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The Chemical Bases of Behavior: Neurotransmitters and Neuropharmacology

4 The Chemical Bases of Behavior: Neurotransmitters and Neuropharmacology

Many Chemical Neurotransmitters Have Been Identified

Neurotransmitter Systems Form a Complex Array in the Brain Research on Drugs Ranges from Molecular Processes to Effects on Behavior

4 The Chemical Bases of Behavior: Neurotransmitters and Neuropharmacology

Drugs Affect Each Stage of Neural Conduction and Synaptic Transmission

Drugs That Affect the Brain Can Be Divided into Functional Classes Drug Abuse Is Pervasive

4 Many Chemical Neurotransmitters Have Been Identified

Neurochemistry focuses on the basic chemical composition and processes of the nervous system.

Neuropharmacology is the study of compounds that selectively affect the nervous system.

4 Many Chemical Neurotransmitters Have Been Identified

Criteria for neurotransmitters chemicals released onto target cells:

Substance exists in presynaptic axon terminals Is synthesized in presynaptic cells Is released when action potentials reach axon terminals

4 Many Chemical Neurotransmitters Have Been Identified

Receptors for the substance exist on postsynaptic membrane.

When applied, substance produces changes in postsynaptic potentials. Blocking substance release prevents changes in postsynaptic cell.

4 Many Chemical Neurotransmitters Have Been Identified

Types of neurotransmitters: Amine neurotransmitters acetylcholine, dopamine, serotonin

Amino acid neurotransmitters GABA, glutamate Peptide neurotransmitters Gas neurotransmitters

4 Many Chemical Neurotransmitters Have Been Identified

Neurotransmitters affect targets by acting on receptorsprotein molecules in the postsynaptic membrane. Ionotropic receptors are fastopen an ion channel when the transmitter molecule binds

4 Many Chemical Neurotransmitters Have Been Identified

Metabotropic receptors are slow when activated they alter chemical reactions in the cell, such as a G protein system, to open an ion channel.

Receptor subtypesthe same neurotransmitter may bind to a variety of subtypes, which trigger different responses

Figure 4.1 The Versatility of Neurotransmitters

4 Many Chemical Neurotransmitters Have Been Identified

A ligand is a substance that binds to a receptor and has one of three effects:

An agonist initiates the normal effects of the receptor.


An antagonist blocks the receptor from being activated by other ligands. An inverse agonist initiates an effect that is the opposite of the normal function.

4 Many Chemical Neurotransmitters Have Been Identified

Endogenousoccurs naturally within the body:

Endogenous ligandssubstances that the brain produces Exogenousintroduced from outside the body

4 Neurotransmitter Systems Form a Complex Array in the Brain

Co-localizationor co-releaseoccurs when nerve cells contain more than one type of neurotransmitter.

Acetylcholine (ACh) was mapped by the enzymes involved in its synthesis. Cholinergic nerve cell bodies and projections contain ACh.

Figure 4.2 Cholinergic Pathways in the Brain

4 Neurotransmitter Systems Form a Complex Array in the Brain

Two types of ACh receptors: Nicotinicmost are ionotropic and excitatory Example: muscles use nicotinic ACh receptorsparalysis can be induced with an antagonist, such as curare

4 Neurotransmitter Systems Form a Complex Array in the Brain

Muscarinicmetabotropic and can be excitatory or inhibitory

Muscarinic ACh receptors can be blocked by atropine or scopolamine to produces changes in cognition.

4 Neurotransmitter Systems Form a Complex Array in the Brain

Two main classes of monoamine neurotransmitters:

Catecholaminesdopamine, epinephrine, norepinephrine Indoleaminesmelatonin, serotonin

4 Neurotransmitter Systems Form a Complex Array in the Brain

Dopamine (DA) is found in neurons in: the mesostriatal pathwayoriginates in the midbrain, specifically the substantia nigra, and innervates the striatum This pathway is important in motor control and neuronal loss is a cause of Parkinsons disease.

4 Neurotransmitter Systems Form a Complex Array in the Brain

The mesolimbocortical DA pathway originates in the midbrainin the ventral tegmental area (VTA)and projects to the limbic system and cortex.

DA in this pathway is involved in reward, reinforcement and learning abnormalities are associated with schizophrenia.

