Endocannabinoid release from midbrain dopamine neurons: a potential substrate for cannabinoid receptor antagonist treatment of addiction

doi:10.1016/j.neuropharm.2005.03.016

Neuropharmacology

Volume 48, Issue 8, June 2005, Pages 1105-1116

https://doi.org/10.1016/j.neuropharm.2005.03.016 Get rights and content

Abstract

Substantial evidence suggests that all commonly abused drugs act upon the brain reward circuitry to ultimately increase extracellular concentrations of the neurotransmitter dopamine in the nucleus accumbens and other forebrain areas. Many drugs of abuse appear to increase dopamine levels by dramatically increase the firing and bursting rates of dopamine neurons located in the ventral mesencephalon. Recent clinical evidence in humans and behavioral evidence in animals indicate that cannabinoid receptor antagonists such as SR141716A (Rimonabant) can reduce the self-administration of, and craving for, several commonly addictive drugs. However, the mechanism of this potentially beneficial effect has not yet been identified. We propose, on the basis of recent studies in our laboratory and others, that these antagonists may act by blocking the effects of endogenously released cannabinoid molecules (endocannabinoids) that are released in an activity- and calcium-dependent manner from mesencephalic dopamine neurons. It is hypothesized that, through the antagonism of cannabinoid CB1 receptors located on inhibitory and excitatory axon terminals targeting the midbrain dopamine neurons, the effects of the endocannabinoids are occluded. The data from these studies therefore suggest that the endocannabinoid system and the CB1 receptors located in the ventral mesencephalon may play an important role in regulating drug reward processes, and that this substrate is recruited whenever dopamine neuron activity is increased.

Section snippets

Different drugs increase extracellular DA concentrations through distinct mechanisms

Although an increase in DA function is the ultimate result of the use of commonly abused drugs, the mechanisms through which this occurs can differ among distinct classes. Opiate drugs, such as heroin and morphine are thought to increase DA release in the NAc by inhibiting the release of the inhibitory neurotransmitter GABA onto VTA DA neurons (Johnson and North, 1992, Devine and Wise, 1994). This “disinhibition” of the DA neurons increases their rates of spontaneous firing, and increases the

Cannabinoid receptor substrates for marijuana effects on reward circuits

In contrast to the relatively well-understood neurobiological effects of the commonly abused drugs described above, the primary sites of interaction of the primary psychoactive constituent in marijuana, Δ⁹-THC, are only now being elucidated (Lupica et al., 2004). Our relatively primitive state of understanding of the effects of this drug on central reward pathways is primarily attributable to two factors. First, the Δ⁹-THC molecule and all experimentally employed cannabinoid drugs are extremely

The retrograde signaling capacity of endocannabinoids

One objective of the preceding studies has been to discover the substrates upon which Δ⁹-THC acts upon in the drug reward circuitry that may account for its ability to support marijuana use in humans (Lupica et al., 2004, Riegel and Lupica, 2004). However, the physiological effects of endocannabinoids in other brain areas (Alger, 2002) suggest that this system may regulate ongoing brain function, and, if present in reward pathways, may also be involved in gating changes in synaptic efficacy

VTA DA neurons release endocannabinoids

In an attempt to determine whether endocannabinoids might play a role in the VTA, a similar approach to that of Wilson and Nicoll (2001) was utilized during patch clamp recordings from DA neurons (Melis et al., 2004b). However, in this case, rather than measuring endocannabinoid effects on GABAergic synaptic currents, glutamatergic, NMDA receptor-dependent synaptic currents (EPSCs) were measured (Melis et al., 2004b). It was found, similar to previous reports in other brain areas that the

Interpreting VTA endocannabinoid effects

The true consequences of this activity-dependent modulation of synaptic inputs to the VTA DA neurons in the behaving organism are at present unknown. However, we can now make predictions based upon our knowledge of the substrates for endocannabinoid action in the VTA. Part of the difficulty in interpreting these data comes from the observations that both inhibitory GABAergic and excitatory glutamatergic synaptic inputs to VTA DA neurons can simultaneously be inhibited by endocannabinoids acting

Implications for cannabinoid receptor antagonists in the treatment of addiction

The cannabinoid receptor antagonist SR141716A (Rimonabant) can block the subjective rewarding effects of smoked marijuana, and therefore Δ⁹-THC, in humans (Huestis et al., 2001), as well as eliminate the self-administration of Δ⁹-THC in monkeys (Tanda et al., 2000). Furthermore, SR141716A appears to show promise as a useful medication for the treatment of cigarette smoking in humans (Le Foll and Goldberg, 2005), and it has been shown to be effective at blocking the self-administration of

