Psychotomimetic drugs PDF

Preview

Summary

Download Psychotomimetic drugs PDF

Description

Psychotomimetic drugs Cross tolerance between mescaline and LSD – suggests both psychotomimetics act at the same class of receptor site LSD and mescaline structures like 5HT Early in vitro pharmacological studies showed that  

LSD interacts with 5HT receptors in the peripheral vasculature In the periphery it acts as a 5HT2 receptor antagonist

But – LSD decreases 5HT metabolite levels when administered to rats 

In the brain it acts as a 5HT receptor agonist/partial agonist

Effect of LSD on perception suggests it alters transmission in sensory pathways 1. Direct, modality specific pathway  primary somatosensory cortex 2. Reticular formation indirect pathway non-specific arousal  association cortex LSD alters perception  

LSD decreases firing rate of raphe neurones (5HT1A receptor) Raphe neurones send extensive projection to the forebrain

But other classes of hallucinogens did not all exert this effect e.g. mescaline - Lesioning the raphe nucleus in rats: they can still discriminate between saline and LSD   

LSD increases activity in locus coeruleus neurones LSD increases activity of subsets of neurones in the cortex 5HT2A receptors are present in temporal and pre-frontal cortex, and thalamus o Nb. Thalamus processes somatosensory inputs and receives afferents from locus coeruleus

Key points: 1. 2. 3. 4.

LSD extremely potent hallucinogen Structure and its effect on 5HT turnover suggests it acts as an agonist of brain 5HT receptors Distortion of sensory perception indicates an effect in pathways that process sensory info Interest has focused on noradrenergic (LC) input to the thalamus and cortex

LSD exert effects through 5HT2A receptors 

  

If 5HT2 receptor mediates hallucinogenic action of LSD then most potent hallucinogens should have the highest affinity for 5HT2- weakest hallucinogen should have the lowest affinity for 5HT2 [experiment] 5HT2A receptors are highly expressed in cortex: on pyramidal neurones LSD increases activity of layer V pyramidal neurones in cortex Imaging studies indicate increased cortical activity in humans

Psychotomimetic drugs Phencyclidine (PCP) 

‘dissociative’ anaesthetic – same class as ketamine

 

Causes catatonic-like state without muscle relaxation Withdrawn from clinical use due to ‘emergence’ phenomenon

Effects of PCP in controlled studies -

Altered body image, Feeling of isolation, Euphoria and inebriation Exacerbated symptoms of psychotic patients PCP intoxication associated with drug-induced hallucination

Radioligand binding studies have shown that PCP interacts with 2 main classes of receptor 1. Sigma opiate receptor – modulates NAdr release 2. PCP is a non-competitive antagonist of the NMDA (glutamate receptor) Hallucinogenic drugs as models for schizophrenia -

Both LSD and PCP have been used in animal studies as drug-induced models for schizophrenia

PSYCHOACTIVE DRUGS AND ADDICTION Drugs acting on catecholamine neurotransmission: cocaine Actions of cocaine 1. Local anaesthetic (blocks voltage gated NA channels) 2. Causes euphoria 3. Appetite suppressant 4. Increasing dose can elicit tremors, convulsions, CNS depression 5. In susceptible individuals cocaine may precipitate toxic psychosis

high affinity uptake cocaine

catecholamine neurotransmitter Addictive properties provide insight into biochemical basis for motivation and reward

Amphetamine -

-

-

-

First synthesised from ephedrine sympathomimetic amine Actions of amphetamine o Appetite suppressant o Causes euphoria o Raises blood pressure Used for: weight control, narcolepsy, attention deficit disorder Can also cause psychosis Amphetamine is an indirect sympathomimetic – stimulates the release of catecholamines

high affinity uptake AMPH

MDMA ‘ecstasy’

DA

catecholamine neurotransmitter

Addiction “persistent disorder of brain function in which compulsive drug use occurs despite serious negative consequences for the afflicted individual -

Physical and psychological dependence can occur Compulsion to take drug ‘withdrawal’ syndrome – opposite effects to those experienced in presence of drug Tolerance – decreased response to repeated administration

Psychotomimetic drugs with abuse potential have common actions on the limbic system of the brain -

Ventral tegmental area Nucleus accumbens

Reward - Inappropriate activation of these systems underlies addictive behaviour A psychological framework for reward and addiction

