Cannabinoids regulate dopamine

So far, the evidence is still too weak to recommend cannabinoid-based interventions for CNS disorders with dopaminergic dysregulation. Research into the effects of cannabinoids in this area is still in its infancy¹
Nevertheless, it is evident that endocannabinoids are very closely linked to the dopamine system and exert a significant influence on dopamine.

• 1. The dopamine endocannabinoid system
  • 1.1. Cannabinoids and dopamine regulate motivation - mesocortical
  • 1.2. Cannabinoids and dopamine regulate choice impulsivity (delay discounting) via the nucleus accumbens
  • 1.3. Cannabinoids and dopamine regulate reward and addiction - mesolimbic
    • 1.3.1. 2-AG increases reward-seeking behavior
    • 1.3.2. AEA reduces reward-seeking behavior
    • 1.3.3. CB1R agonists increase, CB1R antagonists decrease reward-seeking behavior
    • 1.3.4. CB2R agonists reduce, CB2R antagonists increase reward-seeking behavior
  • 1.4. Cannabinoids and dopamine regulate motor function - via the basal ganglia
  • 1.5. Cannabinoids and dopamine influence working memory, time processing and behavioral adaptation - via PFC
• 2. Cannabinoids regulate dopamine
  • 2.1. Endocannabinoids regulate dopamine via DA neurons in the midbrain
    • 2.1.1. CB1R and CB2R also on dopaminergic neurons
  • 2.2. Endocannabinoids regulate dopamine release from axonal terminals
  • 2.3. Endocannabinoids inhibit DAT dopamine reuptake
  • 2.4. Endocannabinoids act on dopamine receptors
  • 2.5. Endocannabinoids influence phasic and tonic dopamine firing
    • 2.5.1. Cannabinoids increase phasic dopamine firing
    • 2.5.2. Cannabinoids increase tonic dopamine firing
  • 2.6. 2-AG modulates integration of intrinsic and extrinsic dopaminergic inputs
  • 2.7. Inverted-U effect of endocannabinoids
  • 2.8. GABA pathway
  • 2.9. Glutamate pathway
  • 2.10. Stimulants regulate dopamine via endocannabinoids
• 3. Dopamine regulates endocannabinoids
• 4. Endocannabinoid-dopamine-adenosine interaction
• 5. Endocannabinoids regulate synaptic plasticity
  • 5.1. Short-term plasticity
    • 5.1.1. Depolarization induces suppression of inhibition (DSI) or excitation (DSE)
    • 5.1.2. Metabotropic-induced suppression of inhibition (MSI) or excitation (MSE)
  • 5.2. Long-term plasticity
    • 5.2.1. Long-term potentiation (LTP)
    • 5.2.2. Long-term depression (LTD)
    • 5.2.3. Slow self inhibition (SSI)

1. The dopamine endocannabinoid system¶

Cannabinoids and dopamine are not only very closely linked²³ , but also regulate each other, at least in the striatum⁴
A number of behaviors and disorders that were previously considered purely dopaminergic in origin can now be better explained as the result of interactions between the endocannabinoid and dopamine systems⁵, e.g:

• motor control / motor disorders (Parkinson’s, dyskinesia, dystonia)⁶⁷
• Reward⁸
• Addiction⁸
  • Endocannabinoids interact with the opioid system and the dopamine system.⁹
• goal-oriented behavior, motivation¹⁰

The cannabinoid system interacts with dopaminergic neurons that have cell bodies in the reticular formation of the midbrain (e.g. in substantia nigra pars compacta (A9) and VTA (A10)) and axons in the forebrain (e.g. in the caudate/putamen and nucleus accumbens/PFC complex). This influences activities such as movement and various cognitive functions.¹

The interaction of endocannabinoids and dopamine to regulate important brain functions such as motor control, reward and psychosis occurs particularly in the nucleus accumbens, VTA, substantia nigra, striatum and PFC. Motor function is controlled by the basal ganglia with high levels of 2-AG and AEA together with other neurotransmitters such as GABA, glutamate, dopamine and acetylcholine.¹¹

CB1R and dopamine receptors form postsynaptic heteromers.¹

1.1. Cannabinoids and dopamine regulate motivation - mesocortical¶

Mesocorticolimbic dopaminergic neurons control motivation and reward (alongside cognitive functions, the central stress response, reinforcement-induced pleasure and addiction)⁹

Cannabinoids affect the mesocortical dopamine system¹² and, like most habit-forming drugs, act by altering mesocorticolimbic dopamine transmission.¹¹³

Many areas of the brain’s reward circuit are rich in cannabinoid components, especially CB1R.¹
Cannabinoid agonists increase mesolimbic dopaminergic activity by affecting DA receptor density, dopamine release and dopamine metabolism.¹²¹⁴
Cannabinoids increased the firing rate of mesolimbic dopaminergic neurons in the VTA (A10).¹¹⁵
Δ9-THC¹³ as well as other CB1R agonists¹⁶ increase extracellular dopamine levels and dopaminergic neurotransmission in the nucleus accumbens shell.
Presynaptic CB1Rs also appear to inhibit dopamine release from dopaminergic neurons.¹⁷

Endocannabinoids influence various aspects of food reward, e.g. appetite motivation.¹⁸ The CB1R agonists THC, anandamide and 2-AG promote appetite and cravings.¹⁹ Cannabinoid agonists increase euphoria, reward and emotionality and decrease anxiety, motivation and arousal. This is thought to occur primarily through glutamatergic and/or GABAergic innervations to the nucleus accumbens/PFC and VTA, where they cause dopaminergic changes.¹
More on the regulation of appetite and food intake by endocannabinoids in the article Cannabinoids also regulate appetite and food intake via dopamine

A yardstick for measuring reward modulation, and more specifically the relationship between response effort and the value of a particular reward, is the progressive ratio at which the requirements for obtaining a single reward are exponentially increased within a single session until the subject stops responding. The “breakpoint” is the ratio at which the subject stops responding. The breakpoint thus measures the work that an organism is prepared to do for a goal.²⁰²¹²²
Cannabinoid agonists increase the breakpoint, i.e. the amount of work the test subjects are willing to do for a single reward.²³
A 2-AG degradation inhibitor, but not an AEA degradation inhibitor, increased the breakpoint.²⁴
Inhibition of 2-AG degradation in the VTA promoted reward seeking and phasic DA release.²⁴

CB1Rs are also found on a number of other structures that regulate motivation and reward:⁹

• Hippocampus
• basolateral amygdala
• Hypothalamus

1.2. Cannabinoids and dopamine regulate choice impulsivity (delay discounting) via the nucleus accumbens¶

The devaluation of more distant rewards is a natural reaction. The more distant a reward is, the higher the level of devaluation.
Stress leads to a preference for short-term rewards.²⁵

