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PSYC 3030
Rob Foster

NEUROCHEMICAL BASIS OF BEHAVIOR – WEEK 1 INTRODUCTION DSM-IV criteria for substance dependence – manifested by three (or more) of the following, occurring at any time in the same 12-month period: 1. Tolerance, as defined by either of the following: a. Need of increased amounts of the substance to achieve intoxication or designed effect b. Markedly diminished effect with continued use of the same amount of the substance 2. Withdrawal (you don’t feel good if you stop the drug): a. The characteristic withdrawal syndrome for the substance b. The same (or closely related) substance is taken to relieve or avoid withdrawal symptoms. 3. The substance is often taken in larger amounts or over a longer period than was intended 4. There is a persistent desire or unsuccessful efforts to cut down or control substance use 5. A great deal of time is spent in activities necessary to obtain the substance, or recover from its effects 6. Important activities are given up or reduced because of substance use 7. The substance use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance. E.g.: continued abuse even in danger of death or jail. - Stimuli conditioned to drug effects: feeling of power - Aversive effects of drugs – some people may be more or less sensible to this aversive affects; in some cases they are very powerful and you won’t take it again. If the side effect is very minimum, you’ll use it from now until you die. (Negative influence) - Risk factors – e.g. poor, lack of education, stress, abuse. - Protective factors – e.g. proper social support, proper education, goals in life, peers. Animal models of addiction 1. Based on operant conditioning Used to: a. Establish the reinforcing properties of drugs b. Test the rewarding properties of drugs – progressive ratio schedule c. Test the subjective properties of drugs – drug discrimination d. Model features of addiction - Spontaneous drug-seeking: you remove the drug suddenly and see what the animal will do - Precipitated drug-seeking: you study relapse, the causes and what can lead to drug seeking back. Three causes to reinstatement of drug seeking - relapse (priving, environment, stress) 2. Based on classical conditioning Place conditioning (incentive or aversive motivation). Commonly used in psychopharmacology to assess the motivational properties of known or unknown compounds. In addiction research, used to study acquisition, extinction and reinstatement of place (CS) – drug (US) associations. - Disadvantages of place conditioning: how should it be measured? Time in third compartment, Cues. - Balanced or Unbalanced? You need to find our properly a condition perfect for the experiment. o Balanced: it is design to the rats do not prefer a component rather the other, they’ll spend half the time in each component. No bias design. o Unbalanced: the two components are very different from each other, so the rat will have a natural preference, spending more time in a specific ambient. Then you try to change the preference with a drug, you try to turn it into something that they don’t like it anymore. - Data analysis. What about the time spent in the component between the two different compartments? The two experiments cannot be compared, because there’s one that has one more compartment than the other. 3. Combination between operant and classical conditioning Bozarth and Wise 1985 (operant conditioning) Self-administering of heroin has a gradual increase in drug intake and a stable level of self- administration through termination of testing. Daily intake of self-administering cocaine has an erratic pattern of responding across days, with periods of excessive cocaine self-administration alternating with brief periods of abstinence. One of the most striking differences in the effects of continuous drug access in animals self- administering cocaine or heroin was the mortality rate. While many drug users recognize the inherent danger of opiate addiction, they fail to recognize the potential danger of long-term cocaine use. The facts that cocaine is usually not available to humans in unlimited quantities and that the available cocaine tends to be of low purity probably account for the relatively few deaths associated with its use. CELLULAR COMPONENTS OF THE NERVOUS SYSTEM Gene is a section of DNA. Allele is a variation of gene. Transcription factors are proteins not encoded on the same DNA to which they bind. They determine the boundaries of segments of DNA that should be transcribed into RNA. Enzymes are one class of proteins which are biological catalysts, able to facilitate specific chemical reactions. Glial cells provide metabolic support, protection, and insulation for neurons. The principal function of neurons is to transmit information in the form of electrical signaling over long distances. Axon hillock – portion of the axon that is adjacent to the cell body. Myelin sheath – formed by Schwann cells and oligodendroglia (brain and spinal cord). The myelin sheath increases the speed of conduction along the axon; the ticker the myelin, the quicker the conduction. Neurobiologists are finding that experiences such as prolonged stress and chronic drug use may turn on or turn off the production of particular proteins by modifying transcription factors. Astrocytes – intertwine with neurons and provide structural support, help maintain the ionic environment around neurons and modulate the chemical environment as well by taking up excess neurochemicals that might otherwise damage cells. Microglia – act as scavengers that collect at sites of neuron damage to remove dying cells. Besides, they’re the primary source of immune response in the CNS and are responsible for the inflammation reaction that occurs after brain damage. ELECTRICAL TRANSMISSION WITHIN A NEURON - Resting membrane potential – there are more negatively charged particles inside the cell and more positively charged ions outside the cell (-70 mV) - For every three ions of Na pumped out, two K ions are pumped in, keeping the inside of the cell negative. - Absolute refractory period - Relative refractory period Drugs and poisons alter axon conduction - Anesthetics – block voltage-gated Na channels, so an action potential cannot occur, and the transmission of the brain signal cannot reach the brain. ANS  Sympathetic: their axons project for a relatively short distance before they synapse with sympathetic ganglia, releasing acetylcholine. The postganglionic cells release norepinephrine into the target tissues.  