Rodríguez-Manzo Gabriela, González-Morales Estefanía, Garduño-Gutiérrez René
Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados (Cinvestav-Sede Sur), Ciudad de México, Mexico.
Front Synaptic Neurosci. 2021 Aug 18;13:701290. doi: 10.3389/fnsyn.2021.701290. eCollection 2021.
Endocannabinoids modulate mesolimbic (MSL) dopamine (DA) neurons firing at the ventral tegmental area (VTA). These neurons are activated by copulation, increasing DA release in nucleus accumbens (NAcc). Copulation to satiety in male rats implies repeated ejaculation within a short period (around 2.5 h), during which NAcc dopamine concentrations remain elevated, suggesting continuous neuronal activation. During the 72 h that follow copulation to satiety, males exhibit long-lasting changes suggestive of brain plasticity processes. Enhanced DA neuron activity triggers the synthesis and release of endocannabinoids (eCBs) in the VTA, which participate in several long-term synaptic plasticity processes. Blockade of cannabinoid type 1 receptors (CB1Rs) during copulation to satiety interferes with the appearance of the plastic changes. Glutamatergic inputs to the VTA express CB1Rs and contribute to DA neuron burst firing and synaptic plasticity. We hypothesized that eCBs, released during copulation to satiety, would activate VTA CB1Rs and modulate synaptic plasticity processes involving glutamatergic transmission. To test this hypothesis, we determined changes in VTA CB1R density, phosphorylation, and internalization in rats that copulated to satiety 24 h earlier as compared both to animals that ejaculated only once and to sexually experienced unmated males. Changes in glutamate AMPAR and NMDAR densities and subunit composition and in ERK1/2 activation were determined in the VTA of males that copulated to satiety in the presence or absence of AM251, a CB1R antagonist. The CB1R density decreased and the proportion of phosphorylated CB1Rs increased in the animals that copulated compared to control rats. The CB1R internalization was detected only in sexually satiated males. A decrease in α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor (AMPAR) density, blocked by AM251 pretreatment, and an increase in the proportion of GluA2-AMPARs occurred in sexually satiated rats. GluN2A- N-methyl-D-aspartate receptor (NMDAR) expression decreased, and GluN2B-NMDARs increased in these animals, both of which were prevented by AM251 pre-treatment. An increase in phosphorylated ERK1/2 emerged in males copulating to satiety in the presence of AM251. Results demonstrate that during copulation to satiety, eCBs activate CB1Rs in the VTA, producing changes in glutamate receptors compatible with a reduced neuronal activation. These changes could play a role in the induction of the long-lasting physiological changes that characterize sexually satiated rats.
内源性大麻素调节中脑边缘多巴胺（MSL）神经元在腹侧被盖区（VTA）的放电。这些神经元在交配时被激活，增加伏隔核（NAcc）中的多巴胺释放。雄性大鼠交配至饱足意味着在短时间内（约2.5小时）反复射精，在此期间伏隔核多巴胺浓度持续升高，表明神经元持续激活。在交配至饱足后的72小时内，雄性大鼠表现出暗示大脑可塑性过程的长期变化。增强的多巴胺能神经元活动触发内源性大麻素（eCBs）在腹侧被盖区的合成和释放，其参与多个长期突触可塑性过程。在交配至饱足期间阻断1型大麻素受体（CB1Rs）会干扰可塑性变化的出现。腹侧被盖区的谷氨酸能输入表达CB1Rs，并有助于多巴胺能神经元的爆发式放电和突触可塑性。我们假设，在交配至饱足期间释放的内源性大麻素会激活腹侧被盖区的CB1Rs，并调节涉及谷氨酸能传递 的突触可塑性过程。为了验证这一假设，我们确定了与仅射精一次的动物以及有性经验但未交配的雄性大鼠相比，24小时前交配至饱足的大鼠腹侧被盖区CB1R密度、磷酸化和内化的变化。在有或没有CB1R拮抗剂AM251的情况下，对交配至饱足的雄性大鼠腹侧被盖区中谷氨酸α-氨基-3-羟基-5-甲基异恶唑-4-丙酸受体（AMPAR）和N-甲基-D-天冬氨酸受体（NMDAR）密度、亚基组成以及细胞外信号调节激酶1/2（ERK1/2）激活的变化进行了测定。与对照大鼠相比，交配动物的CB1R密度降低，磷酸化CB1Rs的比例增加。仅在性饱足的雄性大鼠中检测到CB1R内化。在性饱足的大鼠中，AM251预处理可阻断α-氨基-3-羟基-5-甲基异恶唑-4-丙酸受体（AMPAR）密度的降低，并使GluA2-AMPARs的比例增加。在这些动物中，N-甲基-D-天冬氨酸受体2A（GluN2A-NMDAR）表达降低，而GluN2B-NMDARs增加，两者均被AM251预处理所阻止。在存在AM251的情况下，交配至饱足的雄性大鼠中磷酸化ERK1/2增加。结果表明，在交配至饱足期间，内源性大麻素激活腹侧被盖区的CB1Rs，产生与神经元激活减少相一致的谷氨酸受体变化。这些变化可能在诱导性饱足大鼠特有的长期生理变化中起作用。