Figure 4.3 Dopaminergic Pathways in the Brain

4 Neurotransmitter Systems Form a Complex Array in the Brain

Norepinephrine (NE) is released in three brainstem regions:

Locus coeruleus (pons) Lateral tegmental system (midbrain) Dorsal medullary group
NE is also known as noradrenaline cells producing it are noradrenergic.

4 Neurotransmitter Systems Form a Complex Array in the Brain

Noradrenergic fibers from the locus coeruleus project broadly.

The CNS has four subtypes of NE receptorsall metabotropic. The NE systems modulate processes including mood, arousal, and sexual behavior.

Figure 4.4 Noradrenergic Pathways in the Brain

4 Neurotransmitter Systems Form a Complex Array in the Brain

Serotonin (5HT) cell bodies are mainly found in the raphe nuclei and its serotonergic fibers project widely. Serotonin is implicated in sleep, mood, sexual behavior, and anxiety. Antidepressants such as Prozac increase 5HT activity, with effects depending on which receptor subtype is affected.

Figure 4.5 Serotonergic Pathways in the Brain

4 Neurotransmitter Systems Form a Complex Array in the Brain

Amino acid transmitters: Glutamate and aspartateexcitatory Glutamatergic transmission uses AMPA, kainate, and NMDA receptors.

4 Neurotransmitter Systems Form a Complex Array in the Brain

Glutamate also acts on mGluRs slower metabotropic receptors

Excitotoxicityneural injury such as stroke may cause excess release of glutamate, which is toxic to neurons Astrocytes are involved in the uptake of glutamate from the synapses.

4 Neurotransmitter Systems Form a Complex Array in the Brain

Other amino acid transmitters: Gamma-aminobutyric acid (GABA) and glycineinhibitory GABA receptors are in classes: GABAAionotropic, producing fast, inhibitory effects

4 Neurotransmitter Systems Form a Complex Array in the Brain

GABABmetabotropic, slow inhibitory effects through neurogliaform interneurons

GABACionotropic with a chloride channel GABA agonists, like Valium, are potent tranquilizers.

4 Neurotransmitter Systems Form a Complex Array in the Brain

Peptides act as neurotransmitters at some synapses, or as hormones:

Opioid peptides mimic opiate drugs such as morphine. Peptides in gut, spinal cord, or brain Pituitary hormones

4 Neurotransmitter Systems Form a Complex Array in the Brain

The gas nitric oxide (NO), differs from other neurotransmitters:

Is produced in locations other than axon terminalsmainly in dendrites, and diffuses as soon as it is produced, rather than released
Diffuses into the target cell and activates cyclic GMP

Serves as a retrograde transmitter by diffusing back into the presynaptic neuron

4 Research on Drugs Ranges from Molecular Processes to Effects on Behavior

Many drugs are ligands that act upon specific receptor molecules.

Drugs may target one or a few receptor subtypes. Because receptor subtypes have different localizations and functions, drug actions can have widely varying effects.

4 Research on Drugs Ranges from Molecular Processes to Effects on Behavior

The binding affinity (or affinity) is the degree of chemical attraction between a ligand and a receptor.

The efficacy (or intrinsic activity) is the ability of a bound ligand to activate the receptor.

Figure 4.6 Using Binding Affinity to Compare Drug Effectiveness

4 Research on Drugs Ranges from Molecular Processes to Effects on Behavior

Agonists have high efficacy antagonists have low efficacy

Partial agonists or antagonists produce a medium response regardless of dose.


Competitive ligands are drugs that bind to the same receptor site as the neurotransmitter.

4 Research on Drugs Ranges from Molecular Processes to Effects on Behavior

A noncompetitive ligand binds instead to a modulatory site on the receptor. The modulatory site, when bound by a compound, alters the receptors response.

Figure 4.7 The Agonistic and Antagonistic Actions of Drugs

4 Research on Drugs Ranges from Molecular Processes to Effects on Behavior

A dose-response curve (DRC) is a graph of the relationship between drug doses and the effects.

The DRC is a tool to understand pharmacodynamicsthe functional relationship between drugs and their targets.

Figure 4.8A The Dose-Response Curve (DRC)

4 Research on Drugs Ranges from Molecular Processes to Effects on Behavior

Relative potency of two drugs can be compared by their ED50 values.

A drug that has comparable effects at lower doses is more potent. The therapeutic index is the separation between the effective dose and a toxic one.

