Short- and Long-Term Cognitive Effects of Chronic Cannabinoids Administration in Late-Adolescence Rats

The use of cannabis can impair cognitive function, especially short-term memory. A controversial question is whether longterm cannabis use during the late-adolescence period can cause irreversible deficits in higher brain function that persist after drug use stops. In order to examine the short- and long-term effects of chronic exposure to cannabinoids, rats were administered chronic i.p. treatment with the CB1/CB2 receptor agonist WIN55,212-2 (WIN; 1.2 mg/kg) for two weeks during the late adolescence period (post-natal days 45–60) and tested for behavioral and electrophysiological measures of cognitive performance 24 hrs, 10 and 30 days after the last drug injection. The impairing effects of chronic WIN on shortterm memory in the water maze and the object recognition tasks as well as long-term potentiation (LTP) in the ventral subiculum (vSub)-nucleus accumbens (NAc) pathway were temporary as they lasted only 24 h or 10 d after withdrawal. However, chronic WIN significantly impaired hippocampal dependent short-term memory measured in the object location task 24 hrs, 10, 30, and 75 days after the last drug injection. Our findings suggest that some forms of hippocampaldependent short-term memory are sensitive to chronic cannabinoid administration but other cognitive impairments are temporary and probably result from a residue of cannabinoids in the brain or acute withdrawal effects from cannabinoids. Understanding the effects of cannabinoids on cognitive function may provide us with tools to overcome these impairments and for cannabinoids to be more favorably considered for clinical use

The effects of chronic exposure to WIN55,212-2 during late adolescence on sucrose consumption.

<p><b>4a.</b> Chronic administration of WIN had no effect on sucrose consumption when measured at baseline, 24 h, 10 d or 30 d after the last drug injection. <b>4b.</b> Chronic administration of WIN had no effect on weight gain compared to the vehicle group when measured at baseline, 24 h, 10 d, or 30 d after the last drug injection.</p

The effects of chronic exposure to WIN55,212-2 during late-adolescence on hippocampal and non-hippocampal dependent tasks.

<p><b>1a.</b> Rats tested in the water maze 24 h, but not 10 d, after the last WIN injection, show increased latency to locate the hidden platform compared with the vehicle group on the first training day (Acq1–7). (*, p<0.05: WIN 24 h different from Vehicle 24 h). <b>Inset:</b> a control experiment where rats were tested in the water maze 24 hours following a single WIN injection. <b>1b.</b> Rats tested in the object location task 24 h, 10 d, 30 d and 75 d after the last vehicle injection spent significantly more time exploring the new location compared with the WIN groups. (*, p<0.05; **, p<0.01: Vehicle different from WIN). <b><u>On the right square</u></b>: a control experiment where rats were tested in the object location task 24 hours following a single WIN injection. <b>1c.</b> Rats tested in the object recognition task 24 h or 10 d, but not 30 d, after the last vehicle injection spent significantly more time exploring the new location compared with the WIN groups (*, p<0.05; ***, p<0.001: Vehicle different from WIN). <b><u>On the right square</u></b>: a control experiment where rats were tested in the object recognition task 24 hours following a single WIN injection.</p

The effects of chronic exposure to WIN55,212-2 during late-adolescence on synaptic-plasticity in the hippocampus and nucleus-accumbens.

<p><b>2a.</b> Chronic administration of WIN had no effect on LTP levels in the PP-DG pathway measured 24 h, 10 d or 30 d after the last drug injection. <b>Inset: </b><b><u>Up</u>:</b> representative traces in the DG for the vehicle group taken before (black) and 5 min after (gray) HFS to the PP (calibration: 0.2 mV, 10 µs); <b><u>Down:</u></b> schematic drawing of electrodes tip positions: left - representative location of the stimulating electrode tip in the perforant path (anteroposterior, −8.0 mm; lateral, ±4.0 mm; ventral, −3.0 mm), right - representative location of the recording electrode tip in the dentate gyrus (anteroposterior, −4.0 mm; lateral, ±2.5 mm; ventral, −3.7 mm). <b>2b.</b> Chronic administration of WIN impaired LTP levels in the vSub-NAc pathway measured 24 h or 10 d, but not 30 d, after the last drug injection. (**, p<0.01: WIN 24 h group different from WIN 30 d and Vehicle groups, and WIN 10 d group different from WIN 30 d group; ***, p<0.001: WIN 10 d group different from Vehicle group). <b>Inset: </b><b><u>Up</u>:</b> representative traces in the NAc for the vehicle group taken before (black) and 5 min after (gray) HFS to the vSub (calibration: 0.2 mV, 10 µs); <b><u>Down:</u></b> schematic drawing of electrodes tip positions: left - representative location of the stimulating electrode tip in the ventral subiculum (anteroposterior, −6.5 mm; lateral, ±5.0 mm; ventral, −6.0 mm), right - representative location of the recording electrode tip in the nucleus accumbens (anteroposterior, +1.6 mm; lateral, ±1.0 mm; ventral, −5.5 mm); <b><u>On the right</u>:</b> a control experiment where acute administration of WIN impaired LTP levels in the vSub-NAc pathway measured 24 h after a single injection (**, p<0.01).</p

The effects of chronic exposure to WIN55,212-2 during late-adolescence on locomotion and anxiety in the open-field.

<p><b>3a.</b> Chronic administration of WIN caused an increase in the time the rats spent in the center when tested in the open field 24 h after the last drug injection. (*, p<0.05: Vehicle different from WIN). <b>3b.</b> Chronic administration of WIN had no effect on the number of rearings the rats performed in the open field when measured 24 h, 10 d or 30 d after the last drug injection. <b>3c.</b> Chronic administration of WIN had no effect on the distance the rats covered in the open field when measured 24 h, 10 d or 30 d after the last drug injection.</p

Summary of results.

<p>The table summarizes the effects of chronic i.p. treatment with the CB1/CB2 receptor agonist WIN55,212-2 (1.2 mg/kg) for two weeks during the late adolescence period (post-natal days 45–60) on behavioral and electrophysiological measures of cognitive performance tested 24 hrs, 10 and 30 days after the last drug injection.</p