Phasic dopamine firing correlates positively with the magnitude of the reward and decreases hyperbolically with the delay of the reward. Dopamine release in the nucleus accumbens decreases correlatively with the length of an announced delay. Phasic DA release during reward delivery is even higher for small to medium delays for the larger reward and decreases with increasing delay to the level of the small immediate reward ^{23 2627}

Cannabinoids influence elective impulsivity only indirectly by modulating dopamine.²³
During intertemporal decision-making tasks, dopamine acutely increasing drugs increase self-control and lead to more frequent choice of the larger delayed reward instead of the immediate smaller reward, while dopamine acutely decreasing drugs promote impulsive choice of the smaller but immediate reward.
The CB1R agonist Δ9-THC increases self-control; previously administered CB1R antagonists block this.
CB1R antagonists reduce the effect of DA agonists.²⁸
CB1R antagonists alone do not influence self-control.
Chronic dopamine elevation through drugs reduces self-control.

Chronic drug exposure leads to plastic changes in the mesolimbic circuitry and other brain areas and neurotransmitters. Endocannabinoids are involved²³

• in the modulation of synaptic plasticity in the VTA
• the increase in phasic DA release following dopaminergic drug intake
• in the development and development of sensitization
• in the conditioned drug search
• relapse and resumption of drug use due to a tip-off

Subjects who were sensitized to the effects of cocaine showed choice impulsivity in intertemporal decision-making tasks.²³
While a higher dopamine release before sensitization encodes a larger reward as long as the delay is less than 10 seconds, the phasic release after sensitization is relatively higher for the small immediate reward regardless of the delay²⁶
A CB1R antagonist prior to cocaine exposure prevented²⁶

• the electoral impulsivity
• the maladaptive patterns of phasic dopamine release
  A CBR1 antagonist after cocaine sensitization²⁶
• corrected the changes in self-control

1.3. Cannabinoids and dopamine regulate reward and addiction - mesolimbic¶

Mesocorticolimbic dopamine influences reward and addiction in humans.¹
Opioids, cannabinoids, psychostimulants, cocaine, alcohol and nicotine acutely increase the release of dopamine in various regions of the brain,^{2930 31} including the mesolimbic dopamine system. CB1Rs are required for this increase in phasic dopamine release.³² The CB1R antagonist rimonabant prevents the increased phasic dopamine release caused by the aforementioned drugs.³³³⁴³⁵

The mesolimbic system is primarily controlled by dopamine, which flows from the VTA (midbrain = meso) to the nucleus accumbens (part of the basal ganglia) and its downstream nuclei of the limbic system. In addition to these, the mPFC, amygdala, substantia nigra, globus pallidus and hippocampus are also involved in the motivating and reinforcing effect of cannabinoids ^{36 3637}
Signals from the mPFC and the basolateral amygdala to extracellular neurons in the nucleus accumbens shell are inhibited by cannabinoid agonists and completely suppressed by rimonabant (CB1R antagonist/inverse agonist).³⁷
CB1R is found in the VTA, nucleus accumbens, striatum and pyriform cortex³⁸ as well as in excitatory projections from subcortical structures to the nucleus bed of the stria terminalis, which in turn projects into the VTA.³⁹

Reward dependence appears to correlate with low levels of AEA, while 2-AG showed no correlation.⁴⁰ Reward dependence, measured with the “Reward Dependence” scale of the Tridimensional Personality Questionnaire (TPQ), is the individual’s dependence on signals of mainly social reward, especially verbal signals of social recognition, social support and current mood.

Dopamine encodes the deviation between the expected and received reward (reward prediction error).
Without mobilization of 2-AG from VTA dopamine neurons, the generation of dopamine-based predictive associations required for the control and stimulation of reward-seeking behavior is not possible.⁴¹
Most midbrain dopamine neurons are activated when the reward is higher than predicted (positive prediction error), remain unchanged when the expectation is realized and show dampened activity when the reward is lower than predicted (negative prediction error). The dopamine signal increases nonlinearly with reward value and encodes the formal economic benefit. Addictive drugs generate, hijack and amplify the dopamine signal for rewards and induce an exaggerated, uncontrolled dopamine effect on neuronal plasticity.
In striatum, amygdala and PFC, only subpopulations of neurons show reward prediction miscoding.⁴²

1.3.1. 2-AG increases reward-seeking behavior¶

Endocannabinoids, especially 2-AG, influence the associated behavior via mesolimbic dopamine release:⁴³

• Reward search
  • 2-AG is necessary to observe the dopamine release triggered by a stimulus, which represents the value of a rewarding outcome
• Interval control
  • 2-AG modulates unique patterns of dopamine release and behavior under conditions of periodic reinforcement
• active avoidance behavior
  • the dopamine concentration caused by a warning signal represents the value of an avoidance result. Disruption of 2-AG signaling reduces the DA level of the avoidance value signal and thus active avoidance

2-AG reinforced the reward-seeking behavior.²⁴³³
2-AG can enhance the effect of stimulus-induced dopamine release³³, e.g. when 2-AG is increased by a MAGL inhibitor such as JZL184. The stimulus-induced dopamine transients then increase in magnitude and occur with a shorter latency.

1.3.2. AEA reduces reward-seeking behavior¶

In contrast, an increase in AEA reduces reward-seeking behavior and dopamine signaling during reward seeking⁴⁴⁴⁵ , e.g., dose-dependently when AEA is increased by VDM11⁴⁶⁴⁷ , a selective AEA reuptake inhibitor⁴⁸ and AEA and 2-AG degradation inhibitors⁴⁹.

It is possible that AEA only acts as a partial CB1R agonist without 2-AG and as a competitive antagonist in the presence of 2-AG.³³ This would be consistent with the fact that AEA in particular is involved in mediating synaptic plasticity in several brain regions, which is suppressed by 2-AG.⁵⁰⁵¹

1.3.3. CB1R agonists increase, CB1R antagonists decrease reward-seeking behavior¶

The mesocorticolimbic pathway and brain regions that influence decision-making, withdrawal symptoms and relapse express CB1R⁵² and CB2R⁵³.

