Psychopharmacology Midterm 2

List the five drug classifications in the Schedule of Controlled Substances and describe each class. Provide at least one example of a drug belonging to classes I through IV. What is the status of alcohol and tobacco in the schedule?

Schedule I: Highest potential for abuse and no accepted medical use (Heroin)

Schedule II: High potential for abuse and high potential for physical and psychological dependence (fentanyl)

Schedule III: Moderate to low potential for physical dependence and high potential for psychological dependence (Ketamine)

Schedule IV: low potential for abuse as well as physical and psychological dependence (Xanax)

Schedule V: Lowest potential for abuse and dependence (cough medicine with low amount of codeine)

Discuss how the route of administration influences the addiction potential of recreational drugs. Provide at least one example of this influence.

Routes that cause the fastest onset of drug action have the greatest potential for addiction through the strongest euphoric effects at the shortest latency. Orally administered drugs have a lower addiction potential than drugs administered by IV because they are absorbed into the bloodstream at a a slower rate.

(a) Animals can be trained to self-administer cocaine by intravenous injection, but they will not self-administer the antipsychotic haloperidol even if given the same training as for cocaine. What does this finding tell us about the two different drugs?

(b) 

a)     Antipsychotic haloperidol is a drug which blocks dopamine receptors, inhibiting the release of dopamine while cocaine is a stimulant which blocks reuptake of dopamine leading to a buildup of dopamine, which causes a rush of pleasure. This rush of pleasure would explain why animals would be more likely to self-administer cocaine.

b)

Why is the measurement of breakpoint for self-administration of a drug a better measure of that drug's reinforcing properties than measuring the number of drug infusions obtained per hour under a continuous-reinforcement schedule?

Measurement of Breakpoint (Progressive ratio response) is a better measure because it can be used to quantify motivation for drug intake, where a higher breakpoint indicates greater motivation to obtain the drug. The continuous-reinforcement schedule (fixed ratio) only effectively measures the amount of drug intake rather than their motivations.  

What does the phrase "reinstatement of drug-seeking behavior" mean, and how is it modeled in laboratory animal studies?

Reinstatement of drug-seeking behavior address relapse which is studied as the restoration of a previously learned drug seeking behavior after it has been extinguished. This behavior modeled in self-administration lab studies where researchers first administer a drug and then stop drug delivery (forced abstinence) and then expose to stimuli that are known to provoke renewed responding as an attempt to obtain the drug again. 

Describe the components of the reward circuit with respect to both anatomy and neurochemistry.

The reward circuit is associated with the VTA and the nucleus accumbens in the brain and it’s DA pathway, where Dopamine is released from the VTA and travels to the nucleus accumbens.

Define the terms incentive salience and incentive sensitization and discuss the hypothesized role of these factors in the development of a substance use disorder.

Incentive sensitization is the theory that repeated drug use leads to an increase in wanting the drug but no increase in the liking of said drug. Incentive Salience is dopamine powered brain response which makes certain cues in drug use seem highly desirable. These factors drive motivation for drug seeking behavior.

Much attention has been paid to the role of dopamine in drug reward.

(a) What are the two primary mechanisms by which addictive drugs can elicit increased dopaminergic transmission in the nucleus accumbens?

(b) Is such an increase in dopaminergic transmission equally important for all addictive drugs? Explain your answer.

a)     1. Addictive drugs can increase the firing rate of dopamine neurons in the VTA, leading to increased dopamine release in the nucleus accumbens.

2. Addictive drugs can block dopamine reuptake at the dopamine terminals in the nucleus accumbens, prolonging dopamine signaling

b)   No, the degree to which the dopaminergic effect drives addiction varies amongst drug class depending on their pharmacological actions

Define the term neuroadaptation and discuss the hypothesized role of neuroadaptive recruitment of an antireward system in the development of a substance use disorder. What are the neuroanatomical and neurochemical features of that system?

Neuroadaptations are changes in brain functioning that attempt to compensate for the effects of repeated substance use. The antireward system is hypothesized to trigger negative emotional and emotional stress states which drive compulsive drug seeking behavior.  The neuroanatomical feature is the extended amygdala, and the neurochemical features are the increased release of Norepinephrine, CRF and dynorphin.

What is the difference between phytocannabinoids and endocannabinoids? List two examples from each category.

Phytocannabinoids are compounds found in the cannabis plant, such as THC and CBD. Endocannabinoids are naturally occurring compounds inside the body which activate CB receptors, such as anandamide and 2-AG.

(a) Discuss the main characteristics of cannabinoid receptors, including receptor subtypes, receptor distribution within and outside of the brain, and whether the receptors are metabotropic or ionotropic.

