Neuropharmacology Exam 3

What was the American temperance movement?

Was a 19th century social movement in the US that aimed to limit or end alcohol consumption. It educated society about the dangers of alcohol use.

When was prohibition, how long did it last, and why was it lifted?

The 18th Amendment took effect in 1920. It lasted 13 years. Lifted in 1933 because crime was at a high, and illegal production called wood alcohol

Explain the concept of alcohol proof

British army tested alcohols by pouring it on gunpowder and trying to light it

• If it lit, the content was 50% ethanol 

• 100% proof= 50% ethanol 

• Proof= twice the % of alcohol

Where is alcohol absorbed?

GI tract, diffuses throughout the body, entering most tissues, including the brain

Mostly absorbed from the small intestine into the blood by passive diffusion, higher concentration in the drink, the faster the absorption

Where is majority of alcohol metabolized?

About 95% of ingested alcohol is metabolized by the liver at a constant rate (1 to 1.5 ounces/ hour) about 5% is excreted by the lungs- which can be measured with a Breathalyzer

Why can a Breathalyzer detect alcohol?

It uses a chemical or light-based technology to measure the amount of alcohol that passes from the lungs into the breath

Recognize the enzymes that oxidize alcohol

Alcohol dehydrogenase and aldehyde dehydrogenase (ALDH)

Tolerance

Effects of alcohol reduced when administered repeatedly

Cross-tolerance

Mix with other drugs in the sedative–hypnotic class, including barbiturates and benzodiazepines

Metabolic tolerance

Increase in P450 liver microsomal enzymes that metabolize alcohol

Pharmacodynamic tolerance

Neurons adapt to continued presence of alcohol by making compensatory changes in cell function

Behavioral tolerance

Practicing behaviors while under the influence of alcohol allows adjustment and compensation

What is a hangover?

A buildup of acetaldehyde

May be evidence of withdrawal or a sign of acute toxicity

Describe health effects of chronic, heavy alcohol use

Heavy long-term alcohol use causes a vitamin B₁ (thiamine) deficiency leading to cell death in the periaqueductal gray, medial thalamus, and mammillary bodies, causing Wernicke’s encephalopathy (WE)

Multiple brain regions may be damaged by glutamate-induced ecotoxicity 

Korsakoff Syndrome

Permanent damage to thalamic nuclei and brain regions involved in memory subsequent to vitamin B₁ deficiency

Fatty Liver

Can cause liver dysfunction

Describe the clinical presentation of fetal alcohol spectrum disorders

Alcohol passes through the placental barrier and the fetus quickly reaches the same BAC as the mother.

•Fetal alcohol spectrum disorders (FASD) and the more severe fetal alcohol syndrome (FAS): intellectual disability and developmental delays, low birthweight, neurological problems, head and facial malformations (worst time for babys to get disorders is in first weeks of conception)

Recognize the neurotransmitter systems impacted by alcohol

Hits GABA and glutamate the worst

Glutamate (excitatory)

Alcohol has greatest effect on NMDA receptors

—ligand-gated channels that allow Ca²⁺ and Na⁺ to enter and cause localized depolarization.

Alcohol affects learning and memory—it is a glutamate antagonist and reduces glutamate release in many brain areas, including the hippocampus.

Repeated use results in up-regulation of NMDA receptors- more receptors to bind

GABA (inhibitory)

Binds to GABA_A receptors and opens the channels, allowing Cl^– to enter the cell to hyperpolarize the membrane.

Alcohol increases Cl^– flux AND stimulates GABA release.

Alcohol acts on some GABA_A receptors and not others.

Dopamine

The dopaminergic mesolimbic system plays a significant role in reinforcement and motivational mechanisms.

The Nacc (nucleus accumbens core) is part of the extended amygdala, which is involved in integrating emotion with hormonal responses and sympathetic nervous system activity.

Increased dopamine transmission in the mesolimbic pathway occurs in response to most drugs.

What is binge drinking?

Drinking five drinks in a row (men) or four (women)

How does Antabuse and Naltrexone work for alcohol use?

Disulfiram (Antabuse) inhibits ALDH (converts acetaldehyde to acetic acid). Drinking even 1 oz of alcohol results in flushing, pounding heart, nausea, vomiting, etc

Naltrexone: an opioid receptor antagonist; reduces the “high” by blocking the effects of alcohol-induced endorphin release

Where do opiates come from?

Naturally derived from the poppy plant

Explain the difference between opiates and opioids

Opioids are natural, semi-synthetic, or synthetic 

Opiates are naturally derived from the poppy plant 

What is Laudanum?

An opium-based medicinal drink, was introduced in 1680 in England

What are natural narcotics vs semisynthetics vs total synthetics?

Natural narcotics- (opiates) naturally occurring substances derived from the opium poppy plant

Semisymmetric- drug that is a compound derived from a natural product and then chemically modified in a lab to create a new drug

Total synthetics- Man made drug made to mimic the effects of natural drugs

Identify the four types of opioid receptors

Selective radioligands were used to identify receptor subtypes: μ, δ, κ, and the nociceptin/orphanin FQ receptor (NOP-R)

Mu (μ)-receptor has a high affinity for morphine; have wide distribution in the brain and spinal cord

Delta (δ)-receptors are predominantly found in forebrain structures; consistent with roles in modulating olfaction, motor integration, reinforcement, and cognitive function

Kappa (κ)-receptors are found in the striatum and amygdala, hypothalamus and pituitary; may participate in regulation of pain perception, gut motility, and dysphoria

NOP-R are widely distributed in the CNS and PNS; receptor localization suggests a role in analgesia, feeding, learning, motor function, and neuroendocrine regulation

