Neuropharmacology of CNS disorders - Psychoactive Drugs PDF

Neuropharmacology of CNS disorders - Psychoactive drugs Dr Emily Brookes [email protected] Summary Potential sites of action for LSD LSD: decreases firing rate of...

Neuropharmacology of CNS disorders - Psychoactive drugs Dr Emily Brookes [email protected] Summary Potential sites of action for LSD LSD: decreases firing rate of raphe neurons increases activity in locus coeruleus neurons increases activity of layer V pyramidal neurons in the cortex expanded primary visual cortex functional connectivity Herian, M. (2022) https://doi.org/10.1007/978-3-030-67928-6_1 Other classes of psychotomimetic drugs Phencyclidine (PCP) is a ‘dissociative’ anaesthetic Same class as Ketamine Causes a catatonic-like state without muscle relaxation Withdrawn from clinical use in 1965 due to ‘emergence phenomenon’ Phencyclidine (PCP) Luby et al., 1959 administered sub-anaesthetic dose in clinic: Altered body image "my arms and legs feel distant’ Feeling of isolation Cognitive disorganization Drowsiness and apathy Negativism and/or hostility Euphoria and inebriation Hypnagogic (dreamlike) states Exacerbated symptoms of psychotic patients PCP intoxication associated with drug-induced hallucinations How does PCP alter perception? Radioligand binding studies have shown that PCP interacts with: Sigma opiate receptor - modulates NAdr release NMDA glutamate receptor (non-competitive antagonist)  Psychedelics in disease modelling Both LSD and PCP have been used in animal studies as drug-induced models for schizophrenia Crunfli et al 2022. https://doi.org/10.1007/978-3-030-97182-3_2 Psychoactive drugs and treatment In Australia and New Zealand: Since 1 July 2023, psychiatrists can be authorised to prescribe products containing: Psilocybin may be prescribed for use in psychedelic- assisted psychotherapy for treatment-resistant depression. Reviews: doi: UK POST https://doi.org/10.1136/bmj-2022-07382 DOI: https://doi.org/10.58248/RR16 3 doi: 10.1111/ejn.16421. DOI: 10.1097/YCO.0000000000000946 Psychoactive drugs So far … Hallucinogens and how this may inform understanding of psychoses Now... Cocaine and how this may inform understanding of addictive behaviours and substance use disorder (SUD) Addiction " persistent disorder of brain function in which compulsive drug use occurs despite serious negative consequences for the afflicted individual” Neuroscience 3rd edition eds Purves p 134-135 Physical and psychological dependence can occur Features of disease: Compulsion to take drug Tolerance (decreased response to repeated administration) Withdrawal syndrome (opposite effects to those experienced in presence of drug)  Addiction and the limbic system Psychoactive drugs with abuse potential have common actions on the limbic system of the brain Amygdala Ventral tegmental area Nucleus accumbens Billes et al., 2014 Addiction and reward Reward - pleasurable experience Selection of behaviours appropriate for survival is achieved by ‘reward’ and ‘punishment’ systems These systems are fundamental to motivation and avoidance Inappropriate activation of these systems underlies addictive behaviour A psychological framework for reward and addiction neural circuit neural circuit food that detects that controls stimulus + behaviour Addictive reinforcing drugs system reinforcing stimulus behaviour e.g. eating Where are the reward centres in the brain? James Olds and Peter Milner (1954) Rat implanted with stimulating electrodes, self- administer (ICSS) “The results indicate that various places exist in the brain where electrical stimulation is rewarding in the sense that the experimental animal will stimulate itself in these places frequently and regularly for long periods of time if permitted to do so.” Septal area (medial forebrain bundle) The behaviour is called REINFORCEMENT  What are the reward pathways in the brain? Medial forebrain bundle contains a mixture of axons that originate in the midbrain/medulla, and project anteriorly to innervate areas throughout the brain including: 5-HT axons from raphe neurons Noradrenergic axons from locus coeruleus neurons Dopaminergic axons from ventral tegmental area Fenoy et al., 2022 https://doi.org/10.1038/s41380-021- 01100-6 What are the reward pathways in the brain? Reinforcement blocked by: spiroperidol (DA antagonist) 6-OH-DA lesions  What are the reward pathways in the brain? Optogenetic stimulation of dopamine neurons drive ICSS Witten et al., 2011 https://doi.org/10.101 6/j.neuron.2011.10.02 8  What are the reward pathways in the brain? Therefore the ‘reinforcing system’ seems to involve dopamine axons in the medial forebrain bundle These axons project to the nucleus accumbens Fenoy et al., 2022 https://doi.org/10.1038/s41380-021- 01100-6 Addiction and reward In operant chambers, rats will also self-administer cocaine or amphetamine – reinforcement behaviour Cocaine Stimulant and also local anesthetic Anesthetic action through blocking voltage-gated sodium channels  Actions of cocaine Local anaesthetic Causes euphoria Appetite suppressant Increasing the dose can elicit tremors, convulsions, CNS depression In susceptible individuals, cocaine may precipitate psychosis Addictive properties provide insight into biochemical basis for motivation & reward Cocaine affects catecholamine neurotransmission Cocaine blocks high affinity transporter on presynaptic terminal Prevents recycling of catecholamines Increased levels of catecholamine in synaptic space De Rubeis et al., 2019 https://doi.org/10.1148/ryct.2019180031 Cocaine and reinforcement Cocaine binds with high affinity to monoamine, including dopamine, transporters Is there evidence for the involvement of specific transporters in the reinforcing properties of cocaine? Conditioned place preference task McKendrick & Graziane, 2020 review https://doi.org/10.3389/fnbeh.2020.5 82147 Cocaine and reinforcement Giros et al 1996 https://doi.org/10.1038/37960 Mice with DA transporter knockout have chronically elevated synaptic dopamine and increased locomotor activity o cocaine administered to these animals produces no change in base-line DA (also no increase in locomotor activity) o BUT these animals will self-administer cocaine, and display conditioned place preference (CPP) to cocaine... ‘reinforcing stimulus’ other than DA Consider - animals have developed with synaptically elevated DA Cocaine and reinforcement Mice with cocaine-insensitive DA transporter knock-in o F105 important for high affinity cocaine binding, but not for DA transport Cocaine in the mutant DAT knock-in mice o did not elevate extracellular dopamine or increase locomotion o did not produce reinforcement as measured by CPP Chen et al., 2006 doi: 10.1073/pnas.0600905103 Cocaine and dopamine in humans PET imaging with 11C- raclopride to label D2 receptors Downregulate D2 receptors in cocaine abusers Volkow et al 2004. Reward system https://doi.org/10.1038/ sj.mp.4001507 compromised Maintained after detoxification Volkow et al 1993 doi: 10.1002/syn.890140210 Reproduced in doi.org/10.1007/978-3-540-68706-  Cocaine and dopamine in humans D2 receptor density age years