CB1R agonists enhance conditioned place preference and increase preference for ethanol- and nicotine-associated stimuli¹
The CB1R antagonist rimonabant

• reduced reinforcement perception for various addictive drugs, CB1R blockades (genetic or pharmacological) prevent the dopamine surge otherwise triggered by Δ9-THC, nicotine, heroin, morphine or ethanol¹
• reduced dopamine levels and reward-seeking behavior significantly¹³
• was helpful in the treatment of alcohol addiction and smoking cessation.¹⁵⁴

CB1R-KO mice show¹² reduced voluntary alcohol consumption and abolition of alcohol-induced dopamine increase in the nucleus accumbens⁵⁵, reduced morphine self-administration⁵⁶, reduced basal and abolition of cocaine-induced hypermotor activity⁵⁷ and the absence of rewarding effects of nicotine in the conditioned place preference test⁵⁸, but no similar responses to reinforcement by cocaine or nicotine in the self-administration paradigm⁵⁶.

1.3.4. CB2R agonists reduce, CB2R antagonists increase reward-seeking behavior¶

CB2Rs are also involved in addiction. β-Caryophyllene (BCP), presumably a CB2R full agonist and possibly a PPAR ligand, prevented and even partially reversed the behavioral changes induced by cocaine, nicotine, alcohol or methamphetamine, such as self-administration, conditioned place preference or self-stimulation.⁵⁹
Pretreatment with the selective CB2R agonist JWH133 attenuated the hyperactivity induced by cocaine and nicotine in WT mice.⁶⁰
Increased alcohol preference/increased alcohol consumption reduced CB2R expression in the ventral midbrain.⁶¹
The CB2R agonist JWH015 increased alcohol preference in mice exposed to chronic mild stress, while the CB2R inverse agonist AM630 prevented the development of alcohol preference.⁶¹ CB2R-KO mice (mice without CB2R) show increased alcohol consumption, increased motivation and changes in relapse behavior⁶²

TRPV1 are essential for the development of place preference and self-administration of methamphetamine.⁶³ TRPV1s appear to be involved in pain stimulus-induced dopamine release in the nucleus accumbens.⁶⁴
CBD (TRPV1 and PPAR agonist) over 10 days reduced cannabis withdrawal symptoms in a case study.⁶⁵
CBD can help prevent addiction relapses.⁶⁶

FAAH inhibitors reduced nicotine-induced activation of dopaminergic neurons, which argues against the idea that endocannabinoids enhance the dopaminergic effect of nicotine via the CB1R. Apparently, FAAH inhibitors in the present case (also) enhance the effect of certain N-acylethanolamines (e.g. OEA and PEA), which do not bind to CB1R but to PPAR-α. Administration of OEA and PEA showed the same effect.⁶⁷

1.4. Cannabinoids and dopamine regulate motor function - via the basal ganglia¶

Endocannabinoids regulate dopaminergic neurotransmission, in particular via:⁵

• the effector sites of the DA neurons in the basal ganglia
  • CB1R are highly expressed on striatal projection neurons, as well as in some fast-spiking parvalbumin-containing interneurons^68697071
  • CB1R activation in the ventral hippocampus led to significantly increased VTA dopamine neuron firing, which correlated with increased morphine reward sensation³⁹

In addition to dopamine, GABA, glutamate and acetylcholine, the basal ganglia, which control motor function, also contain plenty of cannabinoid components such as cannabinoids:¹

• AEA in high concentration
• 2-AG in high concentration
• CB1R, which is significantly involved in movement control in a healthy state

Cannabinoid medications improve movement disorders, e.g:⁷²

• Parkinson’s disease:
  • Bradykinesia: CB1R antagonists
  • Tremor: CB1R agonists
  • delay the development of Parkinson’s disease through neuroprotective properties
    • CB1R agonists reduce excitotoxicity
    • CB2R agonists limit the toxicity of reactive microglia
    • antioxidant cannabinoids reduce oxidative damage
• Huntington:
  • choreic movements: CB1R agonists / TRPV1 agonists

Cannabinoids increase the firing of dopamine neurons and the synaptic release of dopamine in the striatum^473741675

• not directly through activation of striatal CB1R, as the effect did not occur in vitro on striatal tissue or in CB1R KO mice⁷⁶
• rather indirect regulation of the firing of striatal dopamine neurons via activation of dopaminergic neurons at the somatodendritic level in the midbrain (substantia nigra / VTA)⁷⁷⁷⁸⁷⁹
• the midbrain dopamine neurons are also not activated directly, but indirectly via complex pathways⁸⁰ involving
  • terminal fields of the direct and indirect mesoaccumbens projections in the midbrain⁴
  • of the mesocortical projection, e.g. via TRPV1⁸¹
  • local GABA interneurons⁸²

Cannabinoids regulate dopaminergic firing via inhibitory CB1R in GABA and glutamatergic terminals, leading to a functional balance between excitatory and inhibitory inputs. The balance is characterized by a predominance of CB1R-GABAergic-mediated disinhibition of DA neuron activation.⁸³
In addition to the excitatory CB1R-GABA pathway, cannabinoidergic TRPV1 agonists can increase dopamine firing rates, which are likely to be located at glutamatergic terminals (Marinelli et al., 2003, 2007). ⁸¹
While CB1R generally tends to massively increase dopamine release, 2-AG from the VTA regulates the homeostatic control of cortical/subcortical dopamine balance and thus the maintenance of appropriate neuroadaptations and goal-directed behaviors. CB1R activation by 2AG inhibits the increase in firing and bursting activity of dopamine neurons induced by stimulation of the PFC. 2-AG synthesis requires activation of metabotropic glutamate receptors.⁸⁴⁴³

Endocannabinoids locally control the release of dopamine in the nucleus accumbens.^85868733
Optogenetic stimulation of cholinergic interneurons triggered dopamine release in the nucleus accumbens.
A CB1R agonist inhibited this dopamine release.⁸⁸
Stimulation of cholinergic interneurons facilitated glutamatergic transmission via presynaptic α7-expressing nAChRs located on PFC terminals. The increased glutamate controls DA release via at least several mechanisms:

• directly via glutamate release at AMPA receptors on the DA terminals
• indirectly via the excitation of cholinergic interneurons and the activation of nAChRs on DA terminals.
• In the nucleus accumbens, endocannabinoid synthesis triggered by cholinergic interneurons also occurs through the facilitation of glutamate release on NAc-MSNs, which drives eCB mobilization to CB1 receptor-expressing PFC terminals.

