PY222 Final
How does a drug discrimination study tell us about a possible variable that can play a role in drug abuse and addiction?
If injected with heroin, the rat presses the left lever. If injected with saline, the rat presses the right lever. They have learned a drug discrimination.- Subjective stimulus from drug tells rat which lever to press o If you inject morphine, the rat presses the left lever. If you inject any opiate, the rat will press the left lever. If you inject the rat with cocaine, rat will press the right lever. - press the non-drug lever because it produces different internal stimuli. - learn to associate certain internal stimuli with drug
What are the problems associated with this model?
If the monoamine hypothesis was correct, a single dose of an antidepressant should decrease depressive symptoms as soon as drug gets into the brain. It increases the levels of monoamines. However, it takes 4-6 weeks for antidepressants to begin working; the delay is a problem.
Why do the negative consequences of drug addiction fail to prevent drug taking?
Immediate positive reinforcement is more effective in controlling behavior than the long-term consequences.
What are the mechanisms of action of atypical antipsychotic drugs at the nigrostriatal pathway?
In nigrostriatal pathway an atypical antipsychotic blocks the abundant 5HT2A receptors promoting release of dopamine and can compete with atypical antipsychotic for the receptors, leads to a reduction in Eps reducing motor symptoms. The NT competes and gets to the receptor site. The side effect is mediated by dopamine not binding. Remember that the dopamine associates and dissociated (breaks away) from the receptor and so does the antipsychotic so dopamine can sneak in and bind. More dopamine can get to the receptors and decrease the likelihood of motor problems.
What are the mechanisms of action of atypical antipsychotic drugs at the mesolimbic pathway?
In the Mesolimbic pathway the serotonin 2A antagonism fails to reverse D2 antagonism because there are not many serotonin receptors, the increase in dopamine is not substantial. Dopamine doesn't get to D2 receptors keeping positive symptoms at bay.
What are the mechanisms of action of atypical antipsychotic drugs at the mesocortical pathway?
In the mesocortical pathway we see that atypical antipsychotics work differently. Serotonin 2A antagonism reverses dopamine 2 antagonism. This leads to a net gain in dopamine. The mechanism of this is not well understood, however, there is some evidence that the high density of serotonin 2A receptors along this pathway in the cortex helps dopamine release win over dopamine blockade.
What are the mechanisms of action of typical antipsychotic drugs at the tuberoinfundibular pathway? -didn't discuss the mechanisms of action of atypical antipsychotics here.
In the tuberoinfundibular pathway D2 receptors are blocked and prolactin levels rise- milk let down response. As prolactin levels rise, women may begin to lactate as well as show irregular menstrual periods. Other side effects mediated at this pathway include sexual dysfunction and weight gain ---more research is needed to determine if prolactin is causes these problems.
How are the dual serotonin and NE reuptake inhibitors different from the tricyclics?
It does not act as an antagonist at the alpha 1, muscarinic cholinergic receptor, nor the histamine receptor. Therefore, these new compounds do not have the side-effects that are seen with the tricyclics.
What are the differences between the MAOI and the selective MAO A and MAO B inhibitors. How do these drugs help to minimize some of the side effects? What are the advantages of using a reversible MAOI?
MAO exists in two forms, MAO A and MAO B: both forms are inhibited by the original MAO inhibitors, acts in a non-selective manner MAO A metabolizes the monoamines that are most closely linked to depression -MAO A inhibition results in both the antidepressant activity of the drug as well as one of the side effects of these compounds which is hypertension (high BP) -Inhibition of MAO B has been linked to the possible prevention of neurodegenerative processes. Selective MAO B inhibitors don't inhibit MAO A resulting in no increase in blood pressure. -Reversible inhibitors reduce the likelihood of dietary amines increases the levels in blood and as a consequence increase blood pressure, cause intracerebral hemorrhage and possibly death.
What are the side effect profiles of MAO inhibitors?
MAO inhibitors can increase blood pressure, cause intracerebral hemorrhage and possibly death
Which two pathways mediate the positive and negative symptoms?
Mesolimbic and mesocortical respectively
What are the four key dopaminergic pathways that play a role in schizophrenia?
Mesolimbic pathway, mesocortical pathway, nigrostriatal pathway and tuberoinfundibular pathway.
What are the common mechanism of action of natural reinforcers?
