Morphine conditioned taste aversion revered by periaqueductal gray lesions

Blair, Richard; Amit, Zalman

doi:10.1016/0091-3057(81)90224-0

Cited by 15 publications

(7 citation statements)

References 14 publications

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“…In fact, lesion studies indicate that neither vlPAG nor dlPAG lesions impair the acquisition of a CTA (De Oca et al, 1998). On the contrary, Blair and Amit (1981) reported that PAG lesions reversed a CTA – but only if it was produced using morphine as the US. Therefore, the extent to which CTAs may be mediated by PAG neurons remains ambiguous.…”

Section: Discussionmentioning

confidence: 99%

Periaqueductal gray c-Fos expression varies relative to the method of conditioned taste aversion extinction employed

et al. 2011

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A conditioned taste aversion (CTA) is acquired when an animal consumes a novel taste (CS) and then experiences the symptoms of poisoning (US). Following CTA training, animals will avoid the taste that was previously associated with malaise. This defensive reaction to a learned fear can be extinguished by repeated exposure to the CS alone (CS-only; CSO-EXT). However, following a latency period in which the CS is not presented, the CTA will spontaneously recover (SR). Through the use of an explicitly unpaired extinction procedure (EU-EXT) we have shown that we can speed up extinction and attenuate SR of the CTA. Here we compared and contrasted the ability of CSO and EU extinction procedures to affect c-Fos expression in the periaqueductal gray (PAG). Fluid-deprived Sprague-Dawley rats acquired a strong CTA [via 3 pairings of 0.3% oral saccharin (SAC; the CS) and 81 mg/kg i.p. lithium chloride (LiCl; the US)] followed by extinction trials consisting of multiple exposures to either, (a) the CS every-other day (CSO-EXT), or (b) CS and US on alternate days (EU-EXT). A different group of rats did not receive multiple CS exposures and served as a “no extinction” (NE) control. Both extinction procedures resulted in ≥90% reacceptance of SAC (achieving asymptotic extinction). Some of the animals were sacrificed for c-Fos immunohistochemical analysis following asymptotic extinction. Other rats entered a 30-day latency period where they drank water only. These remaining animals were then tested for SR with a final exposure to SAC before being sacrificed for c-Fos immunohistochemistry. As reported previously, rats in the CS-only group exhibited a significant SR of the CTA. However, animals in the EU extinction group reached asymptotic extinction more rapidly than did CSO rats and they did not show SR of the CTA. As compared to rats that retained their CTA, both groups of extinguished rats showed suppression in the number of c-Fos-labeled neurons in all 4 longitudinal columns of the PAG. The number of c-Fos-labeled cells in the PAG was generally low but there was a reliable increase in c-Fos expression in dorsolateral PAG (dlPAG) following the SR test in the brains of rats that went through the EU-EXT procedure as compared with those that either went through the more-traditional CSO extinction procedure or experienced no extinction at all. The number of c-Fos-labeled neurons in the dlPAG was significantly correlated with the amount of SAC consumed at the SR test. Surprisingly, the brains of EU-extinguished rats and CSO extinguished rats did not differ in the number of c-Fos-labeled neurons in gustatory neocortex, medial prefrontal cortex, basolateral amygdala, or the central nucleus of the amygdala. Thus, behavioral differences in SR between the EU and CSO extinction animals were not represented by corresponding changes in the neural activity of several brain nuclei classically associated with extinction learning. However a detailed analysis of PAG c-Fos expression provided hints about some of the physiological changes evoked ...

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Section: Discussionmentioning

confidence: 99%

Periaqueductal gray c-Fos expression varies relative to the method of conditioned taste aversion extinction employed

et al. 2011

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Section: Discussionmentioning

confidence: 99%

“…Previous studies have demonstrated that the periaqueductal gray matter (PAG) was also involved in conditioned aversive learning [ 60 , 61 ] and aversive behaviors induced by morphine or opiate drugs. For example, the PAG lesion interfered with morphine-induced CTA [ 60 ]. Microinjections of the mu-opioid receptor agonist morphine or the kappa-opioid receptor agonist U-50488H in the dorsal PAG caused the CPA effect, indicating the mu- or kappa-opioid receptors mediated the CPA learning [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

The Paradoxical Effect Hypothesis of Abused Drugs in a Rat Model of Chronic Morphine Administration

