Gene transfer of GLT-1, a glutamate transporter, into the nucleus accumbens shell attenuates methamphetamine- and morphine-induced conditioned place preference in rats

Background: Identifying neural substrates that are differentially affected by drugs of abuse and natural rewards is key to finding a target for an efficacious treatment for substance abuse. Melanin-concentrating hormone is a polypeptide with an inhibitory effect on the mesolimbic dopamine system. Here we test the hypothesis that melanin-concentrating hormone in the lateral hypothalamus and nucleus accumbens shell is differentially involved in the regulation of morphine and food-rewarded behaviors. Methods: Male Sprague–Dawley rats were trained with morphine (5.0 mg/kg, subcutaneously) or food pellets (standard chow, 10–14 g) to induce a conditioned place preference, immediately followed by extinction training. Melanin-concentrating hormone (1.0 µg/side) or saline was infused into the nucleus accumbens shell or lateral hypothalamus before the reinstatement primed by morphine or food, and locomotor activity was simultaneously monitored. As the comparison, melanin-concentrating hormone was also microinjected into the nucleus accumbens shell or lateral hypothalamus before the expression of food or morphine-induced conditioned place preference. Results: Microinfusion of melanin-concentrating hormone into the nucleus accumbens shell (but not into the lateral hypothalamus) prevented the reinstatement of morphine conditioned place preference but had no effect on the reinstatement of food conditioned place preference. In contrast, microinfusion of melanin-concentrating hormone into the lateral hypothalamus (but not in the nucleus accumbens shell) inhibited the reinstatement of food conditioned place preference but had no effect on the reinstatement of morphine conditioned place preference. Conclusions: These results suggest a clear double dissociation of melanin-concentrating hormone in morphine/food rewarding behaviors and melanin-concentrating hormone in the nucleus accumbens shell. Melanin-concentrating hormone could be a potential target for therapeutic intervention for morphine abuse without affecting natural rewards.

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The effect of microinjection of CART 55-102 into the nucleus accumbens shell on morphine-induced conditioned place preference in rats: Involvement of the NMDA receptor

10.21203/rs.2.20474/v1 ◽

2020 ◽

Author(s):

Atefeh Bakhtazad ◽

Nasim Vousooghi ◽

Mohammad Nasehi ◽

Nima Sanadgol ◽

Behzad Garmabi ◽

...

Keyword(s):

Nucleus Accumbens ◽

Nmda Receptor ◽

Conditioned Place Preference ◽

Place Preference ◽

Place Conditioning ◽

Nucleus Accumbens Shell ◽

Nmda Glutamate Receptor ◽

Reward Pathway ◽

Dose Dependent Increase ◽

Dose Dependent

Abstract Background The addictive properties of opioids may be mediated to some extent by cocaine- and amphetamine-regulated transcript (CART) in the reward pathway. There are also some claims regarding the interaction of CART and glutamate system. Drug-paired learning and memory may induce conditioned place preference (CPP) or conditioned place aversion (CPA). Here, we have evaluated whether intra-nucleus accumbens (NAc) shell infusions of CART induces CPP or CPA and affect morphine reward. In addition, we have measured the expression of the NR1 subunit of the N-methyl-D-aspartate (NMDA) glutamate receptor in various parts of the reward pathway (NAc, prefrontal cortex (PFC), and hippocampus) after conditioning tests. Bilateral cannulas were implanted in the rats NAc shell and then the animals were exposed to place conditioning. Animals were place-conditioned with several doses of subcutaneous (s.c.) morphine prior to the intra-NAc shell infusion of artificial cerebral spinal fluid (aCSF). Immunohistochemistry (IHC) data showed a dose-dependent increase in the expression of the NR1 subunit in all examined parts. Then, rats were conditioned with intra-NAc shell infusion of different doses of CART. CPP and CPA were induced with 2.5 and 5 μg/side, respectively.Results IHC showed an elevated level of NR1 with 2.5 μg/side and a decrease with 5 μg/side in all areas. Administration of a sub-rewarding dose of CART (1.25 μg/side) prior to the injection of a sub-rewarding dose of morphine (2.5 mg/kg) induced CPP and IHC analysis showed an increased amount of NR1 in all examined tissues. However, infusion of an aversive dose of CART (5 μg/side) prior to the injection of a rewarding dose of morphine (5 mg/kg) produced neither CPP nor CPA and IHC data showed a significant decrease in the amount of NR1 subunit in the NAc and hippocampus.Conclusions It seems that the rewarding or aversive effects of intra-NAc shell CART and its facilitating or inhibiting effects on morphine reward are dose-dependent. Furthermore, the NMDA receptor may be closely involved in the affective properties of opioids and CART in the reward pathway.

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