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. 2010 Jul;15(3):277-88.
doi: 10.1111/j.1369-1600.2010.00222.x. Epub 2010 May 11.

Effects of fatty acid amide hydrolase inhibition on neuronal responses to nicotine, cocaine and morphine in the nucleus accumbens shell and ventral tegmental area: involvement of PPAR-alpha nuclear receptors

Antonio Luchicchi  1 , Salvatore Lecca, Stefano Carta, Giuliano Pillolla, Anna L Muntoni, Sevil Yasar, Steven R Goldberg, Marco Pistis
Affiliations

Effects of fatty acid amide hydrolase inhibition on neuronal responses to nicotine, cocaine and morphine in the nucleus accumbens shell and ventral tegmental area: involvement of PPAR-alpha nuclear receptors

Antonio Luchicchi et al. Addict Biol. 2010 Jul.

Abstract

The endocannabinoid system regulates neurotransmission in brain regions relevant to neurobiological and behavioral actions of addicting drugs. We recently demonstrated that inhibition by URB597 of fatty acid amide hydrolase (FAAH), the main enzyme that degrades the endogenous cannabinoid N-acylethanolamine (NAE) anandamide and the endogenous non-cannabinoid NAEs oleoylethanolamide and palmitoylethanolamide, blocks nicotine-induced excitation of ventral tegmental area (VTA) dopamine (DA) neurons and DA release in the shell of the nucleus accumbens (ShNAc), as well as nicotine-induced drug self-administration, conditioned place preference and relapse in rats. Here, we studied whether effects of FAAH inhibition on nicotine-induced changes in activity of VTA DA neurons were specific for nicotine or extended to two drugs of abuse acting through different mechanisms, cocaine and morphine. We also evaluated whether FAAH inhibition affects nicotine-, cocaine- or morphine-induced actions in the ShNAc. Experiments involved single-unit electrophysiological recordings from DA neurons in the VTA and medium spiny neurons in the ShNAc in anesthetized rats. We found that URB597 blocked effects of nicotine and cocaine in the ShNAc through activation of both surface cannabinoid CB1-receptors and alpha-type peroxisome proliferator-activated nuclear receptor. URB597 did not alter the effects of either cocaine or morphine on VTA DA neurons. These results show that the blockade of nicotine-induced excitation of VTA DA neurons, which we previously described, is selective for nicotine and indicate novel mechanisms recruited to regulate the effects of addicting drugs within the ShNAc of the brain reward system.

