Lecture 6 – amino acid NTs GABA Glutamate

Amino acid NTs GABA (gamma-aminobutyric acid) – the principal inhibitory NT, found throughout the brain and spinal cord glutamate (also called glutamic acid) – the principal excitatory NT, found throughout the brain

Glutamate the principal excitatory NT in the brain - used in about 20% of synaptic connections between neurons MSG = monosodium glutamate some people experience mild neurological symptoms (dizziness, numbness) after eating food containing high levels of MSG

Glutamate there are different sub-types of glutamate receptor, but the most studied is the NMDA (N-methyl-D-aspartate) receptor - important role in learning & memory – responsible for initiating long-term changes in the brain associated with memory formation, also implicated in drug addiction (especially alcoholism), and in schizophrenia

NMDA receptor antagonists – inhibit excitatory effects of glutamate ketamine & phencyclidine (PCP) - have sedative & anaesthetic effects at high doses hallucinogenic & ‘dissociative’ effects at lower doses low dose effects replicate both ‘positive’ and ‘negative’ symptoms of schizophrenia alcohol also acts as an NDMA antagonist

Ketamine & PCP early studies with PCP showed it could produce an extended psychotic breakdown in some individuals, and this drug is no longer used in human research ketamine is used in research with human subjects – although its acute effects are similar, they are less intense and have a shorter duration; adverse reactions are rare and follow-up of participants show no long-term effects (Perry et al, 2007)

Acute effects of ketamine feeling ‘drunk’- euphoria, dizziness, nausea disordered thought and speech memory impairment perceptual distortions and ‘dissociation’-objects and surroundings seem ‘unreal’ delusional thinking - often of a paranoid nature

Brief Psychiatric Rating Scale (BPRS) 1 Somatic concern NA 1 2 3 4 5 6 7 2 Anxiety NA 1 2 3 4 5 6 7 3 Depression NA 1 2 3 4 5 6 7 4 Guilt NA 1 2 3 4 5 6 7 5 Hostility NA 1 2 3 4 5 6 7 6 Suspiciousness NA 1 2 3 4 5 6 7 7 Unusual thought content NA 1 2 3 4 5 6 7 8 Grandiosity NA 1 2 3 4 5 6 7 9 Hallucinations NA 1 2 3 4 5 6 7 10 Disorientation NA 1 2 3 4 5 6 7 11 Conceptual disorganisation NA 1 2 3 4 5 6 7 12 Excitement NA 1 2 3 4 5 6 7 13 Motor retardation NA 1 2 3 4 5 6 7 14 Blunted affect NA 1 2 3 4 5 6 7 15 Tension NA 1 2 3 4 5 6 7 16 Mannerisms and posturing NA 1 2 3 4 5 6 7 17 Uncooperativeness NA 1 2 3 4 5 6 7 18 Emotional withdrawal NA 1 2 3 4 5 6 7 Instructions: Circle the number that best describes the patient’s present condition. If a specific symptom is not being assessed, circle NA. 1 = not present 2 = very mild 3 = mild 4 = moderate 5 = moderately severe 6 = severe 7 = extremely severe

BPRS scores during double-blind placebo-controlled intravenous ketamine infusion (Newcomer et al, 1999)

Ketamine & memory studies consistently show impairment of episodic memory following sub-anaesthetic doses of ketamine, across a wide variety of tasks – recognition memory, recall of spoken prose, recall of word lists, spatial learning, source memory tasks

GABA the principal inhibitory NT in the brain - used in about 40% of synaptic connections between neurons GABA receptors are complex - binding sites for different chemicals on the same receptor

GABA agonists benzodiazepines, barbiturates & alcohol all enhance the inhibitory effects of GABA these drugs all have anxiolytic, sedative & hypnotic effects i.e. they reduce anxiety, produce physical relaxation & promote sleep

GABA antagonists picrotoxin – a poisonous plant alkaloid with stimulant properties flumazenil – benzodiazepine ‘antidote’ blocks benzodiazepine site – binds but does not activate used to treat overdose, and to reverse the sedative effects of benzodiazepines in post-operative patients

