Stowe Z N, Nemeroff C B
Department of Psychiatry, Duke University Medical Center, Durham, North Carolina 27710.
Life Sci. 1991;49(14):987-1002. doi: 10.1016/0024-3205(91)90300-z.
The endogenous neuropeptide, neurotensin (NT) alters the firing frequencies of certain neurons in the central nervous system (CNS). This is one of the findings that support the hypothesis that NT is a neurotransmitter substance. The direct application of NT on CNS neurons causes predominantly excitatory effects. These effects occur in a dose-related fashion via a calcium-dependent postsynaptic mechanism. The C-terminal hexapeptide fragment, NT 8-13 exerts similar electrophysiological effects to NT, while the N-terminal octapeptide fragment, NT 1-8 is devoid of such activity. NT produces a significant increase in the firing rates of individual neurons in the substantia nigra (SN), ventral tegmental area (VTA), medial prefrontal cortex (MPF), hypothalamus, and periaqueductal grey (PAG). This excitation occurs with a rapid onset and is readily reversible after cessation of NT application. In contrast, NT has no effect or weak inhibitory effects on the firing rates of neurons in the locus coeruleus (LC) and cerebellum. These electrophysiological actions of NT appear to be unique and not shared by other neurotransmitter and neuropeptide receptor antagonists and agonists that have been studied via direct co-application. NT attenuates dopamine (DA)-induced inhibition associated with direct application onto neurons in the SN and VTA both in vivo and in vitro. Intracellular recordings suggest that direct application of higher concentrations of NT appears to produce 'depolarization block' on individual neurons in the SN, VTA, MPF, and hypothalamus. The electrophysiological consequences of NT application not only show similarities to clinically efficacious antipsychotic medications, but also demonstrate the ability of NT to modulate the activity of dopamine (DA) neurons at the cellular level via specific NT binding sites. These findings further underscore the possibility that NT may play a pre-eminent role in the pathogenesis of, and psychopharmacological management of neurological and psychiatric disorders purportedly related to perturbation of CNS DA systems including schizophrenia.
内源性神经肽神经降压素（NT）可改变中枢神经系统（CNS）中某些神经元的放电频率。这是支持NT是一种神经递质物质这一假说的研究发现之一。将NT直接应用于中枢神经系统神经元主要产生兴奋作用。这些作用通过钙依赖性突触后机制以剂量相关的方式发生。C末端六肽片段NT 8 - 13对NT具有类似的电生理作用，而N末端八肽片段NT 1 - 8则没有这种活性。NT可使黑质（SN）、腹侧被盖区（VTA）、内侧前额叶皮质（MPF）、下丘脑和导水管周围灰质（PAG）中单个神经元的放电率显著增加。这种兴奋起效迅速，在停止应用NT后很容易逆转。相比之下，NT对蓝斑（LC）和小脑中神经元的放电率没有影响或只有微弱的抑制作用。NT的这些电生理作用似乎是独特的，其他通过直接共同应用研究过的神经递质和神经肽受体拮抗剂及激动剂并未表现出相同作用。NT可减弱多巴胺（DA）诱导的抑制作用，无论是在体内还是体外，这种抑制作用与将DA直接应用于SN和VTA中的神经元有关。细胞内记录表明，直接应用较高浓度的NT似乎会对SN、VTA、MPF和下丘脑中的单个神经元产生“去极化阻滞”。应用NT的电生理结果不仅显示出与临床有效的抗精神病药物相似之处，还证明了NT能够通过特定的NT结合位点在细胞水平调节多巴胺（DA）神经元的活性。这些发现进一步强调了NT可能在据称与包括精神分裂症在内的中枢神经系统DA系统紊乱相关的神经和精神疾病的发病机制及精神药理学治疗中发挥重要作用的可能性。