Natural reinforcers all cause the release of dopamine at the n accumbens.
What are the two hypotheses that account for the delayed response of antidepressant drugs?
Neurotransmitter Receptor Hypothesis of Antidepressant Action and The Monoamine Hypothesis of Antidepressant Action on Gene Expression
Which two pathways mediate the side effects of antipsychotic medication?
Nigrostriatal and Tuberoinfundibular
How does the monoamine hypothesis propose to account for the biological basis of depression?
Says depression is due to a deficiency of the monoamine neurotransmitters (norepinephrine, dopamine, serotonin) -Certain drugs deplete these NTs can induce depression -Antidepressants which increase levels of these monoamines can decrease depression -NE metabolites are lower in some patients with depression compared to controls who are not depressed. These data, however, are not consistently found. -Other studies have found that the serotonin metabolite 5HIAA is reduced in CSF of depressed patients When this data is more closely examined, these lower levels of 5HIAA are much better correlated with patients who have disorders. For example, patients with violent outbursts and patients with borderline personality disorders who show self-destructive behavior.
How does the neurotransmitter receptor hypothesis propose to account for the biological basis of depression?
Says there is the possibility of a linkage between the changes in the receptors and the lower than normal levels of monoamines. For example, low levels of monoamines, could lead to up-regulation of the monoamine receptors on the postsynaptic neuron. This would be a compensatory response to the low levels of monoamines. -there is only evidence from post-mortem studies (not taking anti-depressants) consistently show increased numbers of serotonin 2 receptors in the frontal cortex of patients who commit suicide. -also says antidepressants will eventually result in down regulation of the receptors that key neurotransmitters bind to which corresponds to the delayed on-set of the action of the antidepressant and the time that it takes patients to become tolerant to many of the side effects of the medication.
What studies used self-stimulation procedures?
Studies show that the threshold for the amount of electrical brain stimulation needed to maintain lever pressing is lowered when there is acute administration (one or two injections) of drugs including, psychomotor stimulants, opiates, nicotine, sedative hypnotics and THC. - you need lower amplitude electrical stimulation to maintain lever pressing. These data provide evidence that the same circuitry that mediates self-stimulation, mediates drug reward
What is the evidence that drug craving is a key factor associated with withdrawal?
Subjective responses of Cocaine- dependent and Not Cocaine dependent subjects to a 30 min video of a crack ritual. Cocaine-dependent people show a much larger change/increase in response to video.
What is the key difference between the way that natural reinforcers work in the brain compared to drugs of abuse.?
The activation of the mesolimbic pathway by natural reinforcers confers an advantage on the organism. Drugs, however, take control over the circuitry that mediates reinforcement
What is the anatomical location in the brain where it is thought addiction begins?
The development of addiction seems to begin in the mesolimbic pathway by increasing the release of dopamine, followed by long-term changes in brain that receive inputs from the mesolimbic pathway.
What are the mechanisms of action of typical antipsychotic drugs at the mesocortical pathway?
The typical antipsychotic medication also blocks the D2 receptors along the mesolimbic pathway and can increase the negative symptoms. There is evidence that the negative symptoms of schizophrenia are mediated by too little dopamine along the mesocortical pathway; therefore by blocking the D2 receptors in the area, negative symptoms increase.
What are the side effect profiles of tricyclics?
They block other receptors giving rise to the side effects -Block muscarinic cholinergic receptors leading to dry mouth, blurred vision, urinary retention, constipation and memory problems. -Block H1 histamine receptors: Sedation, weight gain -Block alpha 1 adrenergic receptors: Orthostatic hypotension (I stand up and my BP drops, I am dizzy) and dizziness
What are the proposed therapeutic mechanism of actions of the tricyclics? Are they agonists, antagonists or mixed agonists-antagonists?
They block the re-uptake pumps for both serotonin and norepinephrine, and to a lesser degree dopamine. They can differ in the degree to which they block the re-uptake pumps. They are mixed agonist-antagonists (therapeutic effects are due to its work as an agonist and the side effects are due to their work as antagonists.)
What is the action of the SSRI compounds and the explanation(s) for why they take weeks to a month before they begin to show clinical efficacy?