Name the endogenous opioids

Describe the behavioral and physiological effects of opioids at therapeutic and toxic doses

Create a sense of relaxation and sleep; at high doses can lead to coma and death

They are the best painkillers known; also produce a sense of euphoria that may lead to increased use

Continued use leads to tolerance and sometimes physical dependence

First early pain

Immediate, sensory component; signal carried by myelinated Aδ neurons – conduct action potentials rapidly; transmitted from spinal cord via spinothalamic tract to PVL nucleus of the thalamus, then the somatosensory cortex

Second (late) pain

Emotional component; signal carried by thin, unmyelinated C fibers; transmission is slower; goes to the thalamus, but gives off collaterals to a several limbic structures and the anterior cingulate cortex

Explain how opioids interfere with neural pain signals to produce signals

Opioids reduce transmission of pain signals at the spinal cord in two ways:

• Inhibitory spinal interneurons release endorphins that inhibit activation of spinal projection neurons

• Descending modulatory pathways - inhibit projection neuron or excitatory interneuron, or excite inhibitory opioid neuron; most important pathway originates in the PAG in the midbrain

How does acupuncture work?

Releases endogenous opioids

Describe the neural circulatory that underlines the reinforcing effects of opioids

• Dopaminergic mesolimbic pathway: originates in the VTA of the midbrain and projects to limbic areas, including the NAcc

• Opioid drugs inhibit inhibitory GABA cells, increasing mesolimbic cell firing and DA release in the NAcc.

• The mesolimbic DA system may mediate aversive effects of opioids, as well as their reinforcing properties

Tolerance

Diminishign effects of a drug with repeated use

Cross-tolerance

Related drugs also show reduced effectiveness

Sensitization

Increase in drug effects with repeated administration, craving increases while liking may decrease 

Physical dependence

Neuroadaptive state in response to long-term occupation of opioid receptors

Withdrawal or abstinence syndrome

•When the drug is no longer present, cell function returns to normal but also overshoots basal levels

•Opioids in general depress CNS function; opioid withdrawal is rebound hyperactivity.

Methadone

•Methadone maintenance program: most common and effective treatment for heroin addiction

•Methadone has cross-dependence with heroin – prevents severe withdrawal symptoms; reduces euphoric effect of heroin.

•Programs require daily supervised oral administration; reduces use of the needle and its ritual; reduces risk of unsterile needles

Different forms of cocaine

•Cocaine HCl is water-soluble and thus can be taken orally, intranasally (snorting), or by IV injection; can not be smoked

•Cocaine HCl can be transformed back into cocaine that can be smoked by two methods:

• Freebasing- Dissolve in water, add an alkaline solution such as ammonia, extract the cocaine base with an organic solvent, typically ether. The term freebasing refers to smoking cocaine that was obtained in this manner.

• Crack- Mix dissolved cocaine HCl with baking soda, heat the mixture, then dry it. Chunks of crack are heated and the vapor inhaled.

What 3 neurotransmitters are mainly impacted, and how?

Dopamine, norepinephrine, and 5-HT by inhibiting their membrane transporters; increased synaptic concentrations of transmitters increases rate of transmission

12.2.1

•The cocaine high: feelings of exhilaration, euphoria, well-being, heightened energy, and self-confidence

•Smoked or IV cocaine also causes a “rush”

•Many positive characteristics that may contribute to its reinforcing properties become negative or aversive with higher dose and duration

•Psychological/behavioral symptoms can include agitation, mania, paranoia, and a state of delirium

•High doses can be fatal: seizures, heart failure, stroke, intracranial hemorrhage

Sympathomimetic

Physiological effects include increased heart rate, vasoconstriction, hypertension, hyperthermia

Cocaine binges

Episodic bouts of repeated use lasting hours to days with little or no sleep; users suffer withdrawal afterward

Tolerance- cocaine

Reduced drug responsiveness

Sensitization

Increased responsiveness- reverse tolerance

Discuss the neurobiological changes caused by chronic cocaine exposure

Loss of gray matter with increasing age was much greater in the cocaine-dependent group

Amphetamines

Synthetic, structurally related to dopamine

Methamphetamine

Synthesized from pseudoephedrine, more potent

What neurotransmitter are involved and how in cocaine?

•Amphetamines are indirect catecholamine agonists; stimulate DA and NE release and block reuptake

• Where cocaine blocks reuptake only, these drugs ALSO stimulate release

•Stimulate massive DA release by two means:

• Enters nerve terminal by DAT; stimulates DA release from vesicles

• Alters DAT to act in reverse direction to release DA into synapse

•NE release also affects sympathetic nervous system

Discuss the pharmacology of methylphenidate (Ritalin)

• Activates catecholamine transmission by blocking DAT and NET reuptake - increases extracellular levels of DA and NE

No enhancement of GPA

Background of Tabacco, nicotine

•Nicotine is an alkaloid found in tobacco leaves

•Tobacco and nicotine were unknown to Europeans until Columbus’s expedition to the New World; quickly became popular in Europe

•Cigarettes became popular in the mid-19^th century

•e-cigarettes: the device heats and vaporizes a solution of nicotine, producing an aerosol that is inhaled

Discuss the mechanisms of nicotine action on nicotinic acetylcholine receptors

Nicotine activated nicotinic cholinergic receptors

Ionotropic- produce rapid excitatory responses

Green Tabacco illness

Nicotine exposure in field workers

Mechanisms of caffeine action

(Dose dependent): inhibition of cAMP phosphodiesterase, blockade of GABA_A receptors, stimulation of Ca²⁺ release in cells, and blockade adenosine receptors

Blockade of adenosine receptors, particularly A_2A subtype, underlies caffeine-induced behavioral stimulation