Parasympathetic: preganglionic neurons travel long distance to synapse on cells in the parasympathetic ganglia that are close to individual target organs, releasing acetylcholine. The postganglionic neurons are quite short and also release acetylcholine. TRANSLATION RNA polymerase binds to a particular sequence of nucleotides on one of the DNA strands and assembles a primary RNA transcript with a nucleotide sequence complementary to that of the DNA strand it had bound. This primary RNA transcript engages in a post-transcriptional process called splicing, which removes internal sequences that will not be translated into proteins in that particular cell. The result of splicing is mRNA. mRNA exits the nucleus into the cytoplasm. There, it binds to a ribosome which initiates the process of translation. EPIGENETICS Believe that the environment can change the way a gene expresses Epigenetics: potentially heritable change in gene expression that do not involve changes in DNA sequence. Mechanisms: 1. Altering particular sections of the DNA (DNA methylation) 2. Altering the way the DNA is packed, unpacked sections can be expressed (the packness can be altered by epigenetic factors). This variation in the chromatin template can be brought about by posttranslational modifications (PTMs). PTMs of histones include acetylation, methylation, phosphorylation, ubiquination, etc. All of these mechanisms likely act together to bring about the plasticity that helps to define epigenetic phenomena. Epigenetics & Addiction Exposure to drugs of abuse can: 1. Induce non-coding RNAs 2. Activate/inhibit transcription factors 3. Modify chromatin and DNA structure MicroRNAs They essentially come up from splicing of DNA, they do have functions, they’re everywhere and are pretty small. You can sample your blood and find microRNAs. May there’s a way the body controls the gene expression from distances. They are post-translational regulators that bind to complementary sequences on target mRNAs to repress translation and thus silence gene expression. Like histone modifications and DNA methylation, expression of microRNAs can alter the transcriptional potential of a gene in the absence of any change to the DNA sequence, and thus can be considered an epigenetic phenomenon. Drugs can lead to target gene products that cause long-lasting adaptive changes in neuronal function. Mechanisms of transcriptional and epigenetic regulation by drugs of abuse Drugs of abuse act through synaptic targets such as reuptake mechanisms, ion channels and neurotransmitter (NT) receptors to alter intracellular signalling cascades. This leads to the activation or inhibition of transcription factors (TFs) and of many other nuclear targets, including chromatin-regulatory proteins. These processes ultimately result in the induction or repression of particular genes, including those for non-coding RNAs such as microRNAs; altered expression of some of these genes can in turn further regulate gene expression. It is proposed that some of these drug- induced changes at the chromatin level are extremely stable and thereby underlie the long- lasting behaviours that define addiction. Reward Circuitry Virtually all rewarding drugs or This reward circuitry is activated by stimuli or pursuits that promoactivities increase evolutionary fitness of the organism, such as nutrient-rich foods, sex and social stimulation. As drugs of abuse activate this circuitry far morepaminergic transmission strongly and persistently than natural rewards, and without being from the VTA to the NAc and associated with productive behavioural outcomes, chronic exposure toother target limbic regions. drugs modulates brain reward regions partly through a homeostatic desensitization that renders the individual unable to attain sufficient feelings of reward in the absence of drug. This transcriptional and epigenetic model of chronic drug action provides a plausible mechanism for how environmental influences during development can increase (or decrease) the risk for addiction later in life. Histone tail modification Numerous types of post-translational modifications of the amino-terminal tails of histones alter chromatin compaction to create more ‘open’ states (euchromatin, which is transcriptionally permissive) versus ‘closed’ states (heterochromatin, which is transcriptionally repressive). Many residues in the tails of histones are modified in numerous ways, resulting in a complex ‘code’ that is thought to control the accessibility of individual genes to the transcriptional machinery.  Histone acetylation – associated with transcriptional activation. Acetylation negates the positive charge of lysine residues in the histone tail. This process is controlled by histone acetyltransferases (HATs) and deacetylases (HDACs).  Histone methylation – associated with both transcriptional activation and repression, depending on the particular residue and the extent of methylation. Both lysine and arginine residues can be methylated by several families of histone methyltransferases (HMTs) and reversed by demethylases (HDMs).  