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

Abstract

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.

Methamphetamine and Modulation Functionality of the Prelimbic Cortex for Developing a Possible Treatment of Alzheimer’s Disease in an Animal Model

“…The study also clarified whether MAMPH administered to the PrL affected CTA, neural activity, or plasticity in the mPFC, NAc, amygdala, and hippocampus. Our study found that the short-term administration of MAMPH serves as a cognitive enhancer in a typical animal model of CTA (Yu et al, 2021); however, the model used in this study was not a typical animal model of AD. Repeating these tests in a suitable animal model of AD [e.g., a transgenic (Weishaupt et al, 2018) or a neurotoxic lesion-induced mouse model (Ando et al, 2002) of AD] and examining the effects on CTA under AD conditions remains necessary in future studies to determine whether these findings are applicable in the AD brain.…”

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

“…Under these conditions, amphetamine induced significant taste aversions and place preferences, again demonstrating both aversive and rewarding effects of the same drug and under identical parametric conditions. Subsequent to the initial work by Reicher and Holman, a variety of drugs have now been shown to support both effects in the combined CTA/CPP procedure including 3,4-methylenedioxypyrovalerone (MDPV) [ 144 ], α -pyrrolidinopentiophenone ( α -PVP) [ 104 , 145 , 146 ], nicotine [ 147 ], amphetamine [ 148 – 150 ], morphine [ 150 – 157 ], cocaine [ 158 – 160 ], alcohol [ 161 ], and caffeine [ 162 ]; for several drugs, e.g., ethanol [ 163 ] and ∆ 9 -tetrahydrocannabinol (THC) ([ 164 , 165 ], both taste and place aversions were reported with the combined design (for reviews, see [ 166 , 167 ]).…”

“…Further, adolescents were more sensitive to the rewarding effects of nicotine (and less sensitive to its aversive effects) relative to adults (for comparison, see [ 168 ] who reported these same relative sensitivities of CPP and CTA when separately assessed). Other comparisons across studies have shown that place preference conditioning is comparable when assessed in a combined CTA/CPP design or as an independent CPP and that manipulations in either design impact place preference conditioning similarly (see [ 152 , 157 ] for assessments of the combined CTA/CPP assay with morphine compared to [ 169 , 170 ] for assessments of morphine using only CPP; for a similar comparison with MDPV, see [ 171 ] compared to [ 172 ]; for α -PVP, see [ 104 ] compared to [ 173 , 174 ]; and for caffeine, see [ 162 ] compared to [ 175 ]).…”

“…Such a position is supported by other assessments of drug-induced taste aversions and place preferences that have found similar dissociations between the two effects in a number of studies evaluating the impact of a variety of manipulations on their acquisition and display, e.g., age [147, 168, 181], sex [ 145 ], strain [ 181 – 183 ], drug history [ 146 , 152 , 182 , 184 ], drug interactions [ 116 ], genetic knockouts/knockins [ 185 , 186 ], lesions [ 133 , 187 ], state dependency [ 188 ], role of DARRP-32 [ 189 ], effects of LPS [ 190 ], effects of 56 Fe particles [ 191 ], neuroanatomical and neurochemical mediation [ 157 , 192 , 193 ], and receptor subtype [ 186 , 194 ]. For these assessments, CTA and CPP were differentially affected, suggesting that the two were unrelated, i.e., if related one would expect that the two effects would be similarly impacted.…”

“…Although each of these mechanistic accounts has been offered as a basis for taste aversion learning and most papers refer to one of these interpretations in their analysis of CTAs, no individual perspective is generally accepted. Independent of which interpretation eventually garners consensus, all argue that the drug (whether a toxin, exogenous chemical agent, peptide, neurochemical, or drug of abuse) has some adverse effect that induces aversions (for an alternative interpretation that argues that the avoidance of drug-paired tastes is a function of a reward comparison in which the taste is devalued relative to the injected drug, i.e., anticipatory contrast, see [ 155 – 157 , 233 – 235 ]; see [ 20 ] for a review of the reward comparison hypothesis).…”