Involvement of the ventral tegmental area but not periaqueductal gray matter in the paradoxical rewarding and aversive effects of morphine.

Wu, Chi-Wen; Ou, Chen Yin; Yu, Ying; Yu, Yi Chun; Shyu, Bai-Chuang; Huang, Andrew Chih Wei

doi:10.1037/bne0000483

Cited by 3 publications

(8 citation statements)

References 31 publications

(53 reference statements)

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“…The Cg1, PrL, IL, BLA, NAc, and DG showed more c-Fos expression after the morphine-induced CTA and CPP at a lower dose of 10 mg/kg of morphine ( Yu et al, 2021 ). Moreover, our lesion study indicated that destroying the VTA with a high concentration of NMDA impaired morphine-induced CTA and CPP ( Wu et al, 2021 ). A periaqueductal gray matter lesion did not change morphine’s aversive and reward conditioning at a 20 mg/kg dose of morphine ( Wu et al, 2021 ).…”

Section: Discussionmentioning

confidence: 96%

“…Moreover, our lesion study indicated that destroying the VTA with a high concentration of NMDA impaired morphine-induced CTA and CPP ( Wu et al, 2021 ). A periaqueductal gray matter lesion did not change morphine’s aversive and reward conditioning at a 20 mg/kg dose of morphine ( Wu et al, 2021 ). In conclusion, we suggested that the Cg1, PrL, IL, BLA, NAc, DG, and VTA were involved in the morphine’s CTA and CPP.…”

Section: Discussionmentioning

confidence: 96%

“…The evidence of the simultaneous existence of reward and aversion created by abused drugs challenges the conventional viewpoint of drug abuse solely being the result of drugs' rewarding properties (Wang et al, 2010;Wu et al, 2021;Yu et al, 2021). The reward hypothesis of abused drugs proposes that the acute administration of abused drugs induces impulsive behaviors and that chronic drug administration elicits compulsive Frontiers in Pharmacology frontiersin.org behaviors.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, the paradoxical effect hypothesis of abused drugs has suggested the simultaneous existence of morphine’s reward and aversion, which could affect drug misuse ( Wang et al, 2021 ; Wu et al, 2021 ; Yu et al, 2021 ). For example, the rewarding effect of abused drugs elicits approaching behavior to access to the abused drugs and increased its probability of their abuse; in contrast, abused drugs also induce aversion which results in avoidance behaviors for the drug use ( Wang et al, 2021 ; Wu et al, 2021 ; Yu et al, 2021 ). Furthermore, it was demonstrated many neural substrates were involved in the paradoxical effect of morphine.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, it was demonstrated many neural substrates were involved in the paradoxical effect of morphine. For example, under a 20 mg/kg dose of morphine, a lesion of the ventral tegmental area (VTA) disrupted the drug’s aversive effect in the CTA test and rewarding effect in the CPP test ( Wu et al, 2021 ). Morphine-induced CTA conditioning could activate more c-Fos expression in the cingulate cortex 1 (Cg1), PrL, infralimbic cortex (IL), BLA, NAc, and dentate gyrus (DG) ( Yu et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Neuronal activity of the medial prefrontal cortex, nucleus accumbens, and basolateral amygdala in conditioned taste aversion and conditioned place preference induced by different doses of morphine administrations in rats

et al. 2023

Front. Pharmacol.

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To re-examine the paradoxical effect hypothesis of abused drugs, the present study concerned whether different doses of morphine disparately affect neuronal activity and associations among the subareas of the medial prefrontal cortex (mPFC: cingulate cortex 1-Cg1, prelimbic cortex-PrL, infralimbic cortex-IL), the subregions of the nucleus accumbens (NAc; both core and shell), and the basolateral amygdala (BLA) following conditioned taste aversion (CTA) and conditioned place preference (CPP). All rats were given a 0.1% saccharin solution for 15-min, and they were intraperitoneally injected with saline or 20, 30, or 40 mg/kg morphine to form the aversive CTA learning. Later, half of the rats were tested for CPP (including the CTA and then CPP tests) for 30-min. Finally, the immunohistochemical staining with c-Fos was conducted after the behavioral test. After the CTA test, c-Fos (%) in the Cg1 and PrL (but not the IL) was more in 20–40 mg/kg of the morphine groups; c-Fos (%) in the NAc core, NAc shell, and BLA was more in the 30–40 mg/kg morphine group. After the CPP test, the Cg1, PrL, IL, and BLA showed more c-Fos (%) in 20 mg/kg morphine; the NAc core showed fewer in c-Fos (%) in the 30–40 mg/kg morphine groups. The mPFC subregions (e.g., Cg1, PrL, and IL), NAc subareas (e.g., NAc core and NAc shell), and BLA were involved in the different doses of morphine injections. The correlation analysis showed that a positive correlation was observed between PrL and IL with NAc core with low doses of morphine and with NAc shell with increasing doses of morphine after the CTA test. After the CPP, an association between PrL and NAc core and NAc shell at low doses and between IL and BLA and NAc shell with increasing doses of morphine. Therefore, different neural substrates and the neural connectivity are observed following different doses of morphine and after the CTA and CPP tests. The present data extend the paradoxical effect hypothesis of abused drugs.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neuronal activity of the medial prefrontal cortex, nucleus accumbens, and basolateral amygdala in conditioned taste aversion and conditioned place preference induced by different doses of morphine administrations in rats

et al. 2023

Front. Pharmacol.