Figure 4.8 B and C The Dose-Response Curve (DRC)

Figure 4.8D The Dose-Response Curve (DRC)

Figure 4.8E The Dose-Response Curve (DRC)

4 Research on Drugs Ranges from Molecular Processes to Effects on Behavior

Drug tolerance can developsuccessive treatments have decreasing effects

Metabolic toleranceorgan systems become more effective at eliminating the drug


Functional tolerancetarget tissue may show altered sensitivity to the drug

4 Research on Drugs Ranges from Molecular Processes to Effects on Behavior

Changes in numbers of receptors can alter sensitivity in the direction opposite to the drugs effects: Neurons down-regulate in response to an agonist drugfewer receptors available

They up-regulate in response to an antagonist.

4 Research on Drugs Ranges from Molecular Processes to Effects on Behavior

Cross-tolerance is tolerance to a whole class of chemically similar drugs. Withdrawal symptoms may be caused by drug tolerance. Sensitization occurs when drug effects become stronger with repeated treatment.

4 Research on Drugs Ranges from Molecular Processes to Effects on Behavior

The amount of drug that is bioavailablefree to act on the targetvaries with route of ingestion. Duration of a drugs effect is determined by how it is metabolized. Biotransformation produces active metabolites that may produce side effects.

4 Research on Drugs Ranges from Molecular Processes to Effects on Behavior

Pharmacokinetics refer to factors that affect the movement of a drug through the body.

The blood-brain barriertight junctions within the CNS that prevent the movement of large molecules can limit drug availability.

4 Drugs Affect Each Stage of Neural Conduction and Synaptic Transmission

Presynaptic events are affected by drugs that:

Inhibit axonal transport


Prevent release of neurotransmitter Example: Local anesthetics block sodium channels, and therefore block action potentials.

4 Drugs Affect Each Stage of Neural Conduction and Synaptic Transmission

Neuromodulators affect either transmitter release or receptor response.

Caffeine is an exogenous neuromodulator that blocks the effect of adenosine, an endogenous neuromodulator that normally inhibits catecholamine release.

4 Drugs Affect Each Stage of Neural Conduction and Synaptic Transmission

Caffeine stimulates catecholamine release, causing arousal.

Adenosine is normally released along with the catecholamines and acts on autoreceptorsreceptors on the same terminal that released it.

4 Drugs Affect Each Stage of Neural Conduction and Synaptic Transmission

Some drugs affect how long transmitters remain in the synapse.

They interfere with transporters, specialized proteins that return the transmitter to the presynaptic membrane. Drugs may also interfere with degradation, or breakdown of neurotransmitters.

Figure 4.9 Drug Effects on Presynaptic Mechanisms

4 Drugs Affect Each Stage of Neural Conduction and Synaptic Transmission

Postsynaptic receptors can be blocked or activated by drugs.

Prolonged transmitter-receptor activity can alter behavior: Cholinesterase inhibitors inhibit the breakdown of ACh at the synapse by the enzyme AChE, causing prolonged muscle contraction.

Figure 4.10 Drug Effects on Postsynaptic Mechanisms

4 Drugs That Affect the Brain Can Be Divided into Functional Classes

Antipsychotic (neuroleptic) drugs: a class of drugs to treat schizophrenia

Typical neuroleptics are selective dopamine D2 antagonists. Atypical neuroleptics block serotonin receptors and may reduce negative symptoms of schizophrenia.

4 Drugs That Affect the Brain Can Be Divided into Functional Classes

Antidepressants treat depression. Monoamine oxidase (MAO) inhibitors prevent the breakdown of monoamines at the synapses.

Accumulation of monoamines and prolonging their activity is a major feature of antidepressants.

4 Drugs That Affect the Brain Can Be Divided into Functional Classes

Tricyclic antidepressants increase norepinephrine and serotonin at the synapses by blocking their reuptake into presynaptic axon terminals. Selective serotonin reuptake inhibitors (SSRIs) like Prozac or Zoloft allow serotonin to accumulate in the synapses, with fewer side effects than tricyclics.

4 Drugs That Affect the Brain Can Be Divided into Functional Classes

Anxiolytics, or tranquilizers, are depressantsdrugs that reduce nervous system activity.

Benzodiazepine agonists act on GABAA receptors and enhance the inhibitory effects of GABA.

4 Drugs That Affect the Brain Can Be Divided into Functional Classes

GABA receptors have several binding sites, that enhance or inhibit GABAs effects.

