Perez Stephanie M, McCoy Alexandra M, Prevot Thomas D, Mian Md Yeunus, Carreno Flavia R, Frazer Alan, Cook James M, Sibille Etienne, Lodge Daniel J
Department of Pharmacology and Center for Biomedical Neuroscience, UT Health San Antonio, San Antonio, Texas.
Audie L. Murphy Memorial Veterans Hospital, South Texas Veterans Health Care System, San Antonio, Texas.
Biol Psychiatry Glob Open Sci. 2022 Jan 14;3(1):78-86. doi: 10.1016/j.bpsgos.2021.12.010. eCollection 2023 Jan.
Aberrant dopamine neuron activity is attributable to hyperactivity in hippocampal subfields driving a pathological increase in dopamine neuron activity, which is positively correlated with psychosis in humans. Evidence indicates that hippocampal hyperactivity is due to loss of intrinsic GABAergic (gamma-aminobutyric acidergic) inhibition. We have previously demonstrated that hippocampal GABAergic neurotransmission can be modulated by targeting α5-GABA receptors, which are preferentially expressed in hippocampal regions. Positive and negative allosteric modulators of α5-GABA receptors (α5-PAMs and α5-NAMs) elicit effects on hippocampal-dependent behaviors. We posited that the selective manipulation of hippocampal inhibition, using α5-PAMs or α5-NAMs, would modulate dopamine activity in control rats. Further, α5-PAMs would reverse aberrant dopamine neuron activity in a rodent model with schizophrenia-related pathophysiologies (methylazoxymethanol acetate [MAM] model).
We performed in vivo extracellular recordings of ventral tegmental area dopamine neurons in anesthetized rats to compare the effects of two novel, selective α5-PAMs (GL-II-73, MP-III-022), a nonselective α-PAM (midazolam), and two selective α5-NAMs (L-655,708, TB 21007) in control and MAM-treated male Sprague Dawley rats ( = 5-9).
Systemic or intracranial administration of selective α5-GABA receptor modulators regulated dopamine activity. Specifically, both α5-NAMs increased dopamine neuron activity in control rats, whereas GL-II-73, MP-III-022, and L-655,708 attenuated aberrant dopamine neuron activity in MAM-treated rats, an effect mediated by the ventral hippocampus.
This study demonstrated that α5-GABA receptor modulation can regulate dopamine neuron activity under control or abnormal activity, providing additional evidence that α5-PAMs and α5-NAMs may have therapeutic applications in psychosis and other psychiatric diseases where aberrant hippocampal activity is present.
多巴胺神经元活动异常归因于海马亚区的活动亢进，这种活动亢进驱动多巴胺神经元活动病理性增加，而多巴胺神经元活动增加与人类精神病呈正相关。有证据表明，海马活动亢进是由于内在γ-氨基丁酸（GABA）能抑制作用丧失所致。我们之前已经证明，通过靶向α5-GABA受体可以调节海马GABA能神经传递，α5-GABA受体在海马区域优先表达。α5-GABA受体的正性和负性变构调节剂（α5-PAMs和α5-NAMs）对海马依赖性行为有影响。我们推测，使用α5-PAMs或α5-NAMs选择性操纵海马抑制作用，将调节对照大鼠的多巴胺活性。此外，α5-PAMs将逆转具有精神分裂症相关病理生理学的啮齿动物模型（乙酸甲基氧化偶氮甲醇[MAM]模型）中异常的多巴胺神经元活动。
我们对麻醉大鼠的腹侧被盖区多巴胺神经元进行了体内细胞外记录，以比较两种新型选择性α5-PAMs（GL-II-73、MP-III-022）、一种非选择性α-PAM（咪达唑仑）和两种选择性α5-NAMs（L-655,708、TB 21007）对对照和MAM处理的雄性Sprague Dawley大鼠（n = 5 - 9）的影响。
选择性α5-GABA受体调节剂的全身或颅内给药调节了多巴胺活性。具体而言，两种α5-NAMs均增加了对照大鼠的多巴胺神经元活性，而GL-II-73、MP-III-022和L-655,708减弱了MAM处理大鼠中异常的多巴胺神经元活性，这一效应由腹侧海马介导。
本研究表明，α5-GABA受体调节可在对照或异常活动状态下调节多巴胺神经元活性，为α5-PAMs和α5-NAMs可能在存在海马活动异常的精神病和其他精神疾病中具有治疗应用提供了额外证据。
