12.1. Dissociatives: History, neurobiology, glutamate transmission

PCP

synthesized as potential anesthetic agent

PCP problem: Did not provide relaxed anesthetic state

Trance-like state with vacant facial expression, fixed and staring eyes, and maintenance of muscle tone

PCP problem: Postoperative issues

- Agitation instead of relaxation

- Blurred vision, dizziness, mild disorientation

- More serious: hallucinations, severe agitation, violence

PCP: Recreational use

- Schedule II

- Low levels of abuse, mostly regarded as unpleasant.

PCP recreational use form: Powder or pills

Taken orally, snorted, i.v., or smoked

PCP recreational use form: Liquid

Tobacco or marijuana cigarettes dipped in a liquid containing PCP and embalming fluid (!)

Ketamine synthesized as a safer alternative to PCP:

Less potent and shorter acting

Ketamine: Medical use

- Still used as a valuable anesthetic for certain medical procedures (procedural sedation in children) and veterinary procedures

- Some postoperative adverse reactions

Ketamine (esketamine)

nasal spray is approved for depression treatment.

- Rapid results (2 hours)

- FDA approved ketamine for Treatment-resistant depression

Major depression with suicidal thoughts and behavior

Ketamine: Recreational use

-ketamine use and abuse much greater than PCP

-liquid: injectable liquid

-powder or pills: powder for snorting or compress into pill

Ketamine: Acute effects- Low (sub-anesthetic) doses

- Feeling of being detached from body, sensations of floating, numbness, dreamlike state

- Euphoria

- Cognitive disorganization

Ketamine: Acute effects- Higher (sub-anesthetic) doses

Dissociative: loss of all mental contact with environment

- detachment

Ketamine: Negative effects of chronic use

- ketamine bladder syndrome

- memory and cognitive impairments.

- Gray and white matter abnormalities

Dextromethorphan: Medical use

- Dextromethorphan (DM) cough suppressant

- substitute for codeine

Dextromethorphan: Recreational use

Also used recreationally: At high doses acts as a dissociative anesthetic

Dextromethorphan Effects at high doses

Impaired balance, hallucinations, intoxication, euphoria, cognitive impairment, dissociation, delusions

Another cough syrup (promethazine/codeine) is also abused.

Opioid agonist (codeine) + promethazine (antihistamine, anticholinergic, NMDA antagonist...)

Salvinorin A is the psychoactive ingredient in Salvia divinorum

- Chew, smoke, through sublingual/buccal absorption (inactivated in GI tract).

- Low toxicity; low abuse potential.

What is Salvinorin A?

The most potent naturally-occurring hallucinogen.

How long do the effects of Salvinorin A last when smoked?

The effects are short-lasting, typically over in 8 minutes.

What are some acute effects of Salvinorin A?

Speech and coordination effects.

What types of experiences can Salvinorin A induce?

Out-of-body experiences and hallucinations.

Does Salvinorin A act on 5-HT2A receptors?

No, it has no actions at 5-HT2A receptors.

What are the similarities between Salvinorin A and psychedelics?

There are some similarities, but Salvinorin A does not act on 5-HT2A receptors.

Pharmacodynamic actions- PCP, ketamine, & dextromethorphan:

- Noncompetitive antagonists for NMDA glutamate receptor (different binding site than glutamate)

DA and non-DA mechanisms of reinforcement

Pharmacodynamic actions- Salvinorin A:

Agonist at kappa (κ) opioid receptor (KOR)

What type of neurotransmitter is glutamate?

Glutamate is an excitatory amino acid neurotransmitter.

What is the major function of glutamate in the nervous system?

It is the major transmitter for fast excitatory signaling.

Where is glutamate found in the brain?

Glutamate is found throughout the brain.

What is the precursor to glutamate?

The precursor to glutamate is glutamine.

How is glutamate synthesized from glutamine?

Glutamine is converted to glutamate via the enzyme glutaminase.

Glutamate: Synaptic transmission

Packaged into vesicles by VGLUT1, 2, 3

- Inactivation primarily via uptake transporters: EAAT 1-5 (excitatory amino acidtransporters; in neurons and glia)

Three ionotropic receptors for glutamate.

Each comprised of 4 subunits

- AMPA receptor

- Kainate receptor

- NMDA receptor

What two substances are required for NMDA receptor activation?

Binding of both glutamate and a co-agonist

What process removes magnesium (Mg2+) from the NMDA receptor?

Depolarization

What role do AMPA receptors play in NMDA receptor activation?

Glutamate acting at AMPA receptors causes necessary depolarization.

What is the function of the PCP binding site on the NMDA receptor?

It is a site for noncompetitive antagonists.

Glutamate: Metabotropic receptors

Eight metabotropic receptors (GPCRs) for glutamate

Glutamate: Functional roles

- Glutamate is important for synaptic plasticity, learning and memory,

- AMPA and NMDA receptors: Important role in synaptic plasticity(long-term potentiation, LTP).

Ketamine: Reward mechanism

- Ketamine is self-administered by animals: DA release in nucleus accumbens

- lower addiction liability

What type of receptor does Salvinorin A selectively agonize?

Kappa opioid receptor (KOR)

How does Salvinorin A differ from other KOR agonists?

Salvinorin A is rewarding and hallucinogenic, while other KOR agonists are aversive and not hallucinogenic.

What behavioral effects does Salvinorin A have in animals?

It is rewarding (conditioned place preference) and reinforcing (self-administration).

What can block self-administration of Salvinorin A?

KOR antagonist and CB1 antagonist.

Salvinorin A: Psychedelic effects

Salvinorin A decreases activity in the default mode network (DMN) in humans, like classical psychedelics.