Cannabinoids activate mesolimbic dopamine neurons by an action on cannabinoid CB1 receptors

Self Cite

138

163

Recent findings have underlined the rostromedial tegmental nucleus (RMTg), a structure located caudally to the ventral tegmental area, as an important site involved in the mechanisms of aversion. RMTg contains g-aminobutyric acid neurons responding to noxious stimuli, densely innervated by the lateral habenula and providing a major inhibitory projection to reward-encoding midbrain dopamine (DA) neurons. One of the key features of drug addiction is the perseverance of drug seeking in spite of negative and unpleasant consequences, likely mediated by response suppression within neural pathways mediating aversion. To investigate whether the RMTg has a function in the mechanisms of addicting drugs, we studied acute effects of morphine, cocaine, the cannabinoid agonist WIN55212-2 (WIN), and nicotine on putative RMTg neurons. We utilized single unit extracellular recordings in anesthetized rats and whole-cell patch-clamp recordings in brain slices to identify and characterize putative RMTg neurons and their responses to drugs of abuse. Morphine and WIN inhibited both firing rate in vivo and excitatory postsynaptic currents (EPSCs) evoked by stimulation of rostral afferents in vitro, whereas cocaine inhibited discharge activity without affecting EPSC amplitude. Conversely, nicotine robustly excited putative RMTg neurons and enhanced EPSCs, an effect mediated by a7-containing nicotinic acetylcholine receptors. Our results suggest that activity of RMTg neurons is profoundly influenced by drugs of abuse and, as important inhibitory afferents to midbrain DA neurons, they might take place in the complex interplay between the neural circuits mediating aversion and reward.

Section: Discussionmentioning

confidence: 99%

Section: Effects Of Drugs Of Abuse On Rmtg Neuronsmentioning

confidence: 99%

Effects of Drugs of Abuse on Putative Rostromedial Tegmental Neurons, Inhibitory Afferents to Midbrain Dopamine Cells

Lecca

Melis

Luchicchi

et al. 2010

Self Cite

138

163

“…For example, GABAergic cells within intercalated cell masses (ICM), which lie at the anatomical interface of the BLA and CeA, generate feedforward inhibition of CeA neurons in response to BLA activation (Royer et al, 1999(Royer et al, , 2000, and are regulated by extrinsic glutamatergic afferents from the prefrontal cortex and dopaminergic afferents from the ventral midbrain (Bissiere et al, 2003;. Therefore, cannabinoid actions within these regions, which are known to occur (French et al, 1997;Gessa et al, 1998;Auclair et al, 2000;Patel and Hillard, 2003), could modulate CeA activity independently of the BLA, via modulation of ICM neuronal activity. Determining the contributions of these potential mechanisms to the effects observed in this study remains an important future goal.…”

Section: Discussionmentioning

confidence: 99%

Synergistic Interactions between Cannabinoids and Environmental Stress in the Activation of the Central Amygdala

Patel

Cravatt

Hillard

2004

148

100

Anxiety and panic are the most common adverse effects of cannabis intoxication; reactions potentiated by stress. Data suggest that cannabinoid (CB 1 ) receptor modulation of amygdalar activity contributes to these phenomena. Using Fos as a marker, we tested the hypothesis that environmental stress and CB 1 cannabinoid receptor activity interact in the regulation of amygdalar activation in male mice. Both 30 min of restraint and CB 1 receptor agonist treatment (D 9 -tetrahydrocannabinol (2.5 mg/kg) or CP55940 (0.3 mg/kg); by i.p. injection) produced barely detectable increases in Fos expression within the central amygdala (CeA). However, the combination of restraint and CB 1 agonist administration produced robust Fos induction within the CeA, indicating a synergistic interaction between environmental stress and CB 1 receptor activation. An inhibitor of endocannabinoid transport, AM404 (10 mg/kg), produced an additive interaction with restraint within the CeA. In contrast, fatty acid amide hydrolase (FAAH) inhibitor-treated mice (URB597, 1 mg/kg) and FAAH À/À mice did not exhibit any differences in amygdalar activation in response to restraint compared to control mice. In the basolateral (BLA) and medial amygdala, restraint stress produced a low level of Fos induction, which was unaffected by cannabinoid treatment. Interestingly, the CB 1 receptor antagonist SR141716 dose-dependently increased Fos expression in the BLA and CeA. These data suggest the CeA is an important neural substrate subserving the interactions between cannabinoids and environmental stress, and could be relevant to understanding the context-dependent emotional and affective changes induced by marijuana intoxication and the role of endocannabinoid signaling in the modulation of amygdalar activity.

“…In rats, opioid antagonists also decrease: (1) cannabinoid-induced reinstatement of extinguished cannabinoid self-administration (Spano et al, 2004), (2) THC-enhancement of intracranial self-stimulation (Chen et al, 1991), (3) THC's discriminative-stimulus effects (Solinas et al, 2004b), and (4) THC-induced dopamine release in the nucleus accumbens (French, 1997;Chen et al, 1990Chen et al, , 1991Casteñada et al, 1991;Tanda et al, 1997;Gessa et al, 1998), hypothesized to be one of the neural sites mediating drug reinforcement (Di Chiara, 1995).…”

Section: Introductionmentioning

confidence: 99%

Opioid Antagonism of Cannabinoid Effects: Differences between Marijuana Smokers and Nonmarijuana Smokers

Haney

2006

102

In non-human animals, opioid antagonists block the reinforcing and discriminative-stimulus effects of D 9 -tetrahydrocannabinol (THC), while in human marijuana smokers, naltrexone (50 mg) enhances the reinforcing and subjective effects of THC. The objective of this study was to test a lower, more opioid-selective dose of naltrexone (12 mg) in combination with THC. The influence of marijuana-use history and sex was also investigated. Naltrexone (0, 12 mg) was administered 30 min before oral THC (0-40 mg) or methadone (0-10 mg) capsules, and subjective effects, task performance, pupillary diameter, and cardiovascular parameters were assessed in marijuana smoking (Study 1; n ¼ 22) and in nonmarijuana smoking (Study 2; n ¼ 21) men and women. The results show that in marijuana smokers, low-dose naltrexone blunted the intoxicating effects of a low THC dose (20 mg), while increasing ratings of anxiety at a higher THC dose (40 mg). In nonmarijuana smokers, low-dose naltrexone shifted THC's effects in the opposite direction, enhancing the intoxicating effects of a low THC dose (2.5 mg) and decreasing anxiety ratings following a high dose of THC (10 mg). There were no sex differences in these interactions, although among nonmarijuana smokers, men were more sensitive to the effects of THC alone than women. To conclude, a low, opioid-selective dose of naltrexone blunted THC intoxication in marijuana smokers, while in nonmarijuana smokers, naltrexone enhanced THC intoxication. These data demonstrate that the interaction between opioid antagonists and cannabinoid agonists varies as a function of marijuana use history.