Endocannabinoids regulate motor activity in a dose-dependent manner:¹⁸⁹⁹⁰

• Low doses of cannabinoids stimulated motor activity
• High doses of cannabinoids reduced motor activity to the point of severe catalepsy (body rigidity)
• The CB1R antagonist rimonabant blocked these motor effects

Endovanilloid and dopamine signaling systems appear to work together to control movement, among other things. ¹
Eicosanoid cannabinoids such as anandamide, AM404 or N-arachidonoyl-dopamine also bind to the vanilloid TRPV-1 receptor.⁶
TRPV1R¹

• can be found
  • on sensory neurons
  • on nigrostriatal dopaminergic neurons in the basal ganglia⁹¹
    • which could mean a direct dopaminergic effect of endocannabinoids⁹²
• act as molecular integrators of nociceptive stimuli⁹³

AEA leads to hypokinesia in rats, which correlates with reduced activity of nigrostriatal dopaminergic neurons (de Lago et al., 2004). This may be due to an effect of AEA at TRPV1 rather than CB1R. AEA caused:⁹¹⁹²

• reduced urge to move
• reduced stereotypes
• reduced exploration in the field test
• increased inactivity time

The TRPV1 antagonist capsazepine abolished the AEA effect
AEA reduced the dopamine metabolite 3,4-dihydroxyphenylacetic acid in the putamen caudatus. Capsazepine reversed this, suggesting that TRPV1 agonists reduce dopamine turnover in the basal ganglia.
AEA also reduced stimulus-induced dopamine release from nigrostriatal terminals.⁹¹

1.5. Cannabinoids and dopamine influence working memory, time processing and behavioral adaptation - via PFC¶

Moderate amounts of CB1R are found in the PFC.
Acute administration of CB1R agonists increases presynaptic dopamine release⁹⁴ and extracellular dopamine in the cortex.⁹⁵
Acute cannabinoid agonist administration increases the activity of dopaminergic neurons in the VTA that project to the PFC.¹²
The PFC controls many cognitive functions in a dopaminergic manner, including

• Working memory
• temporal organization of behavior
• Adaptation of behavioral strategies

Repeated cannabinoid agonist administration reduced dopamine turnover in the PFC, but not in the nucleus accumbens and striatum, which persisted 2 weeks after discontinuation.¹²⁹⁶⁹⁷

This long-term effect correlates neurochemically with hypofrontality[^4][^103] [^104] , defined as a state of reduced cerebral blood flow and reduced neuronal activity of the PFC[^105][^106] and an imbalance of the cortical-subcortical network in terms of dopamine, glutamate and especially acetylcholine, among other things.[^107] Hypofrontality is also present in ADHD, where it is considered the cause of executive dysfunction.[^105][^108]

CB1R antagonists regulate dopamine differently depending on the brain region. Systemic CB1R antagonist administration significantly increases dopamine only in the cortex and leaves dopamine in the nucleus accumbens unchanged¹⁰³, which indicates an addiction-inhibiting and pro-cognitive effect of CB1R agonists⁴
Cortical DA circuits control mesolimbic DA activation, and an increase in DA in the prefrontal cortex is expected to reduce DA activity in the accumbens.⁴ This ties in with the PFC-striatum-dopamine seesaw that we have mentioned several times before. More on this under The dopamine seesaw between the PFC and subcortical regions (including the striatum) In the article Interactions of the dopaminergic brain areas in the section Neurotransmitters in ADHD / Dopamine in the chapter Neurological aspects.

2. Cannabinoids regulate dopamine¶

2.1. Endocannabinoids regulate dopamine via DA neurons in the midbrain¶

Endocannabinoids regulate dopaminergic neurotransmission, in particular via:⁵

• the activity of the DA neurons in the midbrain
  • CB1R agonists increase in vivo
    • the firing of DA cells in SNc and VTA in vivo^1047779105
      • with rapid desensitization through repeated cannabinoid administration¹⁰⁶
      • In detail⁷⁷
        • Cannabinoid agonists increased the firing rate of PFC pyramidal neurons projecting into the VTA
        • Electrical VTA stimulation led to phasic inhibition in 79% of PFC pyramidal neurons
        • Cannabinoid agonists reversed this inhibition in 73% to 100% of the neurons tested
        • A subsequent selective CB1R antagonist suppressed the effect of the cannabinoid agonists and restored the inhibitory response to VTA stimulation
    • dA release in the nucleus accumbens in vivo¹⁰⁷¹⁰⁸
      • Cannabinoid mimetics inhibited stimulus-induced GABA-mediated inhibitory postsynaptic currents (IPSC) in the nucleus accumbens¹⁰⁹
      • Cannabinoid agonists also inhibit the increased firing rate of nucleus accumbens shell neurons caused by stimulation of the basolateral amygdala or the mPFC³⁷
    • the single-spike firing and burst rates of DA neurons in vitro⁵
    • CB1R agonists mediate presynaptic inhibition of glutamatergic transmission in dopamine neurons of the VTA²⁴
    • activation of CBR at infralimbic glutamatergic terminals in the nucleus bed of the stria terminalis inhibits dopamine neurons in the VTA³⁹
  • CB1R antagonists in VTA, PFC or nucleus accumbens, but not in amygdala, reduce reward-seeking behavior²⁴¹¹⁰
  • CB1Rs facilitate or suppress the activity of dopamine neurons depending on their presynaptic location
    • CB1Rs reduce the likelihood of neurotransmitter release, which promotes dopaminergic activity at GABAergic terminals by suppressing inhibitory input to GABA-A or GABA-B receptors on dopamine neurons^11111280
    • at glutamatergic synapses, CB1R suppress excitatory drive to AMPA or NMDA receptors on DA neurons⁸⁰
  • 2-AG⁵
    • is synthesized by dopamine neurons via DGLα
    • is then released postsynaptically by the dopamine neurons
    • binds to presynaptic CB1R of
      • GABAergic terminals
      • glutamatergic terminals
    • DGLα activity is influenced by
      • increased Ca2+ flow (e.g. after iGluR signaling)
      • Gg/11-GPCR binding
        • Orexin-1 receptors¹¹³¹¹⁴
        • Alpha1-adrenoceptors³⁴
        • mGluR5 glutamate receptors³⁴
        • Insulin receptors¹¹⁵
        • Neurotensin receptors¹¹⁶¹¹⁷

2.1.1. CB1R and CB2R also on dopaminergic neurons¶

Contrary to the previous assumption that dopamine neurons do not express CB1R¹¹⁸ CB1R are also found on dopaminergic neurons of the VTA ^{119 12038}

The CB1R is also found on neurons that express DRD1¹²¹
The CB1R could therefore directly influence the release of dopamine.¹²²

CB2R receptors on dopaminergic neurons have also been reported.^5360123124
A deletion of CB2Rs in dopamine neurons⁵³

• improved motor activity
• modulates anxiety- and depression-like behaviors
• reduced the rewarding properties of alcohol

2.2. Endocannabinoids regulate dopamine release from axonal terminals¶

Endocannabinoids regulate dopaminergic neurotransmission, in particular via the release of dopamine at axonal terminals:⁵¹²⁵

• Endocannabinoids also control dopamine release via local modulation of the afferent terminal input at the dopamine axon terminals
• MSNs of the striatum can synthesize endocannabinoids “on-demand” and release them postsynaptically, which then bind to presynaptic CB1Rs (mostly GABAergic or glutamatergic neurons).
• Striatal cholinergic interneurons are a potential source of endocannabinoid modulation. These regulate dopamine release independently of cell body activation.¹²⁶¹²⁷ So far, however, no CB1Rs have been found on striatal cholinergic interneurons.

