neuropharmacology exam two

How is glutamate synthesized in neurons?

From glutamine supplied by astrocytes, converted to glutamate by the enzyme glutaminase in presynaptic terminals.

What enzyme converts glutamate to glutamine in astrocytes?

Glutamine synthetase.

What is the glutamate–glutamine cycle?

A cooperative metabolic loop where astrocytes take up glutamate, convert it to glutamine, and return it to neurons for resynthesis, preventing excitotoxicity.

What was observed in EAAT2 knockout mice?

They had seizures, increased brain excitability, reduced weight gain, and early death, showing EAAT2 is essential for glutamate clearance.

What are the three vesicular glutamate transporters and where are they found?

VGLUT1 (cortex/hippocampus), VGLUT2 (thalamus/brainstem), VGLUT3 (non-glutamatergic neurons that co-release glutamate).

What are the major excitatory amino acid transporters (EAATs) and their functions?

EAAT1/GLAST (astrocytes, cerebellum), EAAT2/GLT-1 (astrocytes, forebrain), EAAT3/EAAC1 (neurons). They clear glutamate and prevent excitotoxicity.

What happens if EAAT2 function is lost?

Extracellular glutamate accumulates, causing neuronal overexcitation and cell death (excitotoxicity).

What are the three types of ionotropic glutamate receptors?

AMPA, kainate, and NMDA receptors.

What ions do AMPA and NMDA receptors conduct?

AMPA conducts Na⁺ and K⁺; NMDA conducts Na⁺, K⁺, and Ca²⁺.

What makes NMDA receptor activation unique?

Requires glutamate and glycine (or D-serine) as co-agonists and removal of Mg²⁺ block via depolarization.

What are the major agonists for ionotropic glutamate receptors?

AMPA → AMPA; kainate → kainic acid; NMDA → NMDA.

What are the main antagonists for ionotropic glutamate receptors?

NBQX blocks AMPA; CNQX blocks kainate; AP5 is a competitive NMDA blocker; PCP and MK-801 are uncompetitive NMDA channel blockers.

What are the three groups of metabotropic glutamate receptors and their effects?

Group I (mGluR1,5): Gq, excitatory; Group II (mGluR2,3): Gi/o, inhibitory; Group III (mGluR4,6–8): Gi/o, inhibitory.

What is the relationship between mGluR5 and Fragile X Syndrome?

Loss of FMRP leads to overactive mGluR5 signaling, excessive LTD, and abnormal dendritic spines; mGluR5 antagonists like mavoglurant may normalize synapses.

What is long-term potentiation (LTP)?

A long-lasting increase in synaptic strength following high-frequency stimulation, considered a cellular model of learning and memory.

What triggers LTP induction?

Glutamate binding to AMPA → depolarization → removal of NMDA Mg²⁺ block → Ca²⁺ influx activates kinases (CaMKII, PKC).

How does LTP convert silent synapses into active ones?

By inserting AMPA receptors into synapses that previously contained only NMDA receptors.

What is glutamate excitotoxicity?

Neuronal death caused by excessive glutamate activity and Ca²⁺ influx through NMDA/AMPA receptors, leading to oxidative stress and apoptosis.

What disorders involve glutamate excitotoxicity?

Stroke, traumatic brain injury, ALS, Alzheimer’s disease.

What NMDA antagonist is used to reduce excitotoxicity in Alzheimer’s disease?

Memantine.

How is GABA synthesized?

From glutamate by glutamic acid decarboxylase (GAD) using vitamin B₆ (pyridoxal phosphate) as a cofactor.

How is GABA metabolized?

By GABA aminotransferase (GABA-T) into glutamate and succinate.

What drug blocks GABA breakdown?

Vigabatrin, an antiepileptic that inhibits GABA-T to increase GABA levels.

What transporter loads GABA into vesicles?

VGAT (also called VIAAT), which also loads glycine.

What are the main plasma membrane GABA transporters and their functions?

GAT-1 (neurons, reuptake into terminals) and GAT-2/3 (astrocytes, uptake for metabolism).

What drug blocks GABA reuptake and what is it used for?

Tiagabine blocks GAT-1, used as an antiepileptic.

How is GABA recycled through astrocytes?

Astrocytes take up GABA, convert it to glutamate → glutamine, release it, and neurons convert glutamine back to GABA via glutaminase + GAD.

What are examples of GABA co-release?

ACh + GABA (separate vesicles, basal forebrain), DA + GABA (same vesicle via VMAT2), Glu + GABA (same vesicle via VGLUT2 + VGAT).

What are the main functions of GABA as a neurotransmitter?

Mediates inhibition in local interneurons and projection neurons across the CNS to prevent overexcitation.

What is the structure of the ionotropic GABAA receptor?

A pentameric Cl⁻ channel typically composed of 2 α, 2 β, and 1 γ subunit.