Anxiolytics anxiolytic = drug used to reduce anxiety barbiturates are direct GABA receptor agonists – bind to and activate GABA receptors benzodiazepines do not directly activate GABA receptors – they enhance the effects of endogenous GABA, but GABA must also bind to receptor for drug to have effect

Barbiturates amobarbital, pentobarbital, secobarbital, phenobarbital, etc. first available in 1903 (Barbital) euphoric effects of these drugs mean they have high potential for abuse, dependence & addiction increasing dose leads to increased central nervous system depression sedation → sleep → coma → death pronounced respiratory depression (especially when mixed with alcohol) means high risk of fatal overdose

Benzodiazepines first available in 1960 (Librium) have replaced barbiturates in treatment of anxiety disorders and insomnia - produce less respiratory depression have pronounced sedative effect, but less euphoric lower incidence of dependence (but may still occur in 10-30% of long-term users)

Benzodiazepines many different benzodiazepines (BDZs) are now available - diazepam (Valium), temazepam (Restoril), lorazepam (Ativan, Temesta), alprazolam (Xanax), midazolam (Dormicum), etc. these differ in potency, primary effect (anxiolytic, hypnotic, muscle relaxant), time to produce effect, and duration of effect

Benzodiazepines the most commonly prescribed psychotropic drugs in the world estimated 20-30% of adult population are prescribed BDZ at some time up to 5% of adult population on long-term (one year or more) prescriptions used in treatment of anxiety disorders, insomnia, drug & alcohol withdrawal also used as pre-anaesthetics & muscle-relaxants in surgical operations

Benzodiazepines side-effects – drowsiness (e.g. following day when BDZ is used for insomnia) impaired motor co-ordination & balance slowed reaction times impaired vigilance task performance impaired memory performance

Benzodiazepines & memory effects are found mainly for long-term episodic memory – short-term memory is less affected & semantic memory is generally intact (see Curran, 1999) studies consistently show anterograde amnesia – i.e. memory impairment for information presented after the drug has been administered but not retrograde amnesia – i.e. no impairment for information learned before drug administration suggests impairment of encoding processes rather than retrieval

Measuring drug effects in on-the-road driving (Verster et al 2005, Current Psychiatry Reviews 1, 215-225)

Alprazolam (‘Xanax’) & driving - Verster et al (2002) (A) Weaving (SDLP) (B) Speed variability

Alcohol

alcohol = any drink containing ethanol (ethyl alcohol) produced by fermentation (conversion of sugar to alcohol by yeast) probably the oldest recreational drug - archaeological evidence for beer & wine since about 10,000 years acute subjective effects of alcohol are biphasic - low doses are mildly stimulating high doses have the opposite effect – i.e. are sedating or depressant

Biphasic effect of alcohol BAL (U.S.) measured in grams of alcohol per 100ml of blood BAC measured in grams per litre, or mg per 100ml (U.K.) U.K. legal driving limit = .08g/100ml (BAL) = 0.8g/l = 80mg/100ml

Alcohol & neurotransmitters alcohol is a pharmacologically ‘messy’ drug acute effects on NT systems are wide-ranging and complex - increases inhibitory NT activity (GABA) & decreases excitatory NT activity (glutamate) this causes knock-on effects on other NT systems throughout the entire brain

Alcohol abuse & dependence chronic alcohol abuse leads to adaptations in physiological processes that act in opposition to drug effects in order to maintain homeostasis sudden withdrawal of alcohol leads to rebound effects, which are opposite to the effects of drug these are experienced as an unpleasant withdrawal syndrome, which can only be alleviated by reinstating alcohol use so individual becomes dependent on alcohol for normal functioning

Opponent processes in alcohol abuse (see Valenzuela, 1997)

acute withdrawal effects in long-term alcoholics – anxiety, delirium, hallucinations & potentially fatal seizures these reflect state of excessive neural excitation alcohol withdrawal symptoms are reduced by administering benzodiazepines (to enhance inhibitory GABA-ergic activity)