2.3. Endocannabinoids inhibit DAT dopamine reuptake¶

A number of endocannabinoids¹²⁸, such as AEA, reduce DAT activity.¹²⁹¹³⁰ AEA strongly reduces DAT uptake Vmax, with a simultaneous slight decrease in Km.¹³¹
Endocannabinoids also inhibit striatal adenosine reuptake¹²⁸, which counteracts the positive effect of DAT inhibition on ADHD.

FAAH inhibition could be replicated in the mouse striatum by stimulating D2 dopamine receptors, but not D1R. The D2R/D3R/D4R agonist quinpirole increased AEA in the dorsal striatum by 8-fold and simultaneously increased motor hyperactivity.¹³²
DAT-KO mice showed reduced AEA levels in the striatum.¹³³

RTI-371 is both a positive allosteric modulator of CB1R and a selective DAT inhibitor.¹³⁴

2.4. Endocannabinoids act on dopamine receptors¶

Endocannabinoids⁶⁹

• act on dopamine D1 receptors
  • the AEA reuptake inhibitor AM404 blocked D1R-mediated grooming
    • but not with D1R-KO mice
  • aEA reuptake inhibitor AM404 inhibits contralateral turning induced by unilateral intrastriatal infusion of D1 receptor agonists
  • the cannabinoid antagonist SR141716A enhances the contralateral turning induced by unilateral intrastriatal infusion of D1 receptor agonists
• act on dopamine D2 receptors
  • the AEA reuptake inhibitor AM404 blocked D2 receptor-mediated oral stereotypies

2.5. Endocannabinoids influence phasic and tonic dopamine firing¶

CB2 agonists inhibit dopamine neuron firing and terminal dopamine release.^135136137 The CB2R agonist JWH133 reduced behavioral deficits and iron accumulation caused by dopaminergic neuron destruction in Parkinson’s disease model rats.¹³⁸

2.5.1. Cannabinoids increase phasic dopamine firing¶

2-AG is synthesized “on demand” during increased activity and then increases the phasic release of dopamine. 2-AG has little effect on tonic dopamine release.
Stimuli that enhance the firing of DA cells (e.g., rewards) promote the mobilization of 2-AG and initiate a positive feedback loop that facilitates subsequent DA function and appetitive behavior.⁵
CB1R antagonists or 2-AG synthesis inhibitors do not impair the firing of dopaminergic neurons per se¹³⁹ or the dopamine increase in the nucleus accumbens per se³⁴, but limit the increase in dopaminergic firing caused by behavioral changes or medication.³⁵³²
CB1R antagonists inhibit the ability of dopaminergic drugs (e.g. cannabinoids, nicotine, ethanol, cocaine, amphetamine) to cause a high phasic dopamine release.^140125141

Exogenous cannabinoids such as THC and WIN55,212-2 increased phasic neuronal dopamine activity, the number of burst events and the number of impulses occurring per burst in the VTA^{33142 143} and increased extracellular dopamine in the nucleus accumbens¹⁴³

2.5.2. Cannabinoids increase tonic dopamine firing¶

THC and WIN55,212-2 increase dopamine levels in the nucleus accumbens via CB1R via increased tonic dopamine firing in the VTA.³³

2.6. 2-AG modulates integration of intrinsic and extrinsic dopaminergic inputs¶

Dopamine neurons of the substantia nigra pars compacta, the VTA and the retrorubal field integrate intrinsic and extrinsic inputs of sensory, motor and cognitive information to determine the highest reward probability.¹⁴⁴
2-AG is involved in the fine regulation of the excitability of dopamine neurons by modulating the strength of the synapses that hit them.¹⁴⁵¹⁴⁶

2.7. Inverted-U effect of endocannabinoids¶

Like catecholamines, endocannabinoids also exhibit an inverted-U mechanism of action. While medium doses increase sexual activity and motivation, higher doses lead to reduced motivation.⁹
Study results on the effects of cannabinoids must therefore be set in relation to the respective doses used.

2.8. GABA pathway¶

This paragraph is mainly based on the review by El Khoury et al.⁴

Normally, VTA dopamine neurons are subject to constant and significant inhibition by GABAergic inputs.³³
Endocannabinoids can inhibit GABA and thereby eliminate the GABA-mediated inhibition of the VTA dopamine neurons. as a result, the VTA dopamine neurons become more active.

CB1R can be found

• in high numbers on GABAergic interneurons in the hippocampus, amygdala and PFC.¹⁴⁷ Significantly fewer CB1Rs are found on glutamatergic, dopaminergic or cholinergic neurons than on primarily GABAergic projecting neurons. This shows the importance of the GABAergic influence of cannabinoids. For example, the CB1R agonist WIN55,212-2 reduces GABAergic neurotransmission in vitro by an order of magnitude more than glutamatergic neurotransmission.⁴
• moderately abundant in various cortical structures, especially in superficial and deep layers, presumably on GABAergic interneurons.^148149150 The same applies to endocannabinoids binding to CB1R (ARA, 2-AG and the AEA precursor N-arachidonoyl-phosphatidylethanolamine (NArPE).¹⁵¹

Cannabinoid agonists from midbrain dopaminergic neurons¹²⁵ inhibit GABA release via presynaptic CB1R, which subsequently increases the activity of dopaminergic neurons.¹²
The activation of⁴

• CB1R in GABAergic terminals disinhibits the network and increases glutamate
• CB1R in pyramidal neurons reduces glutamatergic activity

Due to the predominant expression of CB1R on GABA interneurons, cannabinoids increase the activity of pyramidal neurons in layers II and III⁴
In layer V, the CB1R-glutamate effect predominates, resulting in reduced selective excitatory outputs, leading to glutamatergic hypoactivity.⁴¹⁵²

The duration of CB1R-mediated plasticity is determined by different stimuli¹⁵³

• short-term GABAergic transmission inhibition by short-term postsynaptic depolarization via inhibition of voltage-gated calcium channels by CB1R¹⁴⁸¹⁵⁴
• long-term disinhibition of pyramidal cells in the CA1 hippocampus (eCB-dependent long-term depression, eCB-LTD) by intense high-frequency synaptic stimulation^{155154 156} via CB1R-mediated regulation of presynaptic protein kinase A (PKA) and the phosphatase calcineurin¹⁵⁷¹⁵⁸ .

