Opposing actions of chronic Δ⁹-tetrahydrocannabinol and cannabinoid antagonists on hippocampal long-term potentiation

Abstract

Memory deficits produced by marijuana arise partly via interaction of the psychoactive component, ⌬ 9 -tetrahydrocannabinol (⌬ 9 -THC), with cannabinoid receptors in the hippocampus. Although cannabinoids acutely reduce glutamate release and block hippocampal long-term potentiation (LTP), a potential substrate for learning and memory, the consequences of prolonged exposure to ⌬ 9 -THC for hippocampal function are poorly understood. Rats were injected with ⌬ 9 -THC (10 mg/kg, i.p., q.d.) for 1, 3, or 7 d, and electrophysiological recordings were performed in hippocampal slices 1d after the final injection. At this time, ⌬ 9 -THC was undetectable in hippocampus using liquid chromatography-mass spectrometry (LC-MS). Hippocampal LTP generated using high-frequency (HFS) or theta burst stimulation was not observed in brain slices from the 7-d ⌬ -THC also produced tolerance to the inhibition of synaptic GABA, but not glutamate release by the agonist WIN55,212-2. These data define consequences of repeated ⌬ 9 -THC exposure for synaptic plasticity in the hippocampus that may help explain memory impairments in humans following chronic marijuana use.

Cellular and intracellular mechanisms involved in the cognitive impairment of cannabinoids

“…A similar result was obtained after chronic THC in hippocampal perforant path LTP induced by theta-burst stimulation [59]. The blockade of LTP as the result of chronic exposure to THC persisted for 3 days after its last administration, and did not fully recover until 14 days of the last THC injection [58]. On the other hand, hippocampal slices of mice lacking CB1R showed an increase in LTP in Schaffer collateral-CA1 synapses [60], as well as in the dentate gyrus at perforant path-granule cell layer synapses [61].…”

A Cannabinoid CB1 Receptor Antagonist Ameliorates Impairment of Recognition Memory on Withdrawal from MDMA (Ecstasy)

“…The importance of the hippocampal LTP in learning and memory has also been shown that hippocampal LTP is facilitated after following exposure to a novel environment but not by exposure to a familiar environment . In addition, it has been shown that the cannabinoid system affects the hippocampal LTP by chronic D 9 -THC blocking hippocampal LTP via CB 1 receptors after withdrawal (Hoffman et al, 2007). It has been shown that cannabinoids inhibit neurotransmitter release via presynaptic cannabinoid CB 1 receptors (Schlicker and Kathmann, 2001).…”

Neurobiologia da Cannabis: do sistema endocanabinoide aos transtornos por uso de Cannabis

“…Por exemplo, a presença do SEC em áreas relacionadas com a memória e o seu papel na modulação dela é bastante relevante, facilitando a extinção e inibindo a consolidação de memórias aversivas 28,[30][31][32][33][34][35][36] . A interferência exercida sobre esse sistema pelo Δ 9 -THC, bloqueando a LTD e, assim, modificando o setpoint para extinção de memórias aversivas, pode alterar o impacto de memórias relacionadas com a recompensa 9,30,32,36,73,76 . Assim, as ações dos canabinoides exógenos não se limitam ao mero papel de reforçadores positivos por ativação do sistema dopaminérgico mesocorticolímbico, mas são de extrema relevância na fenomenologia da dependência ao induzirem setpoints mais permissivos em diversas vias neuronais (Figura 4 -THC mimetiza as ações dos endocanabinoides, mas o faz difusamente (violando a especificidade espacial), inibindo a transmissão sináptica por meio da ativação indiscriminada dos receptores 24,27,39 .…”

“…Diversos casos de antagonismo pelo Δ 9 -THC foram descritos 24,27,[37][38][39]76,77 . Adicionalmente, a administração aguda ou crônica de Δ 9 -THC induz a tolerân-cia de receptores CB 1 e tolerância cruzada para ROM no NAc, induzindo bloqueio de LTD/LTP 29,37,38,42,76,78 . A administração crônica de Cannabis pode levar à tolerância e à tolerância inversa/sensibilização comportamental, contribuindo para a apetência e a motivação aumentadas pela substância 40,79 .…”