The anti-addictive properties of cannabinoid receptor antagonists may reflect their interaction with endocannabinoids in the VTA

Although the neurobiological mechanisms for the potentially beneficial effects of cannabinoid antagonists on drug use and addiction are at present unknown, we propose that the antagonism of CB1 receptors located within the VTA, and the blockade of endocannabinoid action on these receptors represents a critical substrate (Fig. 1). This idea is supported by recent data described above that endocannabinoids are released in an activity-dependent fashion from mesencephalic DA neurons (Melis et al.,

References (96)

A. Bonci et al.
The dopamine-containing neuron: maestro or simple musician in the orchestra of addiction?
Trends Pharmacol. Sci.
(2003)
M.S. Brodie et al.
Ethanol increases the firing rate of dopamine neurons of the rat ventral tegmental area in vitro
Brain Res.
(1990)
D.L. Cameron et al.
A subset of ventral tegmental area neurons is inhibited by dopamine, 5-hydroxytryptamine and opioids
Neuroscience
(1997)
J.F. Cheer et al.
Lack of response suppression follows repeated ventral tegmental cannabinoid administration: an in vitro electrophysiological study
Neuroscience
(2000)
D.C. Cooper
The significance of action potential bursting in the brain reward circuit
Neurochem. Int.
(2002)
G. Cossu et al.
Cannabinoid CB1 receptor knockout mice fail to self-administer morphine but not other drugs of abuse
Behav. Brain Res.
(2001)
E.L. Gardner et al.
Cannabinoid transmission and reward-related events
Neurobiol. Dis.
(1998)
G.L. Gerdeman et al.
It could be habit forming: drugs of abuse and striatal synaptic plasticity
Trends Neurosci.
(2003)
G. Gessa et al.
Cannabinoids activate mesolimbic dopamine neurons by an action on cannabinoid CB₁ receptors
Eur. J. Pharmacol.
(1998)
F.G. Gonon
Nonlinear relationship between impulse flow and dopamine released by rat midbrain dopaminergic neurons as studied by in vivo electrochemistry
Neuroscience
(1988)

A.A. Grace et al.

Low doses of apomorphine elicit two opposing influences on dopamine cell electrophysiology

Brain Res.

(1985)

P.W. Kalivas

Neurotransmitter regulation of dopamine neurons in the ventral tegmental area

Brain Res. Brain Res. Rev.

(1993)

S.T. Kitai et al.

Afferent modulation of dopamine neuron firing patterns

Curr. Opin. Neurobiol.

(1999)

R. Mechoulam et al.

Endocannabinoids

Eur. J. Pharmacol.

(1998)

P.G. Overton et al.

Burst firing in midbrain dopaminergic neurons

Brain Res. Brain Res. Rev.

(1997)

R.G. Pertwee

Pharmacology of cannabinoid CB1 and CB2 receptors

Pharmacol. Ther.

(1997)

M. Poncelet et al.

Overeating, alcohol and sucrose consumption decrease in CB1 receptor deleted mice

Neurosci. Lett.

(2003)

M. Rinaldi-Carmona et al.

SR141716A, a potent and selective antagonist of the brain cannabinoid receptor

FEBS Lett.

(1994)

V. Seutin et al.

Apamin increases NMDA-induced burst-firing of rat mesencephalic dopamine neurons

Brain Res.

(1993)

S. Sugita et al.

Synaptic inputs to GABA_A and GABA_B receptors originate from discrete afferent neurons

Neurosci. Lett.

(1992)

F. Trent et al.

Amphetamine exerts anomalous effects on dopaminergic neurons in neonatal rats in vivo

Eur. J. Pharmacol.

(1991)

E.J. Van Bockstaele et al.

GABA-containing neurons in the ventral tegmental area project to the nucleus accumbens in rat brain

Brain Res.

(1995)

I. Walaas et al.

Biochemical evidence for gamma-aminobutyrate containing fibres from the nucleus accumbens to the substantia nigra and ventral tegmental area in the rat

Neuroscience

(1980)

T. Wenger et al.

Neuromorphological background of cannabis addiction

Brain Res. Bull.

(2003)

R.I. Wilson et al.

Presynaptic specificity of endocannabinoid signaling in the hippocampus

Neuron

(2001)

M.E. Wolf et al.