The disinhibition of VTA dopamine neurons by endocannabinoids can be intrinsic or extrinsic:²³

• intrinsic by acting on GABAergic interneurons¹⁵⁹
  • GABAergic interneurons preferentially target GABA-A receptors located on DA neurons of the VTA¹⁶⁰
    • Interneurons targeting GABA-B-R do not appear to respond to endocannabinoids¹⁶¹
  • The GABA-A receptor antagonist bicuculline as well as the CB1R antagonist SR141716A (rimonabant) inhibit the excitatory effect of CB1R agonists HU-210 in vitro¹⁰⁶
  • The CB1R agonist WIN55, 212-2 inhibits IPSC (electrically evoked inhibitory postsynaptic currents) via the GABA-A receptor¹¹¹
    • The CB1R antagonist rimonabant prevents this inhibition.
• extrinsic via GABAergic afferents (inputs)¹⁵⁹⁸⁰
  • GABAergic afferents preferentially target GABA-B receptors¹⁶⁰
  • The CB1R agonist WIN55, 212-2 reduces the amplitude of GABAB-mediated IPSCs via CB1R
  • The origin of these VTA-GABA afferents is still unknown. They are conceivable:²³
    • Nucleus accumbens (mediates appetitive behavior via the integration of inputs from cortical and limbic structures)⁹
      • No direct influence of CB1R on MSNs of the NAc:²³ The MSNs of the nucleus accumbens do not project directly into the VTA via axon terminals to dopamine neurons (as previously assumed, which would directly inhibit dopamine activity), but the axons from the NAc mainly form synapses to non-DA neurons, but to neurons that have a fast inhibitory effect via GABA-A-R.¹⁶² In addition, MSNs of the NAc do not possess CB1Rs. In the NAc, CB1Rs are rather located on fast-spiking interneurons (FSI).¹⁶³
      • However, CB1R strongly inhibits MSN of the NAc via FSI in the NAc, which express CB1R. In addition, CB1R-FSI synapses on MSN of the NAc undergo LTD by endocannabinoids¹⁶⁴
    • ventral pallidum (involved in the differentiation of wanting, liking and reward expectation)¹⁶⁵⁹
      • GABA projections from the ventral pallidum modulate the neuronal firing of VTA dopamine neurons under cannabinoid control:¹⁶⁶
        • Endocannabinoids in the ventral pallidum reduced the neuronal activity of VTA dopamine neurons
        • The NMDA glutamate receptor antagonist phencyclidine increased the neuronal activity of VTA dopamine neurons
    • rostromedial tegmental nucleus (important for processing aversive and appetitive stimuli):²³¹⁶⁷
      • GABA projections from the RMTg modulate cannabinoid-controlled neuronal firing of VTA dopamine neurons
      • The RMTg receives dense, mostly glutamatergic inputs from the lateral habenula (which encodes aversive stimulation) and mediates the inhibitory effect of the lateral habenula on midbrain dopamine neurons. The RMTg neurons that project to the VTA form inhibitory synapses, so that activation of this input by electrical stimulation inhibits DA firing.
      • CB1R agonists inhibit the firing rate of RMTg-GABA neurons in a long-lasting manner by reducing the amplitude of excitatory postsynaptic currents. CB1R agonists significantly increase the paired-pulse ratio, suggesting that the CB1R agonist causes a reduction in glutamate release by activating presynaptic receptors. Inhibition of GABA neurons in the RMTg correlates with an increase in firing of VTA dopamine neurons.

The CB1R agonist THC activates dopamine. THC activates CB1R on GABA neurons, which inactivate the GABA neurons. This deactivates the GABA neurons, which inhibit the dopamine neurons. The dopamine neurons are thus less inhibited and therefore more active.^168169142
The CB1R agonist THC thus has a dopamine-increasing effect in the nucleus accumbens. Adenosine A2A receptor antagonists (e.g. caffeine) counteract this.¹⁷⁰
Pretreatment with the cannabinoid antagonist rimonabant (SR141716A) enhanced the locomotor activation induced by dopamine agonists¹³²¹⁷¹ , while CB1R antagonists alone did not induce activation.
THC also acts on CB2R.¹⁷²
Cannabinoid agonists inhibited the effects of cocaine¹⁷³
This indicates that CB1R has an inhibitory effect on motor activity.
Against this background, it seems conclusive that a reduced CB1R level correlates with hyperactivity and impulsivity.¹⁷⁴

2.9. Glutamate pathway¶

This section is mainly based on the review by El Khoury et al.⁴

Dopaminergic activity is modulated by glutamatergic projections, including those from the cortex and amygdala:¹⁷⁵

• indirect modulation inhibits dopamine release:
  • Glutamatergic inputs and dopaminergic projections converge on GABAergic striatal MSNs¹⁷⁶
• direct innervation increases dopamine release
  • cortical glutamatergic neurons transmit directly to VTA dopamine neurons
    The net effect of dopamine release is the sum of inhibition and increase.

Endocannabinoids from midbrain dopaminergic neurons¹²⁵ mediate presynaptic inhibition of glutamatergic transmission in dopamine neurons of the VTA via CB1R.⁵¹ CB1R activation causes a decrease in glutamate release, followed by a decrease in GABA activity, which in turn leads to an increase in firing of dopaminergic neurons.¹²¹⁷⁷

CB1R are found in glutamatergic and/or GABA-ergic synapses in cortical and subcortical structures.¹²
The acute increase of the dopamine level in the PFC by cannabinoids via VTA presumably occurs by means of a prior increase in glutamate release and/or inhibition of GABA. However, this view from 2002 still assumed that no CB1Rs are found on dopaminergic neurons.⁹⁵

Activation of CB1R on glutamatergic neurons reduces the probability of glutamate release, which has several Consequences:²³

• the excitatory glutamatergic inputs to dopamine neurons are reduced⁵¹, which limits their burst firing
• the inhibitory effect of GABA on dopamine neurons is reduced
  • Glutamate binds to (presumably GluN2A-¹⁷⁸
  • a lower release of glutamate reduces the inhibitory effect of dopamine
    Endocannabinoids can theoretically reduce the probability of glutamate release. In practice, however, this effect is limited because CB1Rs are more abundant on GABAergic terminals than on glutamatergic terminals¹⁷⁹. The simultaneous effect of reduced glutamate release and CB1R-induced activation of GABA neurons would reduce the number of tonically firing dopamine neurons, increasing the likelihood of bursts once NMDA receptors are activated.¹⁸⁰¹⁸¹ However, there are also other explanatory models¹⁸²