(b) Why did the discovery of cannabinoid receptors prompt a search for endocannabinoids?

a)     Cannabinoid receptors mediate cannabinoid effects in the brain. CB1 receptors are found in the central nervous system, they regulate psychological functions.  CB2 receptors are found in the in white blood cells and the GI tract and regulate the immune system. Both are metabotropic receptors.

b)     The discovery of cannabinoid receptors prompted researchers to search for endocannabinoids within the body to understand how the body’s endocannabinoid system regulates release of molecules within this system.  

(a) For a typical neuron expressing CB1 receptors, what part of the neuron would be most likely to contain these receptors? What is the functional implication of this subcellular localization?

(b) CB1 receptor stimulation _________ (activates or inhibits) Ca2+ channel opening and _______________ (activates o r inhibits) K+ channel opening.Describe the features of cannabinoid receptor pharmacology presented in the text. Your answer should include a description of receptor agonists (natural versus synthetic, full versus partial agonism) and antagonists.       

a)     CB1 receptors are most likely to be found in the presynaptic terminals, which allows them to regulate or inhibit the release of endocannabinoids

b)     CB1 receptor stimulation inhibits Ca2+ Channels opening and activating K+ channels. Cannabinoid receptor pharmacology involves agonists which activate receptors and antagonist which block receptors. THC is a natural partial agonist while lab made cannabinoids such as K2 are often synthetic full agonists. Cannabinoid antagonists are synthetic drugs which block activation of the endocannabinoids. One example is Rimonabant.

(a) Describe the retrograde signaling mechanism used by endocannabinoids, particularly 2-AG. How does this kind of signaling produce DSE or DSI, and what are the presynaptic neurotransmitters associated with those two processes?

(b) A different mechanism sometimes used by anandamide involves signaling within the same cell and subsequent activation of an excitatory ion channel called __________.

a)     Endocannabinoids such as 2-AG are lipid soluble. They are synthesized in the postsynaptic neuron and triggered to release by a rise in Ca2+ levels. Retrograde signaling produces DSE by blocking the release of excitatory transmitters, like glutamate. It produces DSI by blocking the release of inhibitory transmitters such as GABA.

b)     Non-retrograde signaling

Describe the evidence for cannabinoid-mediated reward and reinforcement. How does the strength of cannabinoid reinforcement compare with the reinforcing effects of, for example, psychostimulants or opioid drugs?

Laboratory studies on animals have demonstrated that cannabinoid reinforcement is dependent on the activation of dopaminergic cell firing and DA release in the nucleus accumbens. Cannabinoids found in Cannabis, such as THC, have fewer reinforcing effects than psychostimulants and opioids, since THC is only a partial agonist for the CB1 receptor.

Chronic cannabis use, especially early and heavy use, has been associated with a variety of adverse effects. Summarize these effects in the realms of (a) educational performance and IQ, (b) cognitive effects, (c) neuropsychiatric effects, and (d) overall health effects.

1. Education

• Amotivational syndrome: low educational achievement and motivation 

2. Cognitive 

• Impaired verbal learning and memory 

• Impaired attention 

• Impaired psychomotor function 

3. Neuropsychiatric effects 

• Dysregulated emotional and social behaviors 

• Impaired cognitive functions 

        E) Overall health effects 

• Depression and anxiety 

• Increased risk of developing a psychotic disorder

Neuroimaging studies have found a number of differences between regular cannabis users (including some with CUD) and non-users with respect to regional gray matter volumes and neural activation either at rest or in response to various cognitive tasks. Can we conclude that cannabis use caused these differences in brain structure and function? Why or why not?

We cannot conclude that cannabis use caused a difference in brain structure and function because neuroimaging alone is unable to identify cellular changes that are responsible for decreased or increased volume of gray matter. 

(a) What is meant by the street names "Spice" and "K2"?

(b) How do these substances differ from THC, and how are they typically consumed recreationally?

(c) What are the main adverse effects that can occur from consuming these substances?

a) The street names “spice” and “K2” are used to describe potent synthetic marijuana. 

b) These are more potent than THC and are typically smoked or vaporized. 

c) Some main adverse effects that can occur from consuming these include elevated blood pressure, increased heart rate, nausea, and respiratory failure.

The substances discussed in the first section of this chapter have variously been termed hallucinogenic," "psychedelic," and "psychotomimetic."

(a) What do each of these terms mean?

(b) Why have the authors chosen to use the term "psychedelic" in most of the chapter?

