Hippocampal α5-GABA(A) Receptors Modulate Dopamine Neuron Activity in the Rat Ventral Tegmental Area.
Hippocampal α5-GABA(A) Receptors Modulate Dopamine Neuron Activity in the Rat Ventral Tegmental Area.
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DOI：
10.1016/j.bpsgos.2021.12.010
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发表时间：
2023-01
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异常的多巴胺神经元活性可归因于海马子场中的活动过度，从而驱动多巴胺神经元活性的病理性增加，这与人类的精神病正相关。有证据表明，海马活动过度是由于内在GABA能（γ-氨基丁酸能）抑制的丧失。我们先前已经证明，海马GABA能神经传递可以通过靶向α5-GABAA受体来调节，α 5-GABAA受体优先在海马区域表达。α5-GABAA受体（α5-PAM和α5-NAM）的正性和负性变构调节剂对海马依赖性行为产生影响。我们假设，使用α5-PAM或α5-NAMs选择性操纵海马抑制，将调节对照大鼠的多巴胺活性。此外，α5-PAM可逆转具有精神分裂症相关病理生理学的啮齿动物模型（甲基偶氮甲醇乙酸酯[MAM]模型）中的异常多巴胺神经元活性。我们对麻醉大鼠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-PAM（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-NAM（L-655，708、TB 21007）在对照和MAM处理的雄性Sprague道利大鼠（n = 5-9）中的作用。全身或颅内给予选择性α5-GABAA受体调节剂可调节多巴胺活性。具体而言，两种α5-NAM均增加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MAM处理大鼠的异常多巴胺神经元活性，这是一种由腹侧海马介导的效应。这项研究表明，α5-GABAA受体调节可以在控制或异常活动下调节多巴胺神经元的活动，提供了额外的证据，表明α5-PAM和α5-NAM可能在存在异常海马活动的精神病和其他精神疾病中具有治疗应用。
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-GABAA receptors, which are preferentially expressed in hippocampal regions. Positive and negative allosteric modulators of α5-GABAA 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 (n = 5–9). Systemic or intracranial administration of selective α5-GABAA 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-GABAA 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.
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