Interactions between glutamate, dopamine, cannabinoids and glutamate influence synaptic plasticity.⁴¹⁸³

Dopamine regulates long-term potentiation (LTP) as well as long-term depression (LTD)¹⁸³ in the striatum, PFC and VTA.
Stimulants modulate LTP and LTD in the PFC.¹⁸⁴¹⁸⁵
Glutamate regulates dopamine in the soma as well as on terminals of the VTA and substantia nigra. Deactivation of glutamatergic inputs in the VTA alters burst firing patterns in the VTA.¹⁸⁶
Endocannabinoids modulate the reciprocal regulation of dopamine and glutamate in the striatum and cortex at terminals.⁴

In the striatum:⁴

• Dopamine receptors
  • D1R promote striatal glutamatergic LTP^183187188
  • D1Rs inhibit AEA in D1-expressing MSNs¹⁸⁹, which increases glutamate release. CB1Rs counteract this by presynaptically reducing glutamate and postsynaptically inhibiting adenylyl cyclase (while D1Rs increase it), which counteracts LTP induction.¹⁸⁷
  • D2R promote striatal glutamatergic LTD^187190191
  • D2R and NMDA-NR2B form heteromers in the striatum.¹⁹²
  • Dopamine increases (via CB1R) the frequency of glutamatergic inputs in D1-expressing medium spiny neurons and decreases them (via CB1R) in D2-expressing MSNs.¹⁹³¹⁹⁴
  • D2Rs increase the synthesis and release of AEA in the striatum.¹⁹⁵ When AEA binds to presynaptic CB1R on glutamatergic terminals, this decreases glutamate. This could contribute to corticostriatal LTD.¹⁹⁶¹⁸⁷
• CB1R
  • CB1R attenuate ¹⁹⁷ (as well as D2R¹⁹⁸ ) cortical glutamate input and regulate corticostriatal LTD¹⁹¹
  • Other representation: CB1R act in the opposite direction to D2R.¹⁹⁹
    • Cannabinoid modulation of presynaptic glutamate release on neurons expressing Gi-coupled D2Rs appears to facilitate D2R-mediated inhibition, while CB1R activation in GABAergic terminals may counteract this inhibition.
  • the influence of CB1R appears to be stronger than that of TRPV1, which could also be due to the rapid desensitization of TRPV1²⁰⁰
• TRPV1
  • tRPV1 increase glutamatergic transmission presynaptically²⁰⁰ and promote striatal LTD¹⁹⁶
• Endocannabinoids promote LTD in D2-expressing MSN by binding to postsynaptic TRPV1¹⁹⁶

In the cortex:⁴

• Dopamine receptors
  D1R and D2R are colocalized in many cortical pyramidal neurons and interneurons.
  • D1R activate glutamate in the cortex²⁰¹
    • via postsynaptic intracellular Ca2+ and protein kinase A (PKA), independent of membrane depolarization
  • D2R inhibit glutamate in the cortex²⁰¹
    • indirectly via GABA interneurons
    • postsynaptically via phospholipase lipase C-IP3, intracellular Ca2+ and inhibition of PKA
  • GABA interneurons modulate glutamatergic plasticity and cortical functions²⁰²
  • Excitatory and inhibitory neuronal activity form a dynamic balance to map executive functions and goal-oriented behavior²⁰²
• Interneurons
  There are several types of cortical interneurons with different functions, only some of which contain CB1R.^1532034
  • CB1R are found on cholecystokinin-containing cortical interneurons²⁰²
  • Since CB1R is found on some fast-spiking (striatal)^{6869 70 71} parvalbumin-containing interneurons, an existence on cortical parvalbumin-containing interneurons is conceivable
• TRPV1
  • TRPV1 are strongly expressed in the cortex on pyramidal neurons.²⁰⁴
  • TRPV1 are also involved in synaptic plasticity in the hippocampus²⁰⁵ and striatum (see above).

Glutamate is also released from gliosomes in response to stimuli. CB1R increased, CB2R and TRPV1 decreased this glutamate release from gliosomes²⁰⁶

Cortical and subcortical glutamate circuits show different binding methods and consequently different effects:⁴
At corticostriatal MSN synapses, subcortical thalamostriatal glutamatergic projections enter at the same time.²⁰⁷
In the striatum, cortical and subcortical projections enter spatially clearly separated synapses. At the same time, the expression of presynaptic glutamatergic elements differs at cortical and subcortical terminals.²⁰⁸²⁰⁹

• cortical glutamatergic synaptic terminals:
  • express VGLUT1 ²⁰⁷ (changes have a long-term effect)
  • less than 5 % express mGluR1a ²¹⁰ (binding is acute)
• subcortical, especially thalamic glutamatergic terminals:
  • express VGLUT2 ²⁰⁷ (changes have a long-term effect)
  • more than 50 % express mGluR1a ²¹⁰ (binding acts acutely)

CB1R are found in the striatum on terminals of both cortical (VGLUT1-positive) and subcortical (VGLUT2-positive) axons.⁷⁶
Presynaptic D2Rs on corticostriatal terminals (VGLUT1-positive) inhibit inputs from the cortex without affecting VGLUT2-positive inputs of glutamatergic afferents from the ventral subiculum.²²¹

Endocannabinoids mediate LTD in the striatum²²² and in the cortex²²³ via mGluR5 activation.
mGluR of groups I and II such as D1R and D2R trigger LTD in the cortex via mitogen-activated protein kinases (MAP-K). MGluR activation with simultaneous strong dopamine input had a synergistic effect.²²⁴²²⁵
Acute cocaine administration inhibits endocannabinoid-mediated LTD by reducing surface expression of the functional mGluR5 receptor complex, possibly via D1R.²²⁶
Acute THC administration also inhibits endocannabinoid-mediated LTD. This can be reversed by activation of mGluR2/mGluR3 in corticostriatal glutamatergic terminals (where the receptors are co-expressed).²²⁷

Endocannabinoids, dopamine and mGluR5 receptors appear to interact for optimal synaptic plasticity
Plasticity of inhibitory transmission in the PFC (I-LTD) is regulated by endocannabinoids via mGluR5 activation and facilitated by D2R transactivation.³²²⁸
VTA-D2R in conjunction with group I - mGluR (mGluR1, mGluR5) induced endocannabinoid-mediated LTD and I-LTD in excitatory glutamatergic and inhibitory GABAergic synapses.²²⁸

