RESUMEN
The widespread distribution of heteroreceptor complexes with allosteric receptor-receptor interactions in the CNS represents a novel integrative molecular mechanism in the plasma membrane of neurons and glial cells. It was proposed that they form the molecular basis for learning and short-and long-term memories. This is also true for drug memories formed during the development of substance use disorders like morphine and cocaine use disorders. In cocaine use disorder it was found that irreversible A2AR-D2R complexes with an allosteric brake on D2R recognition and signaling are formed in increased densities in the ventral enkephalin positive striatal-pallidal GABA antireward neurons. In this perspective article we discuss and propose how an increase in opioid heteroreceptor complexes, containing MOR-DOR, MOR-MOR and MOR-D2R, and their balance with each other and A2AR-D2R complexes in the striatal-pallidal enkephalin positive GABA antireward neurons, may represent markers for development of morphine use disorders. We suggest that increased formation of MOR-DOR complexes takes place in the striatal-pallidal enkephalin positive GABA antireward neurons after chronic morphine treatment in part through recruitment of MOR from the MOR-D2R complexes due to the possibility that MOR upon morphine treatment can develop a higher affinity for DOR. As a result, increased numbers of D2R monomers/homomers in these neurons become free to interact with the A2A receptors found in high densities within such neurons. Increased numbers of A2AR-D2R heteroreceptor complexes are formed and contribute to enhanced firing of these antireward neurons due to loss of inhibitory D2R protomer signaling which finally leads to the development of morphine use disorder. Development of cocaine use disorder may instead be reduced through enkephalin induced activation of the MOR-DOR complex inhibiting the activity of the enkephalin positive GABA antireward neurons. Altogether, we propose that these altered complexes could be pharmacological targets to modulate the reward and the development of substance use disorders.
RESUMEN
Objetivo: El incremento en el contenido de GABA cerebral o la administración de un agente GABA-mimético se emplea como un tratamiento antiepiléptico eficaz. Sin embargo, se sugiere que el empleo de farmacos que alteran continuamente la transmisión sinoptica puede afectar al sistema nervioso. En el presente estudio se evaluaron los efectos del pretratamiento agudo (una administración) y subcrónico (administraciones diarias por 7 días) de diazepam (DZP; 10 mg/kg, ip), gabapentina (GBP, 100 mg/kg, vo) y vigabatrina (VGB, 500 mg/kg, vo) en las crisis generalizadas inducidas por pentilenetetrazol (PTZ, 80 mg/kg ip). Materiales y métodos: Ratones macho de la cepa taconic (20-25 g) recibieron tratamiento agudo y subcrónico de DZP, GBP o VGB y 24 h después de la última administración se aplicó PTZ. Se evaluaron las latencias a la primera crisis clónica, a la fase tónica así como la incidencia de muerte. Resultados: El pretratamiento agudo con DZP protegió 100 por ciento a los animales de los efectos del PTZ, mientras que su administración subcrónica redujo la latencia a la crisis clónica (21 por ciento; p<0.05), la fase tónica (27 por ciento, p<0.05) y muerte (37 por ciento, p<0.05). La aplicación aguda de VGB protegió 100 por ciento a los animales de los efectos del PTZ, mientras que su aplicación subcrónica aumentó la latencia a las crisis clónicas (32 por ciento, p<0.05), aunque facilitó la aparición de la crisis tónica (55 por ciento, p<0.05) y la muerte (58 por ciento, p<0.05). La administración aguda de GBP elevó la latencia a la crisis clónica (52 por ciento, p<0.05), mientras que su administración subcrónica no modificó el efecto producido por PTZ. Conclusiones: Estos resultados sugieren que el pretratamiento agudo y subcrónico de farmacos que incrementan la transmisión GABAérgica modifican diferencialmente la susceptibilidad a las crisis por PTZ y que su administración repetida puede facilitar la producción de crisis convulsivas.
Objetives: The increased GABA content or administration of a centrally active GABA-mimetic agent have been used as a efficacious anticonvulsant therapeutic approach. However, it has been suggested that the use of drugs that continually and noncontingently alter synaptic transmission could alter at the nervous system. The present study was carried out to investigate the effects of acute (one administration) and subchronic (7 daily administrations) treatments with Diazepam (DZP; 10 mg/kg, ip), Gabapentin (GBP, 100 mg/kg. vo) and Vigabatrin (VGB, 500 mg/kg, vo) on pentylenetetrazol-induced generalized seizures (PTZ, 80 mg/kg, ip). Materials and methods: Male Taconic mice (20-25 g) received acute or subchronic treatment with DZP, VGB or GBP and 24 h after the last administration, the effects of PTZ (latency to the clonus, forelimb extension and death incidence) were evaluated. Results: Acute DZP protected all animals (100 percent) to the convulsant effects of PTZ, whereas subchronic DZP decreased the latency to the clonic (21 percent; p<0.05), tonic (27 percent, p<0.05) and death (37 percent, p<0.05). The acute treatment with VGB protect all animals (100 percent) to the effects of PTZ, whereas its subcronic administration enhanced the latency to clonus (32 percent, p<0.05), but facilitated the appearance of tonic seizures (55 percent, p<0.05) and death (58 percent, p<0.05). The acute administration of GPB increased the latency to clonus (52 percent, p<0.05), whereas its subchronic treatment did not modify the PTZ-induced effects. Conclusions: The present results indicate that the acute pretreatment with drugs enhancing GABAergic transmission differently modifies the seizure susceptibility, and that the subchronic administration may facilitate the seizure activity.