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Impact of the Aversive Effects of Drugs on Their Use and Abuse

Riley

Manke

Huang

2022

Behavioural Neurology

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Drug use and abuse are complex issues in that the basis of each may involve different determinants and consequences, and the transition from one to the other may be equally multifaceted. A recent model of the addiction cycle (as proposed by Koob and his colleagues) illustrates how drug-taking patterns transition from impulsive (acute use) to compulsive (chronic use) as a function of various neuroadaptations leading to the downregulation of DA systems, upregulation of stress systems, and the dysregulation of the prefrontal/orbitofrontal cortex. Although the nature of reinforcement in the initiation and mediation of these effects may differ (positive vs. negative), the role of reinforcement in drug intake (acute and chronic) is well characterized. However, drugs of abuse have other stimulus properties that may be important in their use and abuse. One such property is their aversive effects that limit drug intake instead of initiating and maintaining it. Evidence of such effects comes from both clinical and preclinical populations. In support of this position, the present review describes the aversive effects of drugs (assessed primarily in conditioned taste aversion learning), the fact that they occur concurrently with reward as assessed in combined taste aversion/place preference designs, the role of aversive effects in drug-taking (in balance with their rewarding effects), the dissociation of these affective properties in that they can be affected in different ways by the same manipulations, and the impact of various parametric, experiential, and subject factors on the aversive effects of drugs and the consequent impact of these factors on their use and abuse potential.

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Optogenetic stimulation in the medial prefrontal cortex modulates stimulus valence from rewarding and aversive to neutral states

Tsai

et al. 2023

Front. Psychiatry

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IntroductionUnderstanding the modulations of the medial prefrontal cortex (mPFC) in the valence of the stimulus from rewarding and aversive status to neutral status is crucial for the development of novel treatments for drug addiction. This study addressed this issue and examined whether optogenetic ChR2 photostimulation in the cingulate, prelimbic, and infralimbic cortices of the mPFC regulated the valence of saccharin solution consumption from the rewarding property, the aversive property induced by morphine’s conditioning, and the neutral states via saccharin extinction processes after morphine’s conditioning.MethodsAll rats received virus infection, buried optical fiber, optical stimulation, water deprivation, and saccharin solution consumption phases. In Experiment 1, rats were given ChR2 virus infection into the cingulate cortex (Cg1), prelimbic cortex (PrL), and infralimbic cortex (IL) to influence the rewarding saccharin solution consumption under photostimulation. In Experiment 2, rats were given ChR2 or EYFP virus infection into the Cg1, PrL, and IL to alter the saccharin solution consumption in the morphine-induced aversively conditioned taste aversion (CTA) and the saccharin solution consumption in the neutral state following the extinction process under photostimulation. Later, the immunohistochemical staining with c-Fos protein was performed for the Cg1, IL, PrL, nucleus accumbens core, nucleus accumbens shell, central amygdala, basolateral amygdala, ventral tegmental area, and dentate gyrus.ResultsThe results showed that optogenetic PrL stimulation decreased the rewarding valence of saccharin solution consumption and increased the morphine-induced, aversive valence of saccharin solution consumption. PrL stimulation decreased the neutral valence of saccharin solution consumption via the extinction process. Cg1 optogenetic stimulation increased the rewarding valence of saccharin solution consumption and the aversive valence of saccharin solution consumption induced by morphine in conditioning. Optogenetic IL stimulation increased the aversive valence of saccharin solution consumption induced by morphine via conditioning.ConclusionAltogether, optogenetic stimulation in the subareas of the mPFC modulated the reward, aversion, and neutral valences of the stimulus and altered neuronal activity in the mPFC, amygdala, nucleus accumbens, and hippocampus. Notably, the change of valence was temporary alternation during light-on related to the light-off periods. However, the findings may provide insights in the development of novel treatments for addictive symptoms.

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Involvement of the ventral tegmental area but not periaqueductal gray matter in the paradoxical rewarding and aversive effects of morphine.

Cited by 3 publications

References 31 publications

Neuronal activity of the medial prefrontal cortex, nucleus accumbens, and basolateral amygdala in conditioned taste aversion and conditioned place preference induced by different doses of morphine administrations in rats

Neuronal activity of the medial prefrontal cortex, nucleus accumbens, and basolateral amygdala in conditioned taste aversion and conditioned place preference induced by different doses of morphine administrations in rats

Impact of the Aversive Effects of Drugs on Their Use and Abuse

Optogenetic stimulation in the medial prefrontal cortex modulates stimulus valence from rewarding and aversive to neutral states

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