Psychomotor stimulants and neuronal plasticity

Neuropharmacology

(2004)

X. Wu et al.

Effects of chronic delta9-tetrahydrocannabinol on rat midbrain dopamine neurons: an electrophysiological assessment

Neuropharmacology

(2000)

B.E. Alger

Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids

Prog. Neurobiol.

(2002)

K. Anggadiredja et al.

Endocannabinoid system modulates relapse to methamphetamine seeking: possible mediation by the arachidonic acid cascade

Neuropsychopharmacology

(2004)

M. Arnone et al.

Selective inhibition of sucrose and ethanol intake by SR 141716, an antagonist of central cannabinoid (CB1) receptors

Psychopharmacology (Berl.)

(1997)

A. Bonci et al.

Glutamate metabotropic receptor agonists depress excitatory and inhibitory transmission on rat mesencephalic principal neurons

Eur. J. Neurosci.

(1997)

M.S. Brodie et al.

The effects of ethanol on dopaminergic neurons of the ventral tegmental area studied with intracellular recording in brain slices

Alcohol Clin. Exp. Res.

(1998)

M.S. Brodie et al.

Cocaine effects in the ventral tegmental area: evidence for an indirect dopaminergic mechanism of action

Naunyn Schmiedebergs Arch. Pharmacol.

(1990)

D.L. Cameron et al.

Cocaine inhibits GABA release in the VTA through endogenous 5-HT

J. Neurosci.

(1994)

D.B. Carr et al.

GABA-containing neurons in the rat ventral tegmental area project to the prefrontal cortex

Synapse

(2000)

F. Chaperon et al.

Involvement of central cannabinoid (CB1) receptors in the establishment of place conditioning in rats

Psychopharmacology (Berl.)

(1998)

A. Charara et al.

Glutamatergic inputs from the pedunculopontine nucleus to midbrain dopaminergic neurons in primates: phaseolus vulgaris-leucoagglutinin anterograde labeling combined with postembedding glutamate and GABA immunohistochemistry

J. Comp. Neurol.

(1996)

J.P. Chen et al.

Delta 9-tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleus accumbens of conscious, freely-moving rats as measured by intracerebral microdialysis

Psychopharmacology (Berl.)

(1990)

K. Chergui et al.

Subthalamic nucleus modulates burst firing of nigral dopamine neurones via NMDA receptors

Neuroreport

(1994)

C. Cohen et al.

SR141716, a central cannabinoid (CB(1)) receptor antagonist, blocks the motivational and dopamine-releasing effects of nicotine in rats

Behav. Pharmacol.

(2002)

G. Colombo et al.

Reduction of voluntary ethanol intake in ethanol-preferring sP rats by the cannabinoid antagonist SR-141716

Alcohol Alcohol.

(1998)

T.J. De Vries et al.

Cannabinoid modulation of the reinforcing and motivational properties of heroin and heroin-associated cues in rats

Psychopharmacology (Berl.)

(2003)

T.J. De Vries et al.

A cannabinoid mechanism in relapse to cocaine seeking

Nat. Med.

(2001)

D.P. Devine et al.

Self-administration of morphine, DAMGO, and DPDPE into the ventral tegmental area of rats

J. Neurosci.

(1994)

G. Di Chiara et al.

Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats

Proc. Natl Acad. Sci. U.S.A.

(1988)

L.C. Einhorn et al.

Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: studies in the ventral tegmental area

J. Neurosci.

(1988)

S. Erhardt et al.

GABA(B) receptor-mediated modulation of the firing pattern of ventral tegmental area dopamine neurons in vivo

Naunyn Schmiedebergs Arch. Pharmacol.

(2002)

R. Ferrari et al.

Acute and long-term changes in the mesolimbic dopamine pathway after systemic or local single nicotine injections

Eur. J. Neurosci.

(2002)

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Citation Excerpt :
In general, acute exposure to these drugs increases DA release in the NAc and other brain regions implicated in reward and behavioral actions of these drug (Volkow and Morales, 2015). Cannabis and THC have similar acute DA-increasing actions thought to arise from decreased inhibition of midbrain dopaminergic neurons (Lupica and Riegel, 2005; Peters et al., 2021). Thus, it is important to understand cannabis effects on DA in the human brain.
The legalization of cannabis in many countries, as well as the decrease in perceived risks of cannabis, have contributed to the increase in cannabis use medicinally and recreationally. Like many drugs of abuse, cannabis and cannabis-derived drugs are prone to misuse, and long-term usage can lead to drug tolerance and the development of Cannabis Use Disorder (CUD). These drugs signal through cannabinoid receptors, which are expressed in brain regions involved in the neural processing of reward, habit formation, and cognition. Despite the widespread use of cannabis and cannabinoids as therapeutic agents, little is known about the neurobiological mechanisms associated with CUD and cannabinoid drug use. In this article, we discuss the advances in research spanning animal models to humans on cannabis and synthetic cannabinoid actions on synaptic transmission, highlighting the neurobiological mechanisms following acute and chronic drug exposure. This article also highlights the need for more research elucidating the neurobiological mechanisms associated with CUD and cannabinoid drug use.

