Tolerance to Ethanol or Nicotine Results in Increased Ethanol Self-Administration and Long-Term Depression in the Dorsolateral Striatum

Abstract

Ethanol (EtOH) and nicotine are the most widely coabused drugs. Tolerance to EtOH intoxication, including motor impairment, results in greater EtOH consumption and may result in a greater likelihood of addiction. Previous studies suggest that cross-tolerance between EtOH and nicotine may contribute to the abuse potential of these drugs. Here we demonstrate that repeated intermittent administration of either EtOH or nicotine in adult male Sprague Dawley rats results in tolerance to EtOH-induced motor impairment and increased EtOH self-administration. These findings suggest that nicotine and EtOH cross-tolerance results in decreased aversive and enhanced rewarding effects of EtOH. Endocannabinoid signaling in the dorsolateral striatum (DLS) has been implicated in both EtOH tolerance and reward, so we investigated whether nicotine or EtOH pretreatment might modulate endocannabinoid signaling in this region. Using similar EtOH and nicotine pretreatment methods resulted in increased paired-pulse ratios of evoked EPSCs in enkephalin-positive medium spiny neurons in DLS slices. Thus, EtOH and nicotine pretreatment may modulate glutamatergic synapses in the DLS presynaptically. Bath application of the CB1 receptor agonist Win 55,2-212 increased the paired-pulse ratio of evoked EPSCs in control slices, while Win 55,2-212 had no effect on paired-pulse ratio in slices from either EtOH- or nicotine-pretreated rats. Consistent with these effects, nicotine pretreatment occluded LTD induction by high-frequency stimulation of the corticostriatal inputs to the dorsolateral striatum. These results suggest that nicotine and EtOH pretreatment modulates striatal synapses to induce tolerance to the motor-impairing effects of EtOH, which may contribute to nicotine and EtOH coabuse.

Acute and chronic modulation of striatal endocannabinoid‐mediated plasticity by nicotine

“…This finding is partially supported by previous studies, showing impaired eCB-LTD and reduced levels of the eCB arachidonoylethanolamide in the dorsal striatum following repeated administration of nicotine (Gonzalez et al 2002;Abburi et al 2016). Impaired eCB-LTD was not restored by TC-2F suggesting that this finding is not caused by enhanced FAAH activity, but rather linked to a reduced postsynaptic release of eCBs.…”

Chronic Nicotine Alters Corticostriatal Plasticity in the Striatopallidal Pathway Mediated By NR2B-Containing Silent Synapses

“…A recent report (Abburi et al, 2016) observed reduced probability of release in mice given repeated nicotine injections. Though we observed a loss of presynaptic depression following HFS in the cNIC mice, at baseline we saw no difference in PPR (Figure 1a).…”

“…In a recent report, Abburi et al (2016) show that pretreatment with nicotine (1 × /day, 3 days) resulted in increased paired-pulse facilitation in striatopallidal MSNs of the DLS. They further show nicotine pretreatment blocked the ability of Win55-2-212 to induce presynaptic depression, suggesting that nicotine pretreatment induces a widespread presynaptic depression in striatopallidal MSNs.…”

Alcohol exposure disrupts mu opioid receptor-mediated long-term depression at insular cortex inputs to dorsolateral striatum

“…MSN activity is driven by glutamatergic input from three distinct sources: cerebral cortex, thalamic nuclei, and cholinergic interneurons (CINs) that can co-release glutamate 9 – 11 . Drugs of abuse that affect glutamatergic input on to MSNs produce alterations in dorsal striatal-dependent behavior 12 – 17 .…”