Experimental evidence of reward pathway -

Evidence provided from animal behavioural experiments conducted by James Old Rats implanted w/ stimulating electrodes in the reticular formation When rat enters shaded are a stimulus is delivered to the electrode In some experiments the animals repeatedly returned to the shaded area = Rewarding stimulus – this behaviour is called REINFORCEMENT In these animals the electrode was placed in the medial forebrain bundle

Operant chamber – allows rat to self-deliver either a stimulus or drug by pressing a lever -

-

Studies showed that rats would self-administer a stimulus if the electrode was placed in the medial forebrain bundle i.e. reinforcement This contains a mixture of axons, but the dopamine containing neurones seem to be crucial for reinforcement o Spiroperidol (DA antagonist blocks reinforcement) o 6-OH-DA lesions block reinforcement Rats will also self-administer cocaine or amphetamine

Dopamine – Noradrenaline – 5HT These pathways  originate in the midbrain/medulla  project anteriorly to innervate areas throughout the brain  are implicated in mood & behaviour

Therefore, the ‘reinforcing system’ seems to involve dopamine axons in the medial forebrain bundle: these axons project to the nucleus accumbens Reward pathway – MFB is a dopamine pathway in the brain Cocaine binds w/ high affinity to monoamine, including dopamine, transporters Role of the dopamine transporter: Evidence from mice ‘knock outs’  mice with DA transporter knockout have chronically elevated synaptic dopamine  cocaine administered to these animals produces no change in baseline DA (also no change in locomotor activity)  nonetheless these animals will self-administer cocaine – therefore may be another ‘reinforcing stimulus’ other than DA study – abolished cocaine reward in mice with a cocaine insensitive dopamine transporter  F105 important for high affinity cocaine binding, but not for DA transport  Generate mouse ‘knock in’ for mutant DAT Role of dopamine transporter  Cocaine in the mutant DAT knock-in mice DID NOT

Elevate extracellular dopamine Increase locomotion The knock in mice insensitive to the neuropharmacological actions of cocaine as predicted  Used conditioned-place preference test to assess reinforcing properties of cocaine [?] o 2 chambers o w/ saline and drug o o o

Key points  Pathways - evidence for common involvement of o limbic system o dopamine signalling especially the VTA (ventral tegmental area) projection to the nucleus accumbens  neurotransmitters – evidence for involvement of o dopamine in the action of cocaine (direct) Alcohol and alcohol use disorder – dopamine a common factor in drugs w/ abuse potential  Ethanol increase DA release in the nucleus accumbens o Evidence for altered dopamine signalling in addiction  18Flouromethylspiroperidol to label dopamine receptors in PET imaging studies on human subjects [pic]  DA receptor antagonist block ethanol self-administration in animal models  Opiates, nicotine, cocaine, amphetamine also increase dopaminergic transmission in the limbic system  But not for aversive drugs  Key paper: Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats [?] Addiction pathway – common adaptation in the limbic circuitry following chronic drug exposure Some imaging studies report a decrease receptor density for DA receptors in cocaine abusers – this may compromise the reward system and produce drug craving – similar observations for different drugs of abuse Long-term changes associated with addiction Animal studies suggest changes in gene expression

↑ DA  ↑ cAMP  CREB  Immediate early gene expression  This may alter levels of receptor expression e.g. changes in dopamine receptors Genetic basis for drug addiction … ALDH2, D2, OPRM1

Interaction of addictive drugs w/ reward pathway: Addictive drugs activate the dopamine pathway in the brain Simple

Complex

But addiction is more than a reward  Impulsive stage  compulsive stage  USEHEAVY USEEARLY DEPENDENCELATE DEPENDENCE Evidence for compromised reward system in addicts Alcohol dependence in a rat ‘model’- msP alcohol preferring rats  Innate/acquired hyperactivity of extrahypothalamic CRF systems is associated with high alcohol preference [?]

Summary Psychotomimetic drugs exert their actions through distinct molecular effectors Subclasses of psychotomimetic drugs with addictive potential share the capability to cause neuroadaptive responses in the limbic circuitry of the brain Currently the evidence suggests that altered signalling in the 'reward' circuitry of the brain underpins the phenomena of drug addiction, especially in the dopaminergic pathway from the VTA to the nucleus accumbens (but it’s not just about dopamine and reward)...