Liou

et al. 2021

JCM

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A growing body of studies has recently shown that abused drugs could simultaneously induce the paradoxical effect in reward and aversion to influence drug addiction. However, whether morphine induces reward and aversion, and which neural substrates are involved in morphine’s reward and aversion remains unclear. The present study first examined which doses of morphine can simultaneously produce reward in conditioned place preference (CPP) and aversion in conditioned taste aversion (CTA) in rats. Furthermore, the aversive dose of morphine was determined. Moreover, using the aversive dose of 10 mg/kg morphine tested plasma corticosterone (CORT) levels and examined which neural substrates were involved in the aversive morphine-induced CTA on conditioning, extinction, and reinstatement. Further, we analyzed c-Fos and p-ERK expression to demonstrate the paradoxical effect—reward and aversion and nonhomeostasis or disturbance by morphine-induced CTA. The results showed that a dose of more than 20 mg/kg morphine simultaneously induced reward in CPP and aversion in CTA. A dose of 10 mg/kg morphine only induced the aversive CTA, and it produced higher plasma CORT levels in conditioning and reacquisition but not extinction. High plasma CORT secretions by 10 mg/kg morphine-induced CTA most likely resulted from stress-related aversion but were not a rewarding property of morphine. For assessments of c-Fos and p-ERK expression, the cingulate cortex 1 (Cg1), prelimbic cortex (PrL), infralimbic cortex (IL), basolateral amygdala (BLA), nucleus accumbens (NAc), and dentate gyrus (DG) were involved in the morphine-induced CTA, and resulted from the aversive effect of morphine on conditioning and reinstatement. The c-Fos data showed fewer neural substrates (e.g., PrL, IL, and LH) on extinction to be hyperactive. In the context of previous drug addiction data, the evidence suggests that morphine injections may induce hyperactivity in many neural substrates, which mediate reward and/or aversion due to disturbance and nonhomeostasis in the brain. The results support the paradoxical effect hypothesis of abused drugs. Insight from the findings could be used in the clinical treatment of drug addiction.

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“…The PAG has also been reported to be involved in the aversive conditioning associated with drug addiction (Blair & Amit, 1981; Motta & Brandao, 1993; Sante et al, 2000). Injections of the μ-opioid agonist morphine into the dorsal PAG in a rat model were shown to cause anxiolytic effects, and the μ-opioid antagonist naloxone blocked this effect, indicating that the dorsal PAG μ-opioid receptors mediate anxiety (Motta & Brandao, 1993).…”

Section: Methodsmentioning

confidence: 99%

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

Wu¹,

Ou²,

Yu³

et al. 2021

Behavioral Neuroscience

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The paradoxical effects of reward and aversion with abused drugs may interact to produce drug addiction, which is the so-called paradoxical effect hypothesis of abused drugs. However, there is no research examining how the ventral tegmental area (VTA) or periaqueductal gray matter (PAG) regulates morphine's paradoxical effect of reward and aversion. The present study addresses this issue, utilizing a high concentration of N-methyl-D-aspartic acid (NMDA) via injections to destroy the VTA or the PAG. Moreover, the study employed the new "preand postassociation" experimental paradigm (2010) to test whether the simultaneous rewarding and aversive effects of morphine can be affected by an NMDA lesion in the VTA or the PAG. The results indicated that the NMDA lesion of the VTA simultaneously reduced morphine-induced conditioned suppression of saccharin solution intake in conditioned taste aversion (CTA) and morphine-induced spent time in the preference compartment in conditioned place preference (CPP), whereas the PAG lesion did not change either measure. Thus, the VTA, but not the PAG, appears to contribute to the paradoxical effect reward in CPP and aversion in CTA induced by morphine. The VTA's involvement in morphine-induced CTA aversion and CPP reward supports the paradoxical effect hypothesis of abused drugs.Keywords: morphine, ventral tegmental area, periaqueductal gray matter, the paradoxical effect hypothesis of abused drugs served in a supporting role for project administration and performed equal contribution in data curation and formal analysis. Yi Chun Yu served in a supporting role for project administration and performed equal contribution in data curation. Bai Chuang Shyu served in a supporting role for formal analysis and funding acquisition; performed equal contribution in resources. Andrew Chih Wei Huang served as lead for conceptualization, data curation, formal analysis, funding acquisition, investigation, methodology, resources, supervision, validation, writing of the original draft, and writing of the review & editing.

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Morphine conditioned taste aversion revered by periaqueductal gray lesions

Cited by 15 publications

References 14 publications

Periaqueductal gray c-Fos expression varies relative to the method of conditioned taste aversion extinction employed

Periaqueductal gray c-Fos expression varies relative to the method of conditioned taste aversion extinction employed

The Paradoxical Effect Hypothesis of Abused Drugs in a Rat Model of Chronic Morphine Administration

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

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