They block the transporters that remove serotonin from the cleft. These are used as the first-line of defense against depression today. -Major advantage is that SSRIs have a better margin of safety than first generation antidepressants Onset of response 3 to 8 weeks- Response is frequently complete remission of symptoms- other data says only 30% of people taking antidepressants show remission.
What is the Belin and Everitt (2008) conception of what mediates addiction?
They provided evidence that reciprocal connections (back and fourth) between the striatum and the VTA mediate addiction.- VTA sends axons to the striatum and the striatum sends axons to the VTA. This back and fourth of the neural activity continues to over time (repeated drug use) strengthen the most dorsal regions of the striatum and produce sensitization of the motor system.
What was the research conducted by Volkow et al., (2011)?
They provided evidence to support the claim that the dorsal striatum is involved in human drug abuse. -Using fMRI, cocaine addicts were given a single injection of methylphenidate. The addicts showed less activity in the n accumbens and the dorsal striatum. These data suggest that less dopamine is released compared to non-addicts. -When addicts were show a video of people smoking crack, more activity was found in the dorsal striatum compared to a single drug infusion. The CS acts to promote drug seeking. *Conclusion: The drug (US) fails to increase incentive motivation, however, CSs can increase incentive motivation.
What are the proposed therapeutic mechanism of actions of MAO inhibitors. Are they agonists, antagonists or mixed agonists-antagonists.
This compound inhibits the enzyme MAO They were originally irreversible enzyme inhibitors( destroys enzyme) they are agonists- more monoamines in synapse.
How does the monoamine hypothesis of gene expression propose to account for the biological basis of depression?
This hypothesis says that depression results from abnormal functioning of gene expression ( A target gene for the expression of brain-derived neurotrophic factor) that is induced as a consequence monoamine neurotransmitters binding to receptors. -The action of antidepressants is to eventually cause key genes to prevent the repression of BDNF. - Antidepressants up-regulate BDNF- increase concentrations of BDNF- more released.
What were the findings from the fMRI part of the Childress et al (1999) study?
fMRI data revealed that Cocaine dependent subjects showed activation in the amygdala and anterior cingulate gyrus compared to controls.
What four variables (Roberts, et al., 2007) do you need to study if you want a good animal model of human drug abuse and addiction?
o Escalation of the drug dose during self-administration- Provides evidence for drug dependence and tolerance o Relapse after abstinence o Drug-seeking behavior despite aversive consequences- addicts and such don't worry about things like prison o Increased breaking point on a progressive ratio schedule of reinforcement over time- getting dependent and tolerant
What are the three models of depression?
o Monoamine hypothesis o Neurotransmitter receptor hypothesis o The monoamine hypothesis of gene expression
What changes in brain are found following habitual drug use?
o The first change occurs in the n accumbens (less dopamine is found in the cleft)- down-regulation o This is followed by sensitization of the dorsal striatum- sensitize motor system
What are the differences between response, relapse, remission, recovery and recurrence?
response- reaction to someting relapse- suffer deterioration after a period of improvement. remission-a diminution of the seriousness or intensity of disease or pain; a temporary recovery recovery-a return to a normal state of health, mind, or strength recurrence-return to a previous condition, habit, subject, etc.
What studies used self-administration procedures?
used to study why drugs are reinforcing
What is a drug discrimination study?
Train rats to press a right lever and a left lever. Day 1: inject rats with heroin. Left lever you get food, right lever you get nothing Day 2: inject rats with saline. Left lever you get nothing, right lever gives you food We continue to alternate over days the injections
What variables increase relapse?
- CS associated with drug (CS+ for drug)- Pavlovian - Stressors (mild shocks) - Small sub-threshold drug primes ( very low doses of the drug- the person/rat is not consciously aware that a drug has been administered)
What are the differences in how a single injection vs. two weeks of injections of cocaine changes the synaptic strength along the mesolimbic pathway?
-A single injection of a drug of abuse can result in synaptic strengthening that lasts for about 5 days. -Injections of cocaine for two weeks results in changes in synaptic strength that persists.
What is the evidence for monoamine hypothesis of depression?
-Certain drugs that deplete these NTs (monoamines-norepinephrine, dopamine, serotonin) can induce depression -Antidepressants which increase levels of these monoamines can decrease depression -NE metabolites are lower in some patients with depression compared to controls who are not depressed. These data, however, are not consistently found. -Other studies have found that the serotonin metabolite 5HIAA is reduced in CSF of depressed patients. When this data is more closely examined, these lower levels of 5HIAA are much better correlated with patients who have disorders. For example, patients with violent outbursts and patients with borderline personality disorders who show self-destructive behavior.