2.10. Stimulants regulate dopamine via endocannabinoids¶

Amphetamine increases dopamine levels in the nucleus accumbens via an action potential-dependent mechanism that is modulated by endocannabinoids.³⁵
Stimulants such as cocaine^{229113 34} and nicotine ²³⁰ trigger 2-AG synthesis in the VTA. This suppresses GABAergic input, which disinhibits the dopamine neurons.⁵
The CB1 receptor antagonist rimonabant and the CB2 receptor agonist JWH133 prevented cocaine-induced hypermotor activity.²³¹
CB1R-KO mice do not experience behavioral stimulation by amphetamines.²³²

The TRPV1 agonist capsaicin increased the firing rate of VTA dopamine neurons in a dose-dependent manner and triggered bursts in almost half of them. This was mediated by enhanced glutamatergic transmission. Consequences were a simultaneous increase in pain stimulus-dependent dopamine release in the nucleus accumbens.⁶⁴

Methylphenidate and MPH-induced increase in dopamine decreased AEA and 2-AG in the limbic forebrain of mice¹⁸⁹

3. Dopamine regulates endocannabinoids¶

Intense neuronal activity leads to the synthesis and release of endocannabinoids. During phasic dopamine bursts, which release significant amounts of dopamine, endocannabinoids are produced by activated enzymes (e.g. DAGL, NAPE) and subsequently released extracellularly by passive diffusion through the cell membrane.⁴³

Dopamine neurons in the midbrain⁹

• synthesize endocannabinoids
• release endocannabinoids⁵¹
• possess CB1R on their own axon terminals
• break down endocannabinoids and endocannabinoid relatives

Dopamine appears to increase the release of endocannabinoids via D2 receptors, which subsequently bind retrogradely to the CB1R

• in the VTA⁵¹
• in the striatum (AEA increased)¹⁹⁵¹³²
• Levodopa caused an increase in AEA in the basal ganglia via D1R and D2R. In rats with dopaminergic and noradrenergic neurons destroyed by 6-OHDA, levodopa did not alter endocannabinoid levels.²³³

AEA in turn inhibits the reactions mediated via D2R.²³⁴

4. Endocannabinoid-dopamine-adenosine interaction¶

The D2 agonist quinpirole induces hyperlocomotion. This is inhibited by CB1R agonists. CB1R inhibition was blocked by the A2AR antagonist MSX-3 as well as by the CB1R antagonist rimonabant.²³⁵
CB1R in caudate and putamen form heteromers with adenosine A2A receptors. CB1R-mediated motor inhibition in the striatum is fully dependent on A2AR activation (in the form of CB1R-ADA2 heteromers) and is abolished by A2AR antagonists. This interaction could be regulated by CB1R-D2R-A2AR heteromultimers²³⁵

5. Endocannabinoids regulate synaptic plasticity¶

General information on synaptic plasticity at Synaptic plasticity: learning and unlearning in the article Neurological basics.

5.1. Short-term plasticity¶

5.1.1. Depolarization induces suppression of inhibition (DSI) or excitation (DSE)¶

Depolarization caused by strong activation (repeated action potential or a step depolarization) induces a transient suppression of inhibition (DSI) or excitation (DSE) in many neurons.²³⁶
This inhibition suppression lasts for a few dozen seconds.
Endocannabinoids, especially 2-AG; are an important retrograde messenger for DSI and DSE in the hippocampus, cerebellum and other brain regions.²³⁶ The sex-dependent differences in DSI strength in Lister Hood rats did not result from the number or function of CB1R (activated by 2-AG), but rather from tonic 2-AG signaling²³⁷
Endocannabinoids regulate DSI more strongly than DSE.²⁴³

5.1.2. Metabotropic-induced suppression of inhibition (MSI) or excitation (MSE)¶

Metabotropic (by means of a metabolic process) induced suppression of inhibition (MSI) or excitation (MSE) are forms of short-term synaptic plasticity²³⁶

Endocannabinoids induce MSI / MSE after the activation of a postsynaptic Gq/11-linked GPCR and the activation of a phospholipase Cβ. Phospholipase C produces diacylglycerol. This is deacylated to 2-AG by the diacylglycerol lipase. The 2-AG diffuses towards the presynapse and binds to CB1R, which inhibits synaptic transmission.¹⁴⁸
The calcium sensitivity of PLCβ1 leads to a synergistic interaction of DSI/DSE and MSI/MSE²³⁶

5.2. Long-term plasticity¶

5.2.1. Long-term potentiation (LTP)¶

Long-term potentiation (LTP) is a universal form of long-lasting strengthening of synaptic connections.

5.2.2. Long-term depression (LTD)¶

Long-term depression (LTD) is a universal form of prolonged reduction in synaptic connections.
There are homosynaptic LTD and heterosynaptic LTD. For an introduction, see Synaptic plasticity: learning and unlearning in the article Neurological basics.

Endocannabinoids can trigger homosynaptic, heterosynaptic or autaptic LTD.²³⁶²³⁸ Heterosynaptic LTD by endocannabinoids at inhibitory synapses in the hippocampus appears to require inhibition of adenylyl cyclase and involvement of the presynaptic proteins RIM1α and RAB3B. Endocannabinoid LTD at inhibitory synapses increases dendritic excitability, which enhances excitatory transmission in a narrow spatial range.
Endocannabinoid-mediated LTD appears to be involved in the maturation of cortical circuits and may occur with or without the involvement of CB1R.{Lu HC, Mackie K (2016): An Introduction to the Endogenous Cannabinoid System. Biol Psychiatry. 2016 Apr 1;79(7):516-25. doi: 10.1016/j.biopsych.2015.07.028. PMID: 26698193; PMCID: PMC4789136. REVIEW}}
According to another account, CB1R in glutamatergic terminals of the PFC projecting to the NAc are indispensable for LTD.²³⁹ CB1R-KO mice showed no LTD at corticostriatal synapses¹⁹¹ and exhibit impaired habit formation and increased exploratory behavior.²⁴⁰ Similarly, FOXP2 is required for LTD and FOXP2-KO mice and blackbirds show disorders in LTD and learning.²³⁹ Both CB1R and FOXP2 are candidate genes in ADHD.
Autaptic LTD: autaptic neurons exhibit both endocannabinoid-mediated DSE and MSE. Autaptic LTD is dependent on CB1R, whereby autaptic LTD is not induced via the G(i/o) or G(s) proteins typically activated by CB1R, but via G(q) proteins²³⁸

5.2.3. Slow self inhibition (SSI)¶

Slow self-inhibition (SSI) is a process that suppresses neuronal excitability. SSI occurs mainly in low-threshold spiking cortical interneurons and cerebellar basket cells, but also in some main cortical cells.²³⁶
Endocannabinoids, in particular the synthesis of 2-AG during intense stimulation of the neuron, leads to activation of somatic CB1R and somatic potassium conductance, probably an inwardly rectifying potassium channel, and causes SSI.²⁴¹²⁴²