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Endocannabinoid release from midbrain dopamine neurons: a potential substrate for cannabinoid receptor antagonist treatment of addiction

Abstract

Section snippets

Different drugs increase extracellular DA concentrations through distinct mechanisms

Cannabinoid receptor substrates for marijuana effects on reward circuits

The retrograde signaling capacity of endocannabinoids

VTA DA neurons release endocannabinoids

Interpreting VTA endocannabinoid effects

Implications for cannabinoid receptor antagonists in the treatment of addiction

The anti-addictive properties of cannabinoid receptor antagonists may reflect their interaction with endocannabinoids in the VTA

Trends Pharmacol. Sci.

Brain Res.

Neuroscience

Neuroscience

Neurochem. Int.

Behav. Brain Res.

Neurobiol. Dis.

Trends Neurosci.

Eur. J. Pharmacol.

Neuroscience

Brain Res.

Brain Res. Brain Res. Rev.

Curr. Opin. Neurobiol.

Eur. J. Pharmacol.

Brain Res. Brain Res. Rev.

Pharmacol. Ther.

Neurosci. Lett.

FEBS Lett.

Brain Res.

Neurosci. Lett.

Eur. J. Pharmacol.

Brain Res.

Neuroscience

Brain Res. Bull.

Neuron

Neuropharmacology

Neuropharmacology

Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids

Prog. Neurobiol.

Endocannabinoid system modulates relapse to methamphetamine seeking: possible mediation by the arachidonic acid cascade

Neuropsychopharmacology

Selective inhibition of sucrose and ethanol intake by SR 141716, an antagonist of central cannabinoid (CB1) receptors

Psychopharmacology (Berl.)

Glutamate metabotropic receptor agonists depress excitatory and inhibitory transmission on rat mesencephalic principal neurons

Eur. J. Neurosci.

The effects of ethanol on dopaminergic neurons of the ventral tegmental area studied with intracellular recording in brain slices

Alcohol Clin. Exp. Res.

Cocaine effects in the ventral tegmental area: evidence for an indirect dopaminergic mechanism of action

Naunyn Schmiedebergs Arch. Pharmacol.

Cocaine inhibits GABA release in the VTA through endogenous 5-HT

J. Neurosci.

GABA-containing neurons in the rat ventral tegmental area project to the prefrontal cortex

Synapse

Involvement of central cannabinoid (CB1) receptors in the establishment of place conditioning in rats

Psychopharmacology (Berl.)

Glutamatergic inputs from the pedunculopontine nucleus to midbrain dopaminergic neurons in primates: phaseolus vulgaris-leucoagglutinin anterograde labeling combined with postembedding glutamate and GABA immunohistochemistry

J. Comp. Neurol.

Delta 9-tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleus accumbens of conscious, freely-moving rats as measured by intracerebral microdialysis

Psychopharmacology (Berl.)

Subthalamic nucleus modulates burst firing of nigral dopamine neurones via NMDA receptors

Neuroreport

SR141716, a central cannabinoid (CB(1)) receptor antagonist, blocks the motivational and dopamine-releasing effects of nicotine in rats

Behav. Pharmacol.

Reduction of voluntary ethanol intake in ethanol-preferring sP rats by the cannabinoid antagonist SR-141716

Alcohol Alcohol.

Cannabinoid modulation of the reinforcing and motivational properties of heroin and heroin-associated cues in rats

Psychopharmacology (Berl.)

A cannabinoid mechanism in relapse to cocaine seeking

Nat. Med.

Self-administration of morphine, DAMGO, and DPDPE into the ventral tegmental area of rats

J. Neurosci.

Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats

Proc. Natl Acad. Sci. U.S.A.

Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: studies in the ventral tegmental area

J. Neurosci.

GABA(B) receptor-mediated modulation of the firing pattern of ventral tegmental area dopamine neurons in vivo

Naunyn Schmiedebergs Arch. Pharmacol.

Acute and long-term changes in the mesolimbic dopamine pathway after systemic or local single nicotine injections

Eur. J. Neurosci.