brain Res.

Brain Res.

Brain Res.

Visualization of mul opiate receptors in rat brain by using a computerized autoradiographic subtraction technique

Opiate influences on nucleus accumbens neuronal electrophysiology: dopamine and non-dopamine mechanisms

J. Neurosci.