Mato Susana, Lafourcade Mathieu, Robbe David, Bakiri Yamina, Manzoni Olivier J
INSERM U862 Equipe Physiopathologie de la Plasticité Synaptique, 146 Rue Léo-Saignat, 33077 Bordeaux Cedex, France.
Neuropharmacology. 2008 Jan;54(1):87-94. doi: 10.1016/j.neuropharm.2007.04.014. Epub 2007 May 5.
Glutamate transmission between prefrontal cortex (PFC) and accumbens (NAc) plays a crucial role in the establishment and expression of addictive behaviors. At these synapses exogenous cannabinoid receptor 1 (CB1R) agonists reversibly inhibit excitatory transmission, and the sustained release of endogenous cannabinoids (eCB) following prolonged cortical stimulation leads to long-term depression (LTD). Activation of presynaptic K(+) channels mediates the effects of exocannabinoids, but the transduction pathway underlying the protracted phase of eCB-LTD is unknown. Here we report that the maintenance of eCB-LTD does not involve presynaptic K(+) channels: eCB-LTD was not affected by blockade of K(+) channels with 4-AP (100 microM) and BaCl(2) (300 microM) (fEPSP=78.9+/-5.4% of baseline 58-60 min after tetanus, compared to 78.9+/-5.9% in control slices). In contrast, eCB-LTD was blocked by treatment of the slices with the adenylyl cyclase (AC) activator forskolin (10 microM), and with the protein kinase A (PKA) inhibitor KT5720 (1 microM) (fEPSP=108.9+/-5.7% in forskolin and 110.5+/-7.7% in KT5720, compared to 80.6+/-3.9% in control conditions). Additionally, selective blockade of P/Q-type Ca(2+) channels with omega-agatoxin-IVA (200 nM) occluded the expression of eCB-LTD (fEPSP=113.4+/-15.9% compared to 78.6+/-4.4% in control slices), while blockade of N- with omega-conotoxin-GVIA (1 microM) or L-type Ca(2+) channels with nimodipine (1 microM), was without effect (fEPSP was 83.7+/-5.3% and 87+/-8.9% respectively). These data show that protracted inhibition of AC/PKA activity and P/Q-type Ca(2+) channels are necessary for expression of eCB-LTD at NAc synapses.
前额叶皮层（PFC）与伏隔核（NAc）之间的谷氨酸传递在成瘾行为的建立和表达中起着关键作用。在这些突触处，外源性大麻素受体1（CB1R）激动剂可逆地抑制兴奋性传递，长时间皮层刺激后内源性大麻素（eCB）的持续释放会导致长时程抑制（LTD）。突触前钾离子通道的激活介导了外源性大麻素的作用，但eCB-LTD延长阶段的转导途径尚不清楚。在此我们报告，eCB-LTD的维持不涉及突触前钾离子通道：用4-氨基吡啶（4-AP，100微摩尔）和氯化钡（BaCl₂，300微摩尔）阻断钾离子通道对eCB-LTD没有影响（强直刺激后58 - 60分钟时，场兴奋性突触后电位（fEPSP）为基线的78.9±5.4%，对照切片为78.9±5.9%）。相反，用腺苷酸环化酶（AC）激活剂福斯高林（10微摩尔）和蛋白激酶A（PKA）抑制剂KT5720（1微摩尔）处理切片可阻断eCB-LTD（福斯高林处理时fEPSP为108.9±5.7%，KT5720处理时为110.5±7.7%，对照条件下为80.6±3.9%）。此外，用ω-芋螺毒素-IVA（200纳摩尔）选择性阻断P/Q型钙离子通道可阻断eCB-LTD的表达（fEPSP为113.4±15.9%，对照切片为78.6±4.4%），而用ω-芋螺毒素-GVIA（1微摩尔）阻断N型或用尼莫地平（1微摩尔）阻断L型钙离子通道则没有作用（fEPSP分别为83.7±5.3%和87±8.9%）。这些数据表明，对AC/PKA活性和P/Q型钙离子通道的持续抑制是NAc突触处eCB-LTD表达所必需的。