(c) What is the definition of a psychedelic drug?

a. Hallucinogenic refers to hallucination producing. Psychedelic refers to mind-manifesting or mind-opening. Psychotomimetic refers to psychosis-mimicking.

b. The change to psychedelic from the preferred hallucinogen is particularly apt in light of the growing interest in applying psychedelic drugs to a therapeutic setting in which the primary aim is to render the individual’s mind open to confronting their sources of trauma.

c. The definition of a psychedelic drug is a psychoactive substance that causes perceptual changes, visual hallucinations, altered awareness of the mind and body, and cognitive distortions without producing a state of toxic delirium.

(a) What experimental evidence supports the contention that 5-HT 2A receptor activation plays a key role in the subjective and behavioral effects of the classical (i.e., indoleamine and phenethylamine) psychedelic drugs?

(b) Lisuride has a structure similar to that of LSD and, like LSD, it binds to the 5-HT 2A receptor. Yet, lisuride does not produce psychedelic effects when administered. What is the presumed mechanism underlying this difference between LSD and lisuride?

(c) What behavioral test procedures are used to screen for psychedelic-like effects in laboratory animals?

a. Effects of psychedelic drugs (subjective perceptual and consciousness-alerting) are blocked with the presence of 5-HT 2A antagonists.

b. The difference lies in the signaling pathways. 5-HT2A receptor can complex with the metabotropic glutamate receptor, formation of this complex alters the receptor’s second-messenger signaling pathways, and these events are necessary for psychedelic activity of 5-HT2A agonists.

c. Two common behavioral test procedures are drug discrimination tests and head-twitch response.

(a) The "trigger population" of neurons hypothesized to elicit the cascade of cellular events that culminate in the psychedelic experience is composed of neurons located in layer ________ of the ________.

(b) By what mechanism is this trigger population activated when a psychedelic drug is consumed?

a) layer 5 of the prefrontal cortex.

b) It is activated by stimulation of 5-HT 2A, AMPA, and NMDA receptors.

(a) Explain the meaning of the term "default mode network (DMN)."

(b) Under what conditions is the DMN most active?

(c) Describe the effect of classical psychedelic drugs on activity within the DMN, and discuss the significance of this effect.

a) The default mode network refers to a neural network that is active when subjects are in a resting state (not performing a task) and engaged in mental wandering or self-related thinking. 

b) The DMN is the most active when not focused on a demanding task, rather during wakeful inactivity or rest.

c) Classical psychedelic drugs reduce DMN activity. This suggests that reduced DMN activity is a common feature of psychedelic agents that act through 5-HT 2A receptor stimulation.

Describe the discovery and development of PCP and ketamine for medical use as anesthetic agents. How does the anesthetic state produced by these compounds differ from the state produced by more traditional anesthetics such as barbiturates?

PCP was synthesized accidentally by a chemist in 1965 as part of an ongoing project to develop new anesthetic agents. Subjects did not show a response to painful stimuli but were not in the typical state of relaxed unconsciousness seen in traditional anesthetics. Instead, they showed a trance-like or catatonic-like state characterized by a vacant facial expression, fixed and staring eyes.

Researchers have hypothesized that PCP and ketamine preferentially block NMDA receptors on GABAergic interneurons innervating cortical pyramidal cells. What is the consequence of this action?

This increases glutamate levels which in turn is significantly correlated with positive psychotic symptoms/symptoms similar to those observed in patients with schizophrenia.

(a) Why is administration of PCP or ketamine usually considered to be a better model of schizophrenia than administration of LSD?

(b) How has the mechanism of action of these drugs been related theoretically to the neurochemical basis of schizophrenia?

a) High doses of PCP or ketamine can produce delusions, disordered thought, and motor disturbances ranging from extreme agitation to catatonia which is more characteristic of schizophrenia.

b) Patients of schizophrenia show an exacerbation of their symptoms following ketamine administration. These findings lead to a glutamate hypothesis of schizophrenia.

Discuss the pharmacology and recreational use of dextromethorphan.

Dextromethorphan is an NMDA receptor antagonist. This produces psychoactive effect

How do glutamatergic and GABAergic cells modulate the firing of VTA dopaminergic neurons and NAcc DA release? How do cannabinoids act within this system to produce their reinforcing/rewarding effects?

Glutamatergic cells have CB1 receptors on their terminals that, when activated, create a decrease in DA release in the Nacc. GABAergic cells create an increase in DA release in the NAcc. Cannabinoids mainly act on the GABAergic cells in order to create an increase in DA release and therefore get the reinforcing/rewarding effects.

What do we know about the initiation of marijuana use, including the typical developmental period of initiation and the risk factors for early marijuana use?

Initiation of marijuana typically begins in adolescence. The prevalence of marijuana usage usually peaks in young adulthood and then slowly declines thereafter. Risk factors for early marijuana use include impulsive behavior, and low academic motivation.