This review (2022) explores the ability of 5-HT2a receptor agonists (most classic psychedelics) to treat substance use disorders. The authors propose that the role of these receptors in BDNF dependent plasticity in the ventral tegmental area (VTA) of the dopamine system may offer a neurobiological explanation as to how 5-HT2a receptors exert their anti-addiction effects.

Abstract

“Aberrant glutamatergic signalling has been closely related to several pathologies of the central nervous system. Glutamatergic activity can induce an increase in neural plasticity mediated by brain-derived neurotrophic factor (BDNF) in the ventral tegmental area (VTA), a nodal point in the mesolimbic dopamine system. Recent studies have related BDNF dependent plasticity in the VTA with the modulation of aversive motivation to deal with noxious environmental stimuli. The disarray of these learning mechanisms would produce an abnormal augmentation in the representation of the emotional information related to aversion, sometimes even in the absence of external environmental triggers, inducing pathologies linked to mood disorders such as depression and drug addiction. Recent studies point out that serotonin (5-hydroxytryptamine, 5-HT) receptors, especially the 2a (5-HT2a) subtype, play an important role in BDNF-related neural plasticity in the VTA. It has been observed that a single administration of a 5HT2a agonist can both revert an animal to a non-dependent state from a drug-dependent state (produced by the chronic administration of a substance of abuse). The 5HT2a agonist also reverted the BDNF-induced neural plasticity in the VTA, suggesting that the administration of 5-HT2a agonists could be used as effective therapeutic agents to treat drug addiction. These findings could explain the neurobiological correlate of the therapeutic use of 5HT2a agonists, which can be found in animals, plants and fungi during traditional medicine ceremonies and rituals to treat mood-related disorders.”

Authors: Hector Vargas-Perez, Taryn E. Grieder & Derek van der Kooy

Summary

Aberrant glutamatergic signaling has been closely related to several pathologies of the central nervous system, including depression and drug addiction. Serotonin (5-HT) receptors play an important role in BDNF-induced neural plasticity in the ventral tegmental area (VTA), and could be used as effective therapeutic agents to treat drug addiction.

Accessed 13 December 2021

Addiction; psychedelic; glutamate; VTA; BDNF; Hallucinogen

Introduction

Aversive motivation is the capacity to avoid potentially noxious, punishing, or life threatening stimulus. This is why people use substances of abuse for negative reinforcement.

The monoamine theory of mood disorders states that a functional deficiency of biogenic amines at critical synapses in the brain causes mood related disorders. A new theory proposes that changes in cortical and hippocampal plasticity cause chronic aversive state.

Animal models have shown that the neurotrophin Brain-derived neurotrophic factor (BDNF) regulates synapses and neurogenesis, and that a decrease in BDNF levels is related to aversive motivation. However, increased levels of BDNF have been associated with multiple pathologies where inflammation occurs, including neuropathic pain, epilepsy, and drug dependency.

Hallucinogens, such as Psilocybin, DMT, Bufotenin, LSD-25 and Mescaline, have an ancient history of medical use, and can be used safely to treat a range of psychiatric conditions related to aversive motivation, such as end-of-life anxiety, drug addiction, obsessive-compulsive disorder and depression. Recent experimental evidence suggests that classical hallucinogens could be acting as a pharmacological agent with high specificity to effectively treat aversive motivation, promoting neural plasticity in the frontal cortex and hippocampus, and reducing BDNF-related increased plasticity in the mesolimbic system.

Evidence points to negative reinforcement as being the motivationally prepotent element of the withdrawal syndrome, and that BDNF-related increased plasticity in the mesolimbic system, mainly in the VTA, plays an important role in the activation of aversive motivation related to withdrawal from a high impact hedonic stimulus. The text addresses the mechanisms of the neurobiological correlate of the therapeutic use of 5HT2a agonists in both reversing and preventing substance abuse disorder associated with BDNF-related exacerbated plasticity in the VTA during drug withdrawal.

The opponent process theory of motivation

Negative reinforcement is a powerful motivational influence on drug use, and the escape from a rewarding stimulus can trigger an aversive motivational state.

The opponent theory suggests that an organism’s reaction to a stimulus is countered by a reaction to the stimulus in order to maintain the system in a basal state of dynamic equilibrium, or homeostasis.