Benzodiazepines bind at an orphan receptorno known endogenous ligand.


Allopregnanolone, a steroid, is elevated during stress and is calming.

Other neurosteroids (steroids produced in the brain) may act on GABAA sites.

Figure 4.11 The GABAA Receptor Has Many Different Binding Sites

4 Drugs That Affect the Brain Can Be Divided into Functional Classes

Alcohols effects are biphasican initial stimulant phase followed by a depressant phase.

Alcohol activates GABAA receptors and increases inhibitory effects. This contributes to social disinhibition and loss of motor coordination.

4 Drugs That Affect the Brain Can Be Divided into Functional Classes

Alcohol also stimulates dopamine pathways, causing euphoric effects.

Alcohol abuse damages nerve cells, especially in the frontal lobe, yet some damage is reversible.
Fetal alcohol syndrome is the result of pregnant women abusing alcohol, with permanent damage to the fetus.

4 Drugs That Affect the Brain Can Be Divided into Functional Classes

The frontal lobes are the most affected by chronic alcohol use, yet some effects are reversible.

Periodic overconsumption, or bingeing, may cause brain damage and reduces neurogenesis.

Figure 4.12 The Effects of Alcohol on the Brain

4 Drugs That Affect the Brain Can Be Divided into Functional Classes

Opium contains morphine, an effective analgesic, or painkiller.

Morphine and heroin are related and are both highly addictive. These opiates bind to opioid receptors in the brain, especially in the locus coeruleus and the periaqueductal gray.

Figure 4.13 The Source of Opium and Morphine

Figure 4.14 The Distribution of Opioid Receptors in the Rat Brain

4 Drugs That Affect the Brain Can Be Divided into Functional Classes

Endogenous opiatespeptides produced in the body that bind to opioid receptors and relieve painare also addictive: Enkephalins

Endorphins Dynorphins

4 Drugs That Affect the Brain Can Be Divided into Functional Classes

Marijuana is derived from Cannabis sativaits active ingredient is 9-tetrahydrocannabinol (THC):

Effects varyinclude relaxation, mood alteration, stimulation, hallucination, and paranoia


Sustained use can cause addiction.

Figure 4.15 An Indoor Marijuana Farm

4 Drugs That Affect the Brain Can Be Divided into Functional Classes

The brain contains orphan cannabinoid receptors to mediate the effects of THC and other compounds.

Endocannabinoidshomologs of marijuana produced in the brainact as retrograde messengers and may influence neurotransmitter release from the presynaptic neuron.

4 Drugs That Affect the Brain Can Be Divided into Functional Classes

Anandamide is an endocannabinoid with many effects:

Altered memory formation Appetite stimulation Reduced pain sensitivity


Protection from excitotoxic brain damage

4 Drugs That Affect the Brain Can Be Divided into Functional Classes

Stimulants increase nervous system activity.

Khat, or qat, is an African shrub that when chewed acts as a stimulant.

4 Drugs That Affect the Brain Can Be Divided into Functional Classes

Nicotine from tobacco: Increases heart rate, blood pressure, hydrochloric acid secretion, and bowel activity

Acts as an agonist on nicotinic ACh receptors in the ventral tegmental area

4 Drugs That Affect the Brain Can Be Divided into Functional Classes

Leaves from the coca shrub alleviate hunger, promote endurance, and enhance sense of well-being. Cocaine, the purified extract:

Can be used as an anesthetic Increases catecholamine stimulation Is highly addictive

4 Drugs That Affect the Brain Can Be Divided into Functional Classes

Crack cocaine is smoked and enters the brain more rapidly.

Cocaine blocks monoamine transportersespecially dopamine slows reuptake of neurotransmitters, enhancing their effects. Dual dependence is addiction to the effects of the interaction of two drugs.

Figure 4.17 Cocaine-Binding Sites in the Monkey Brain

4 Drugs That Affect the Brain Can Be Divided into Functional Classes

Amphetamine and methamphetamine are synthetic stimulants that resemble catecholamines in structure. They cause the release of neurotransmitters even in the absence of action potentials.

4 Drugs That Affect the Brain Can Be Divided into Functional Classes

Short-term effects of amphetamines include alertness, euphoria, and stamina.

Long-term use leads to sleeplessness, weight loss, and schizophrenic symptoms.


