Lecture 3

A class of psychotomimetic drugs that includes LSD, PCP and ketamine. These drugs cause perceptual alterations, hallucinations, and altered states of consciousness.

A hallucinogenic drug that acts primarily by decreasing the firing rate of serotonin neurons in the raphe nuclei and increasing activity in locus coeruleus neurons.

A dissociative anesthetic drug that causes a catatonic-like state without muscle relaxation. It is no longer clinically used due to the 'emergence phenomenon'.

A state where a patient experiences altered perception, feeling of isolation, cognitive disorganization, and emotional changes after administration of a drug.

A receptor that PCP interacts with. It is involved in the modulation of norepinephrine release.

A receptor that PCP acts as a non-competitive antagonist. It plays a crucial role in learning and memory.

Models of psychiatric disorders created by using psychedelic drugs like LSD and PCP in animal studies. These models help us understand the neurobiology of these disorders.

Psilocybin, a psychedelic compound, is now being investigated for its potential therapeutic benefits in treating treatment-resistant depression.

A brain disorder where compulsive drug use occurs despite negative consequences, characterized by physical and psychological dependence.

A decrease in the response to a drug after repeated administrations, requiring higher doses for the same effect.

The opposite effects experienced when a drug is withdrawn after prolonged use. Can include physical discomfort and psychological distress.

A collection of brain structures involved in processing emotions, motivation, and reward. Key areas include the amygdala, ventral tegmental area, and nucleus accumbens.

A pleasurable experience that drives behaviors important for survival, like eating and mating. It reinforces behaviors that lead to this experience.

A neurological system that detects and controls responses to pleasurable stimuli. It involves reward pathways and is activated by both natural rewards and addictive drugs.

A brain area with a high concentration of reward centers. It is responsible for the reinforcing effect of drugs and plays a crucial role in addiction.

A technique where rats were implanted with electrodes that allowed them to self-administer electrical stimulation to specific brain areas. This led to the discovery of reward centers in the brain and the concept of reinforcement.

A brain pathway densely populated with axons that connect the midbrain and medulla to various brain regions, transporting important neurotransmitters like serotonin, norepinephrine, and dopamine.

A highly rewarding experience that acts as a positive reinforcement, promoting the repetition of behaviors that lead to it. It involves specific pathways in the brain closely linked to dopamine.

Drugs like cocaine and amphetamine, which are highly addictive due to their ability to stimulate reward pathways in the brain.

A drug known for its stimulant and anesthetic properties. It works by blocking the reuptake of dopamine, norepinephrine, and serotonin, leading to increased levels in the synapse.

A key mechanism by which cocaine exerts its effects. It prevents the removal of dopamine from the synaptic space, leading to heightened dopamine signaling and the feeling of reward.

The specific receptors that cocaine binds to with high affinity, located on the presynaptic terminals of dopamine neurons.

The ability of a substance, like cocaine, to trigger a rewarding response in the brain, leading to its repeated use and addiction.

A key process in understanding cocaine's reinforcing properties. It involves directly studying the role of specific dopamine transporters in driving cocaine's addictive effects.

Mice lacking the dopamine transporter (DAT) have chronically elevated dopamine levels and show increased locomotor activity. However, cocaine administration in these mice does not further increase dopamine or locomotion. Despite this, these mice still self-administer cocaine and exhibit conditioned place preference (CPP), indicating that cocaine still acts as a reinforcing stimulus in the absence of dopamine increase.

A specific mutation in the dopamine transporter, F105, is crucial for high affinity cocaine binding but not for dopamine transport. Mice with this mutation show no increase in extracellular dopamine or locomotor activity after cocaine administration. Additionally, these mice do not exhibit conditioned place preference (CPP), indicating that cocaine is not reinforcing in this case.

Positron emission tomography (PET) imaging using the radioligand 11C-raclopride shows that cocaine abusers have lower densities of D2 receptors in the brain, especially in the reward system. This D2 receptor downregulation persists even after detoxification.

Cocaine leads to a downregulation of dopamine D2 receptors in the brain, impacting the reward system. This downregulation contributes to the addictive nature of cocaine, as it leads to a decrease in the motivation to seek out natural rewards.

The conditioned place preference (CPP) task is a behavioral test used to assess the reinforcing effects of drugs in animals. In this task, animals are allowed to freely explore two distinct environments, one associated with the drug (conditioned) and the other not (neutral). A preference for the conditioned environment over the neutral environment indicates the drug has reinforcing properties.

The reinforcing effects of cocaine are not always mediated solely by dopamine release. Even in animals with chronically elevated dopamine levels, or those with a mutated dopamine transporter that prevents cocaine from binding, cocaine can still act as a reinforcing stimulus. This suggests that other mechanisms beyond dopamine are involved in the rewarding effects of cocaine.

The research on dopamine transporter knockout mice and cocaine-insensitive DAT knock-in mice demonstrates the complexity of cocaine's reinforcing properties. These studies highlight the potential for other neurochemical systems to play a role in cocaine addiction beyond dopamine.

Studies using PET imaging with 11C-raclopride have shown that cocaine abusers have lower D2 receptor densities in the brain, specifically in the reward system. This downregulation of D2 receptors may contribute to the addictive nature of cocaine and the difficulty of quitting.