Cannabis-induced impairment of learning and memory: effect of different nootropic drugs

Abstract

Cannabis sativa preparations are the most commonly used illicit drugs worldwide. The present study aimed to investigate the effect of Cannabis sativa extract in the working memory version of the Morris water maze (MWM; Morris, 1984[43]) test and determine the effect of standard memory enhancing drugs. Cannabis sativa was given at doses of 5, 10 or 20 mg/kg (expressed as Δ(9)-tetrahydrocannabinol) alone or co-administered with donepezil (1 mg/kg), piracetam (150 mg/ kg), vinpocetine (1.5 mg/kg) or ginkgo biloba (25 mg/kg) once daily subcutaneously (s.c.) for one month. Mice were examined three times weekly for their ability to locate a submerged platform. Mice were euthanized 30 days after starting cannabis injection when biochemical assays were carried out. Malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide, glucose and brain monoamines were determined. Cannabis resulted in a significant increase in the time taken to locate the platform and enhanced the memory impairment produced by scopolamine. This effect of cannabis decreased by memory enhancing drugs with piracetam resulting in the most-shorter latency compared with the cannabis. Biochemically, cannabis altered the oxidative status of the brain with decreased MDA, increased GSH, but decreased nitric oxide and glucose. In cannabis-treated rats, the level of GSH in brain was increased after vinpocetine and donepezil and was markedly elevated after Ginkgo biloba. Piracetam restored the decrease in glucose and nitric oxide by cannabis. Cannabis caused dose-dependent increases of brain serotonin, noradrenaline and dopamine. After cannabis treatment, noradrenaline is restored to its normal value by donepezil, vinpocetine or Ginkgo biloba, but increased by piracetam. The level of dopamine was significantly reduced by piracetam, vinpocetine or Ginkgo biloba. These data indicate that cannabis administration is associated with impaired memory performance which is likely to involve decreased brain glucose availability as well as alterations in brain monoamine neurotransmitter levels. Piracetam is more effective in ameliorating the cognitive impairments than other nootropics by alleviating the alterations in glucose, nitric oxide and dopamine in brain.

Keywords: Cannabis sativa extract; brain monoamines; mice; nootropics, water maze; oxidative stress.

Table 1. Effect of cannabis extract, scopolamine or cannabis + scopolamine on brain monoamines

Table 2. Effect of cannabis extract given with donepezil, piracetam, vinpocetine or Ginkgo biloba on liver alanine aminotransferase (ALT) and aspartate aminotransferase (AST)

Figure 1. Effect of cannabis extract on the latency to find hidden platform in the MWM test. Cannabis was administered daily via subcutaneous route for one month and observations were done three times weekly. Asterisks indicate significant change from the saline control group.

Figure 2. Effect of cannabis extract combined with donepezil, piracetam, vinpocetine or Ginkgo biloba on the latency to find hidden platform in the MWM test. Cannabis and test drugs were administered daily via subcutaneous route for one month and observations were done three times weekly. Asterisks indicate significant change from the cannabis only treated group.

Figure 3. The average mean latency to locate a submerged platform in the MWM test over four weeks. Mice received daily injections of saline or cannabis extract (5, 10 or 20 mg/kg) alone or combined with donepezil, piracetam, vinpocetine or Ginkgo biloba and were tested three times weekly. Asterisks indicate significant change from the saline control group and between different groups as shown in the figure. The plus sign indicates significant change from the cannabis 20 mg/kg group. The # sign indicates significant change from the cannabis 10 mg/kg group. Other statistical comparisons between different treated groups are also shown and are indicated by asterisks.

Figure 4. The average mean latency of first (A); second (B) and third (C) trial to locate a submerged platform in the MWM test over four weeks. Mice received daily injections of saline, scopolamine (1 mg/kg, s.c.) or scopolamine plus cannabis (5, 10 or 20 mg/kg) and were tested three times weekly. Asterisks indicate significant change from the saline control group. The plus sign indicates significant change from the scopolamine only or scopolamine + cannabis 5 mg/kg group.

Figure 5. The average mean latency (in seconds) ± SEM of first (A); second (B) and third (C) trial to locate a submerged platform in the MWM test over four weeks. Mice received daily injections of saline or cannabis extract (5, 10 or 20 mg/kg) alone or combined with donepezil, piracetam, vinpocetine or Ginkgo biloba and were tested three times weekly. Asterisks indicate significant change from the saline control group. The plus sign indicates significant change from the cannabis 20 mg/ kg group. The # sign indicates significant change from the cannabis 10 mg/ kg group.

Figure 6. Effect of cannabis extract on the latency to find hidden platform in the MWM test in mice treated with scopolamine (1 mg/kg, s.c.). The columns represent the first, second and third trail, respectively for each treatment group. Asterisks indicate significant change from trial 1.

Figure 7. The average mean latency to locate a submerged platform in the MWM test over four weeks. Mice received daily injections of scopolamine (1 mg/kg, s.c.) or cannabis extract (5, 10 or 20 mg/kg) and were tested three times weekly. Asterisks indicate significant change from the saline control group. The plus sign indicates significant change from the scopolamine + cannabis 20 mg/kg group.

Figure 8. Effect of cannabis extract alone or in combination with piracetam, vinpocetine, Ginkgo biloba, donepezil or scopolamine on brain malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide and glucose in mice. *: p< 0.05 vs corresponding saline control value. +: p< 0.05 vs. cannabis (20 mg/kg) only-treated group. #: p< 0.05 vs scopolamine only-treated group

Figure 9. Effects of cannabis extract alone, cannabis + memory enhancing drugs or cannabis + scopolamine on liver malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide in mice. *: p< 0.05 vs corresponding vehicle control value. +: p< 0.05 vs. cannabis (20 mg/kg) only-treated group