What drugs act as GABAA receptor agonists and antagonists?

Agonist: muscimol; antagonists: bicuculline (competitive), picrotoxin (noncompetitive).

What are positive allosteric modulators (PAMs) of the GABAA receptor?

Benzodiazepines, barbiturates, and neurosteroids (allopregnanolone, THDOC). They enhance GABAergic inhibition.

How do benzodiazepines modulate GABAA receptors?

They increase the frequency of Cl⁻ channel opening in response to GABA, enhancing inhibitory current.

What clinical effects result from GABAA PAMs?

Sedative, anxiolytic, anticonvulsant, and muscle relaxant effects.

What is the role of GABA and GABAA receptors in epilepsy?

Reduced GABAergic inhibition or receptor dysfunction causes hyperexcitability; enhancing GABA activity prevents seizures.

What is the structure and function of GABAB receptors?

Metabotropic GPCRs (GABAB1 + GABAB2 heterodimer) coupled to Gi/o → inhibit cAMP, open K⁺, close Ca²⁺ → slow IPSPs.

What drug is a GABAB receptor agonist and what is it used for?

Baclofen; used to treat spasticity and muscle rigidity.

What percentage of people aged 12 or older reported illegal drug use in the past year (NSDUH 2019)?

Approximately 20%.

Which age group has the highest rate of drug use in the U.S.?

Young adults aged 18–25.

What is polydrug use?

The concurrent or sequential use of multiple psychoactive substances.

Which drugs are most commonly misused in the U.S.?

Marijuana, prescription opioids, stimulants, and cocaine.

What was the significance of the Harrison Narcotics Act of 1914?

It required registration for the sale of opiates and cocaine, marking the first federal regulation of drug use.

What did the 1970 Controlled Substances Act establish?

Five drug schedules based on medical use and abuse potential.

What social issue emerged from the 'War on Drugs'?

Mass incarceration and racial disparities in drug-related arrests.

How has modern drug policy shifted?

From criminalization to harm reduction and treatment approaches.

How is addiction defined?

A chronic, relapsing behavioral disorder characterized by compulsive drug seeking and use despite negative consequences.

Why is addiction considered chronic and relapsing?

Because vulnerability and craving persist long after detoxification, and relapse can occur due to cues or stress.

What are the 10 classes of drugs recognized under DSM-5 substance-related disorders?

Alcohol, caffeine, cannabis, hallucinogens, inhalants, opioids, sedatives/hypnotics/anxiolytics, stimulants, tobacco, and other substances.

How many DSM-5 criteria exist for Substance Use Disorder?

Eleven.

What are the DSM-5 severity levels for Substance Use Disorder?

Mild (2–3), Moderate (4–5), Severe (6 or more).

What are examples of behavioral addictions?

Gambling disorder, gaming, internet, and food addictions.

What brain system is shared between behavioral and drug addictions?

The mesolimbic dopamine reward pathway.

What is the difference between 'drug switching' and 'pattern escalation'?

Drug switching refers to moving between drug types; pattern escalation involves increased frequency or dose of one drug.

What characterizes the relapse cycle in addiction?

Repeated attempts at abstinence followed by relapse due to conditioned cues or stress.

How does route of administration affect addictive potential?

Faster brain entry increases addiction risk; IV and inhalation are most addictive routes.

What is latency in drug use?

The time between consumption and onset of euphoria.

Why do drugs with shorter latency have higher abuse potential?

Rapid reinforcement strengthens conditioned drug-seeking behavior.

What is drug reward?

The subjective pleasurable experience produced by a drug.

What is reinforcement in the context of drug use?

The process by which drug use increases the likelihood of repeated use.

How is reinforcement tested in animals?

Using self-administration or progressive-ratio schedules to measure motivation for a drug.

What does an inverted U-shaped self-administration curve indicate?

Intermediate doses produce the highest reinforcement; very low or high doses are less reinforcing.

What is withdrawal?

A set of physical and emotional symptoms occurring after drug cessation, motivating renewed use.

What is the main finding of heroin-choice studies in monkeys?

During withdrawal, animals prefer heroin over food, showing the role of negative reinforcement.

What are discriminative stimulus effects?

Internal cues produced by drugs that signal specific behavioral responses, used to study receptor mechanisms.

What is the heritability estimate for addiction vulnerability?

Approximately 40–60%.

What is the telescoping effect in addiction?

The faster progression from initial use to dependence observed in females.

What is natural recovery?

Achievement of abstinence without formal treatment, often through lifestyle or motivational change.

What model explains the interaction of genetics, psychology, and environment in addiction?

The biopsychosocial model.

What are the three stages of the substance use cycle?

Binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation.

Which brain regions are primarily involved in the binge/intoxication stage?

The ventral tegmental area (VTA) and nucleus accumbens (NAcc).

What characterizes the withdrawal/negative affect stage?