Cocaine-and amphetamine-regulated transcript (CART)a peptide in the brain which may be involved in pleasure sensations from drugs

4 Drugs That Affect the Brain Can Be Divided into Functional Classes

Hallucinogens alter sensory perception and produce peculiar experiences.

LSD (acid), mescaline (peyote), and psilocybin (magic mushrooms) have mainly visual effects.

4 Drugs That Affect the Brain Can Be Divided into Functional Classes

Hallucinogens have diverse neural actions, including on the noradrenergic, serotonergic, and ACh systems. LSD resembles serotonin in structure and it acts as an agonist on receptors, including in the visual cortex.

Figure 4.18 The Father of LSD

4 Drugs That Affect the Brain Can Be Divided into Functional Classes

Phencyclidine (PCP) or angel dust, is a dissociative drugproduces feelings of depersonalization and detachment from reality Its many side effects include combativeness and catatonia.

PCP has been proposed as a chemical model for schizophrenia.

4 Drugs That Affect the Brain Can Be Divided into Functional Classes

PCP is an NMDA receptor antagonist and stimulates DA release.

Ketamine (Special K) is a less potent NMDA antagonist that works in the prefrontal cortex. Like PCP, it can produce transient psychotic symptoms, at high doses.

4 Drugs That Affect the Brain Can Be Divided into Functional Classes

MDMA (Ecstasy) is a hallucinogenic amphetamine derivativeits major actions are increases in serotonin levels and changes in dopamine and prolactin levels. Chronic ecstasy use produces persistent effects and damage to serotonin-producing neurons.

Figure 4.19 Long-Term Effects of a Single Dose of Ecstasy on the Monkey Brain

4 Drug Abuse Is Pervasive

Substance-Related Disorders: Dependence (addiction) is the desire to self-administer a drug of abusecriteria include patterns of consumption, craving, time and energy, and impact on ones life. It is a more severe disorder than substance abuse, which is a pattern of use that does not fully meet the criteria for dependence.

4 Drug Abuse Is Pervasive

Models of drug abuse: The Moral Modelblames the abuser for a lack of moral character or a lack of self-control

The Disease Modelsays the abuser requires medical treatment; however, an abnormal condition in abusers has not been identified

4 Drug Abuse Is Pervasive

Models of drug abuse: The Physical Dependence Model called the withdrawal avoidance model, says abusers use drugs to avoid withdrawal symptoms The Positive Reward Modelsays drug use is a behavior controlled by positive rewards, with no disease

Figure 4.20 Experimental Setup for Self-Administration of a Drug by an Animal

4 Drug Abuse Is Pervasive

Many addictive drugs cause dopamine release in the nucleus accumbens.

Some axons that terminate here originate in the ventral tegmental area (VTA) and are involved in the reward pathway. The addictive power of drugs may come from stimulating this pathway.

4 Drug Abuse Is Pervasive

Another pathway may involve the insula, a brain region within the frontal cortex.

People with damage to this area have been able to stop smoking effortlessly.

Figure 4.21 A Neural Pathway Implicated in Drug Abuse (Part 1)

Figure 4.21 A Neural Pathway Implicated in Drug Abuse (Part 2)

Figure 4.21 A Neural Pathway Implicated in Drug Abuse (Part 3)

4 Drug Abuse Is Pervasive

Factors in susceptibility to addiction: Biologicalsex, genetic predisposition

Family situationfamily breakup, poor relationships, sibling drug users Personal characteristicsaggressiveness, emotional control
Environmental factorspeer pressure, social factors

4 Drug Abuse Is Pervasive

Environmental stimuli can become associated with the effects of drugs.

Cue-induced drug use is the increased likelihood of using a drug because factors are present that were also present when the drug was last used.

4 Drug Abuse Is Pervasive

Medications to treat drug abuse: Drugs for detoxification benzodiazepines and drugs to help ease withdrawal symptoms

Agonists or analogs of the addictive drugpartially activate the same pathways, such as methadone or nicotine patches

4 Drug Abuse Is Pervasive

Antagonists to the addictive drug block effects of the abused drug but may produce withdrawal symptoms

Medications that alter drug metabolismlike Antabuse, which makes drinking produce unpleasant side effects

4 Drug Abuse Is Pervasive

Reward-blocking medicationsblock positive reward effects of the abused drug but may produce a lack of all pleasurable feelings Anticraving medicationsreduce the appetite for the abused substance

Immunizationprompts the immune system to remove targeted drugs