The system produces a primary reaction (a-process) to a stimulus, but counteracts this reaction by producing a second reaction (b-process), which is opposite in direction to the initial response, slower to initiate and longer lasting than the stimulus.

The theory of the opponent processes states that the emotional response to the administration of a drug of abuse follows the course established by the theory of the opponent processes, which results in an intake of the drug of such magnitude that it interferes with vital functions.

An excessive demand for the homeostasis response endsanger the balance of the affected system, which requires the participation of extra regulatory mechanisms, which induce and maintain a new equilibrium state of the organism, which has been labeled an allostatic state.

Neural plasticity in the ventral tegmental area and its relationship with drug withdrawal

For approximately the last century, the ventral tegmental area (VTA) was recognized as a nodal point for stimuli related to motivation. However, many studies have shown that the VTA is not necessary for gratification, and individuals who are drug naive do not experience gratification through dopamine signaling. The VTA dopamine system is switched to the TPP reward system when the withdrawal response is reduced by the administration of the drug.

The VTA GABA-A receptor changes its function from inhibitory to excitatory, and this is required for the switch to work. When animals are naive, activation of GABA-A receptors results in an inhibitory conductance mediated by Cl – influx, and inactivation of the VTA dopaminergic system. When animals become drug-dependent, the opposite occurs. BDNF, a neurotrophic substance involved in stimulating the growth, survival and differentiation of neurons, may reduce the levels of the potassium-chloride co-transporter KCC2, thereby increasing the intracellular chloride concentration and making the neuron’s membrane potential more positive, or depolarized, relative to the resting membrane potential.

BDNF levels in the VTA can be elevated due to chronic stress or intense acute stress, and in general, by any event related to inflammatory processes.

BDNF plays a fundamental role in the integration and consolidation of aversive motivational information. Consequently, an uncontrolled increase in BDNF secretion would lead to an increase in the representation of aversive stimuli and even the generation of aversive states (withdrawal) in the absence of the drug.

BDNF regulates the signaling of glutamate, the main excitatory neurotransmitter in the brain, and the imbalance of this signaling is related to various pathologies, including depression, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and epilepsy.

Classic hallucinogenic substances for the treatment of drug withdrawal

Recent findings show that psilacetin prevents and reverses exacerbated BDNF-related plasticity in VTA GABAergic neurons, which would release the inhibitory dopaminergic signaling on the mesolimbic system and relieve negative symptoms associated with aversive motivation.

The serotonin (5-HT) receptor type 2A (5-HT2A) may regulate the expression of BDNF in the ventral tegmental area (VTA) by modulating the function and expression of glutamate receptors.

Psilacetin, a hallucinogen substance, binds to the serotonin 5-HT2A receptor and causes a psychedelic effect. It can also reverse the dependent state induced by the infusion of BDNF in the VTA and block the aversion associated with drug withdrawal.

Psilacetin, a 5-HT2A agonist, can prevent the effects of abstinence from the chronic administration of a drug even if it was injected one day before starting the treatment to induce dependence.

5-HT2A agonists act by restoring the changes induced by BDNF signaling, and may also act in concert with glutamate receptors to inhibit aberrant signaling.

Recently, it has been observed that 5-HT2A agonists restore normal mitochondrial metabolism trough the action of the sigma-1 receptor (Sig-1 R), which may be related to aversive motivation during drug dependent state.

5-HT2A receptors may also regulate NMDA-like glutamate receptors, which are directly related to learning and depression. Agonists of NMDA receptors produce short-term relief of symptoms, while agonists of 5-HT2A receptors produce long-term effects.

5-HT2A receptors are increased in several pathologies, including depression and substance use, and are also increased in the VTA of rats exposed to cocaine. The use of hallucinogenic substances decreases the production of 5-HT2A receptors, thus reversing the increase associated with pathological states.

5-HT2A agonists have been used for more than 40 years as therapeutic agents against addiction. Recent studies have shown that LSD and Psilocybin can reduce alcohol and tobacco use in addicted populations for more than 6 months.

Observational data suggest that Ibogaine and Ayahuasca have promising results in the treatment of various addictions, and that Ketamine may be useful for treating some mental health disorders, including drug use and depression. However, 5-HT2A agonists must be used in an environment conducive to healing.