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Figures

Figure 1
Figure 1. Effects of URB597 on the responses of VTA DA neurons to cocaine
A) Average trace, acquired from a digital storage oscilloscope, showing the typical broad, notched waveform of an isolated VTA DA neuron recorded from an anaesthetized rat. B) Representative firing rate histogram showing the decrease in firing rate of an individual VTA DA neuron produced by intravenous cocaine (COC, 1 mg/kg injected at arrowheads) in control conditions. The injection of vehicle (VEH) is ineffective. C) This rate histogram displays that URB597 pretreatment (0.1 mg/kg, i.v.) does not alter cocaine’s depression of firing rate of a VTA DA neuron. D, E) Graphs illustrating the time course of cocaine’s effects on firing rate and burst firing of VTA DA neurons with and without URB597 pretreatment. Pretreatment with URB597 (0.1 mg/kg, i.v.) does not affect the inhibition of VTA DA neurons induced by cocaine (COC, 1 mg/kg, i.v.; arrow) either in firing rate (D) or burst firing (E). F) These histograms show that the pretreatment with URB597 did not affect baseline firing activity (top) or burst firing (bottom) of recorded VTA DA neurons (P> 0.05, Student's T test). Results are means, with vertical bars representing the SEM of firing rate and burst firing, expressed as a percentage of, or difference from, the baseline (BAS). * P<0.01 vs. baseline, one-way ANOVA and Dunnett’s test.
Figure 2
Figure 2. Lack of effect of URB597 on morphine-induced increases in firing rate and burst firing of VTA DA neurons
A) Representative firing rate histogram showing that intravenous injection of morphine (MORPH, 4 mg/kg) enhances firing rate of VTA DA neurons in control conditions. B) This exemplificative rate histogram displays that the administration of URB597 (0.1 mg/kg, i.v., 2 hours before the recordings) did not affect morphine-induced enhancement of firing rate in a VTA DA neuron. C, D) Graphical depiction of the time-course of firing rate (C) or burst firing (D) of VTA DA neurons following intravenous administration of morphine (MORPH, 4 mg/kg). Pretreatment with URB597 (0.1 mg/kg, i.v.) did not alter the effects of morphine either on firing rate or burst activity of VTA DA neurons. Results are means, with vertical bars representing the SEM of firing rate and burst firing, expressed as a percentage of, or difference from, the baseline (BAS). * P<0.05 vs. baseline, one-way ANOVA and Dunnett’s test.
Figure 3
Figure 3. Nicotine depresses the excitability of MSNs in the ShNAc
A) Superimposed traces acquired from a digital storage oscilloscope showing a relatively constant latency of the orthodromic responses of a representative MSN after BLA stimulation. The arrowhead indicates the artifacts produced by BLA stimulation, the arrow shows evoked action potentials of a MSN. Once a cell was isolated, the current applied to the BLA was adjusted to obtain ~50% of probability to elicit an action potential after a single pulse stimulation. B) Representative peristimulus time-histograms displaying the typical inhibitory response of a MSN in the ShNAc after BLA stimulation and injection of nicotine (0.2 mg/kg, i.v.). C) Graph showing the time-course of nicotine-induced inhibition of spike firing of MSNs. D) Graphical depiction illustrating that nicotine-induced inhibition was prevented by the combined administration (at arrow), but not by the separate injection, of the dopamine D1 receptor antagonist SCH23390 (SCH, 1 mg/kg, i.v.) and the D2 receptor antagonist l-sulpiride (L-Sulp, 10 mg/kg, i.v.). Results are means with vertical bars representing the SEM of evoked spike firing, expressed as a percentage of the baseline (BAS). *P<0.05 vs baseline, one-way ANOVA and Dunnett’s test; #P<0.05 vs vehicle+nicotine, two-way ANOVA and Bonferroni’s test.
Figure 4
Figure 4. URB597 suppresses nicotine’s action on MSNs in the ShNAc
A) Exemplificative peristimulus time-histograms showing that nicotine-induced decrease of MSN excitability is reversed by URB597, whereas the CB1-receptor antagonist rimonabant (SR, 0.5 mg/kg) and the PPAR-α antagonist MK886 (3 mg/kg), administered 15 minutes before URB597, prevented the effects of the FAAH inhibitor and restored nicotine-induced inhibition of MSNs responses to BLA stimulation in the ShNAc. B) and C) Graphical depiction illustrating that URB597 pretreatment prevented nicotine-induced inhibition of MSNs, and that this inhibition by nicotine was reversed by rimonabant (SR, 0.5 mg/kg, i.v.) (B) or MK886 (3 mg/kg, i.p.) (C). The histogram in the inset displays that the mean current administered in the BLA to evoke spike firing in MSNs was not different between controls (CTRL) and URB597-pretreated animals. Results are means with vertical bars representing the SEM of evoked spike firing, expressed as difference percentage of the baseline (BAS). #P<0.05 vs vehicle+nicotine, §§ P<0.001 vs. URB+nicotine, two-way ANOVA and Bonferroni’s test.
Figure 5
Figure 5. URB597 suppresses cocaine’s action on MSNs of the ShNAc
A) Representative peristimulus time-histograms showing the response of recorded ShNAc MSNs neurons after BLA stimulation. The probability of evoking MSN responses after BLA stimulation decreased after cocaine administration. Pretreatment with URB597 reversed cocaine-induced inhibition of MSNs. The PPAR-α antagonist MK886 blocked URB597’s effect and restored cocaine-induced inhibition of MSNs. B,C,D) Graphical depictions of the time-course of cocaine’s effects on MSN excitability in the ShNAc. Cocaine depresses the excitability of MSNs in a long-lasting manner (B). This effect was blocked by URB597, which fully prevented cocaine-induced inhibition (B). Pretreatment with the CB1-receptor antagonist rimonabant (SR; 0.5 mg/kg, i.v.) did not alter URB597’s blockade of cocaine's actions (C), whereas MK886 (3 mg/kg, i.p.) (D) completely prevented URB597’s blockade of cocaine’s actions and restored cocaine-induced inhibition of MSNs. Results are means with vertical bars representing the SEM of evoked spike firing, expressed as a percentage of the baseline (BAS). *P<0.05 vs. baseline, one-way ANOVA and Dunnett’s test; # P<0.05 vs. vehicle + cocaine, § P<0.05 vs URB597+cocaine, two-way ANOVA and Bonferroni’s test
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