Downregulation of reward signaling and activation of stress pathways in the amygdala.

What role does the prefrontal cortex play in addiction?

It controls executive functions such as decision-making, impulse control, and valuation of rewards.

What is the dopamine reward hypothesis?

Dopamine mediates the pleasurable effects of drugs.

What is the incentive sensitization theory?

Repeated drug use sensitizes 'wanting' (craving) more than 'liking' (pleasure).

What is the reward prediction error model?

Dopamine release encodes unexpected rewards and drives learning of drug-related cues.

What is the allostatic model of addiction?

Chronic drug use lowers baseline dopamine activity, leading to use for mood normalization.

Which neurochemicals form the antireward system?

Corticotropin-releasing factor (CRF) and norepinephrine (NE) in the central amygdala.

What is neuroadaptation?

Long-lasting synaptic and molecular changes due to chronic drug exposure, including altered receptor expression and dendritic remodeling.

What is sensitization?

Enhanced response to a drug after repeated exposure, increasing craving and motivation.

What is tolerance?

Decreased drug effect over time, requiring higher doses for the same response.

What is hypofrontality in addiction?

Reduced prefrontal cortex activity leading to impaired impulse control and decision-making.

What are examples of molecular adaptations in addiction?

Changes in AMPA/NMDA receptor ratios, gene expression, and epigenetic modifications.

How does addiction alter behavioral allocation?

It redirects behavior toward drug seeking and away from healthy reinforcers.

What are the key neurotransmitters in the reward circuit?

Dopamine, GABA, glutamate, opioid peptides, and endocannabinoids.

Alcohol absorption: What speeds vs slows it?

Faster with higher dose and higher %ABV; slowed and blunted peak by food (delayed gastric emptying). Women often reach higher BAC (less body water, lower gastric ADH). (Fig. 10.4)

Primary metabolic pathway for ethanol

ADH converts ethanol→acetaldehyde; ALDH converts acetaldehyde→acetic acid→CO₂ + H₂O. Genetics of ALDH alter acetaldehyde buildup and flushing. (Fig. 10.5)

What is CYP2E1/MEOS and why it matters?

Inducible ethanol-oxidizing system; increases with chronic use; causes drug interactions and oxidative stress; competes with other substrates (Slide 13).

Zero-order elimination: meaning for ethanol

Fixed rate elimination (~0.015% BAC/hr typical) largely independent of concentration; individual variability applies.

Acute vs metabolic vs pharmacodynamic vs behavioral tolerance

Acute: less effect at same BAC on descending limb; Metabolic: ↑ADH/CYP2E1 speeds clearance; Pharmacodynamic: receptor/circuit adaptations reduce response; Behavioral: learned compensation. (Fig. 10.6)

Dose-dependent CNS effects of alcohol

Low–mod: disinhibition, slowed RT; Higher: ataxia, slurred speech, blackouts; Very high: anesthesia/coma; driving risk rises steeply with BAC. (Fig. 10.8)

Alcohol withdrawal: timeline & mechanism

Hours: tremor/anxiety/insomnia; 12–48 h seizures; 48–96 h DTs. Mechanism: upregulated glutamate/downregulated GABA → hyperexcitability.

Chronic effects: brain–cardio–liver

Brain: cognitive deficits, Wernicke’s (thiamine) → Korsakoff’s; Cardio: HTN, arrhythmia, cardiomyopathy; Liver: steatosis→hepatitis→cirrhosis.

Wernicke’s encephalopathy (key triad & fix)

Ataxia, confusion, ophthalmoplegia; treat with IV thiamine BEFORE glucose. (Slide 21)

Sexual function & alcohol

Men: ↓ tumescence rate/size; Women: ↑ orgasmic latency; dose-dependent impairment. (Fig. 10.10)

FASD: core features & variability

Growth restriction; craniofacial anomalies; CNS deficits (learning/executive). Variability by dose, timing, pattern, maternal metabolism, nutrition. (Fig. 10.12)

Animal models of alcohol use

Two-bottle choice; operant self-admin; bred lines (AP vs NP rats); microdialysis & ICSS for neurochemistry/reward. (Figs. 10.13, 10.19)

Grm2 knockout finding (Fig. 10.14)

Grm2−/− mice consume more alcohol and prefer it at high concentrations vs wild-type controls.

Acute alcohol on glutamate

↓ presynaptic release; postsynaptic inhibition of NMDA & AMPA currents → reduced excitation.

Chronic alcohol on glutamate & withdrawal

Upregulated NMDA and glutamatergic tone; withdrawal causes glutamate surge → hyperexcitability/seizures. (Fig. 10.16)

Acute alcohol on GABA_A

Potentiates GABA_A Cl⁻ currents (synaptic & extrasynaptic) → anxiolysis/sedation/motor effects; membrane + receptor actions. (Fig. 10.15)