Alcohol & task performance although acute subjective responses to alcohol are biphasic, effects on psychomotor performance appear to be linear i.e. even low-to-moderate doses (which may be subjectively stimulating) can impair task performance impairment in psychomotor tasks (simple & choice reaction time, vigilance) is evident before subject is ‘drunk’ and at BAC levels that are below the legal driving limit impairment increases with increasing dose -

Effects at different blood alcohol concentrations (BAC in grams of alcohol per litre of blood) BAC (g/l) Typical effects 0.1-0.2 Increase in subjective feelings of well-being & warmth 0.3-0.4 Light-headedness, mild euphoria, detectable impairment in some psychomotor tasks 0.5-0.6 Lowered inhibition, impaired judgement, impaired co-ordination 0.7-0.9 Slowed reaction times (0.8 g/l is UK legal driving limit) 1.0 Observable impairment in motor function, slurred speech (legal driving limit in most US states) 2.0-3.0 Movement, balance & reaction times severely impaired; judgement & perception severely impaired; double-vision; possibility of passing out 4.0 Anaesthesia & loss of consciousness 5.0 Depression of circulatory & respiratory processes; human LD50

Alcohol & task performance performance is most affected on more complex tasks (see Kerr & Hindmarch, 1998) so a low dose that doesn’t impair performance on simple psychomotor tasks may still have a negative effect on more complex tasks (e.g. driving) alcohol also produces anterograde amnesia in memory tasks

Effects of 0. 8g/kg alcohol on Tower of London task: ITT = log Effects of 0.8g/kg alcohol on Tower of London task: ITT = log. initial thinking time, STT = log. subsequent thinking time (from Weissenborn & Duka 2003, Psychopharmacology 165, 306-312)

Alcohol & TOL task - Weissenborn & Duka (2003) all differences are p<.05 time to first move (ITT) is shorter in subjects given alcohol but subsequent thinking times (STT) are longer and fewer perfect solutions are achieved shorter ITT may reflect increased impulsivity mean BAC in alcohol group at time of testing was < 0.6 g/l legal driving limit is 0.8 g/l

Glutamate & GABA - summary glutamate - the principal excitatory NT in the brain NMDA glutamate receptors have an important role in learning & memory, schizophrenia & addiction ketamine – NMDA receptor antagonist that produces acute dissociation & schizophrenic-like symptoms GABA - the principal inhibitory NT in the brain GABA agonists (benzodiazepines, barbiturates, alcohol) have anxiolytic, sedative & hypnotic effects benzodiazepines are the most widely prescribed psychoactive drugs in the world; used to treat anxiety & insomnia, side-effects include impaired reaction time, attention & memory alcohol is both a GABA agonist & a glutamate antagonist long-term alcohol abuse alters balance of inhibitory/excitatory neurotransmission, which can lead to alcohol dependence & withdrawal syndromes acute subjective effects of alcohol are biphasic (low doses feel stimulating, high doses sedating), but even low doses can impair cognitive performance – especially on complex tasks (problem solving, driving)

Learning outcomes Be able to describe the acute effects of ketamine intoxication, and how these are related to the ‘positive’ and ‘negative’ symptoms of schizophrenia. Know the main conditions for which benzodiazepine drugs are prescribed, and understand the neuro-chemical basis of the therapeutic effects and side-effects of these drugs. Understand the psychopharmacological basis for the acute effects of alcohol, and the mechanisms underlying alcohol dependence and withdrawal syndromes.

Recommended reading GLUTAMATE & KETAMINE JW Newcomer et al (1999) Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology 20, 106-118 EB Perry et al (2007) Psychiatric safety of ketamine in psycho-pharmacology research. Psychopharmacology 192, 253-260 GABA & ANXIOLYTICS HV Curran (1999) Effects of anxiolytics on memory. Human Psychopharmacology 14, S72-S79 JC Verster et al (2002) Effects of alprazolam on driving ability, memory functioning and psychomotor performance. Neuropsychopharmacology 27, 260-269

ALCOHOL JS Kerr & I Hindmarch (1998) The effects of alcohol alone or in combination with other drugs on information processing, task performance and subjective responses. Human Psychopharmacology 13, 1-9 CF Valenzuela (1997) Alcohol and neurotransmitter interactions. Alcohol Health & Research World 21, 144-148