Histone tail modifications also include phosphorylation, ubiquitylation, sumoylation, among many others. DNA Methylation Methyl marks added to certain DNA bases repress gene activity, and it occur in cytosine nucleotides. In mammals, this occurs almost exclusively in CpG dinucleotides sequences, that are concentrated in regions termed CpG islands. These regions overlap with the promoters of 50-60% of human genes. RESEARCH METHODS Damage to the Insula Disrupts Addiction to Cigarette Smoking (Naqvi et al 2007) Smoker with brain damage involving the insula were more likely to undergo a disruption of smoking addiction, characterized by the ability to quit smoking easily, immediately, without relapse, and without persistence of the urge to smoke. This result suggests that the insula is a critical neural substrate in the addiction to smoking. They found that the likelihood of having a disruption of smoking addiction after a lesion in either the right or the left insula was significantly higher than the likelihood of having a disruption of smoking addiction after a noninsula lesion. In our sample, the patients with insula lesions tended also to have damage in adjacent areas (Fig. 1). This raises the question of whether the observed effects were necessarily due to insula damage or whether they required damage in one or more areas adjacent to the insula. Stereotaxic surgery It is a minimally invasive form of surgical intervention which makes use of a three- dimensional coordinate system to locate small targets inside the body and to perform on them some action such as ablation, biopsy, lesion, injection, stimulation, implantation, radiosurgery (SRS) etc. Guide bars in the x, y and z directions (or alternatively, in the polar coordinate holder), fitted with high precision vernier scales allow the neurosurgeon to position the point of a probe (an electrode, a cannula, etc.) inside the brain, at the calculated coordinates for the desired structure, through a small trephined hole in the skull. In theory, any organ system inside the body can be subjected to stereotactic surgery. However, difficulties in setting up a reliable frame of reference (such as bone landmarks which bear a constant spatial relation to soft tissues) mean that its applications have been limited to brain surgery. Optogenetics Optogenetics (from the Greek optos, meaning "visible") is a neuromodulation technique employed in neuroscience that uses a combination of techniques from optics and genetics to control and monitor the activities of individual neurons in living tissue—even within freely- moving animals—and to precisely measure the effects of those manipulations in real-time. [1] The key reagents used in optogenetics are light-sensitive proteins. It involves light-activated genes (called channel rhodopsin) targeted into a single neuron type, and inserting it into the genome of a mouse e.g. When you shine a light into the mouse’s brain, the channel rhodopsin responds, and the neurons that are now expressing the channel rhodopsin fire. This technique takes advantage of a number of proteins found in various species of algae that respond to light of certain wavelengths by opening a channel in their cell membrane to allow electrochemical ions (like sodium or chloride) to flow in or out of the cell. Controlling the flow of such ions along their fibres is also how neurons conduct electricity. If you take the gene that encodes the light-sensitive channel from algae and force neurons to express it, then they will become responsive to light – if you shine a light on them they will “fire” an electrical signal, or “action potential”. If you turn the light off, they will stop firing action potentials. And if you use a different channel protein, you can silence the neurons and stop them firing action potentials. This gives very tight, reversible control over the activity patterns of the neurons expressing these channel proteins (called channelrhodopsins). This method is better than drugs and electric stimulation of the brain, because is highly specific and target specific neurons. It’s an optimal way to turn on and off systems in the brain. Orexin = Hypocretin They are neurotransmitters that are not found in all the major regions of the brain, they are produced in a small group of cells and projected to other regions of the brain. It is told that narcolepsy is related to dysfunction of hypocretin systems. They discovered that there were less orexin in neurons of narcoleptic. “Orexin, also called hypocretin, is a neurotransmitter that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, in which the sufferer briefly loses muscle tone (cataplexy), is caused by a lack of orexin in the brain due to destruction of the cells that produce it.[2] The brain contains very few cells that produce orexin; in a human brain, about 10,000 to 20,000 neurons in the hypothalamus. However, the axons from these neurons extend throughout the entire brain and spinal cord, where there are also receptors for orexin.” SAKURAI 2007 Orexin A and orexin B are crucial regulators of sleep and wakefulness. The finding that an orexin deficiency causes narcolepsy in humans and animals indicated that these hypothalamic neuropeptides also have a crucial role in regulating sleep and wakefulness. A recent study showed that a short 2 hour period of total sleep deprivation changed the action of noradrenaline on orexin neurons from excitation to inhibition. This mechanism might contribute to the growing sleepiness that accompanies sleep deprivation, although this phenomenon was not observed in mice. Orexin neurons receive abundant input from the limbic system, which might be important for increasing arousal during emotional stimuli. Anatomically, orexin neurons are well-positioned to alter reward functioning. In fact the activation of orexin neurons was shown to be strongly linked to preferences for cues associated with drug and food rewards. ICV or local VTA infusions of orexin have been shown to reinstate drug-seeking or food-seeking behavior in rodents. Furthermore, in vivo administration of an OX1R antagonist blocks locomotor sensitization to cocaine and occludes cocaine-induced potentiation of excitatory currents in VTA dopamine neurons64. These results suggest an important role for orexin signalling in the VTA in the neural plasticity associated with reward, and indicate that orexins also contribute to cocaine-induced psychomotor sensitization and reward-seeking. These findings highlight the key role of orexin in the mechanisms of reward and drug addiction. Insular hypocretin transmission regulates nicotine reward (Hollander et al 2008) Emerging evidence
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