What are the consequences of the strengthening of synaptic connections in habitual drug use?
-Increased activation can now be measured in other circuits including the ventral striatum ( includes the n accumbens- reinforcement) and the dorsal striatum (caudate n and putamen- motor system) -Following long-term use of the drug, there are changes in the synaptic connections that mediate compulsive use of the drug. The most important changes are occurring in the dorsal striatum. -At the start of drug use the pleasurable effect of the drugs control the behavior via positive reinforcement. Overtime, as drug taking becomes habitual impulse control is diminished, the drug becomes less pleasurable. -Early reinforcing effects of the drugs of abuse occur in the ventral striatum (n accumbens) and increase incentive motivation.
What is the research on the role of peptides in the reinforcing effects of drugs of abuse?
-Orexin- Plays a role in control of sleep stages and food seeking behavior and is synthesized in neurons in the lateral hypothlamus and released into many areas of the brain including the VTA, n accumbens and dorsal striatum. -Findings: Several studies have demonstrated that CS's associated with drugs of abuse activate orexin neurons- o Infusion of Orexin in the VTA reinstates drug seeking that was extinguished. o Infusion of an antagonist that blocks Orexin receptors in the VTA blocks cocaine seeking triggered by CS's associated with the drug. o The Orexin antagonist also prevents learning in a Conditioned Place Preference Procedure for morphine. -MCH (Melanin Concentrating Hormone) is synthesized in the Lateral Hypothalamus. Stimulates hunger and reduces metabolic rate -MCH receptors found on neurons that also contain dopamine receptors o Chung et al., (2009) - If you stimulate (agonist) both dopamine receptors and MCH receptors you see increased firing of the n accumbens neurons. If you block (antagonize) the MCH receptors the effectiveness of cocaine self administration as well as CS's ability to promote drug seeking o Cippitelli et al., (2010) - Mutated the gene that codes for MCH receptors. Both drug CS's associated with the drug did not effectively control drug seeing behavior Provides additional evidence for the role of MCH in drug reinforcement.
How does conditioned withdrawal develop?
-Repeated use of the drug -Physical Dependence -Reduced levels of the drug (US)-> Unconditioned Response = Withdrawal (UR) -Environmental Stimuli (CS) associated with withdrawal (UR) leads to conditioned withdrawal (CR). One CR is craving. This would be an example of S-R learning. • CS-UR association • Conditioned withdrawal- CS directly activates the response craving
What is the research on bilateral and unilateral administration of antagonists and lesions in the n accumbens and dorsal striatum on drug seeking.
-Research has demonstrated that bilateral (both sides) infusions of a dopamine antagonist into the dorsal striatum will suppress responding to a light that was associated with the infusion of cocaine. -Unilateral infusions of a dopamine antagonist into the dorsal striatum had no effect on an operant. -Unilateral lesions of the n accumbens had no effect on operant behavior ( e.g. lever pressing), -Lesions to the n accumbens on one side of the brain and a dopamine antagonist infused on the other side of the brain resulted in suppressed responding to a light (CS+) that was previously associated with cocaine. *These data suggest that the control of compulsive behavior observed in drug addiction is mediated by an interaction between the ventral and dorsal striatum. These are dopamine synapses.
What factors play a role in the development and maintenance of drug abuse and addiction?
-Route of administration: Fast onset of drug action is the factor that plays the greatest role in addiction potential. Fast onset of drug produces the most euphoria. (the faster a drug gets into the brain the more addictive the drug tends to be) -Most abused drugs are reinforcing and rewarding. Drugs are powerful positive reinforcers (increase incentive motivation- I want it) Drug reward refers to the positive subjective feelings activated by the drug (increase in pleasure- I like it) -The rewarding properties of drugs are a key factor in why drugs are reinforcing but not the only factor. -Better attention from psychomotor stimulants can serve to increase the likelihood of taking the drug.
What are the results of the Saal and colleagues (2003) experiment?
-Single administration of a number of different addictive drugs increased the strength of excitatory synapses on dopamine neurons in the VTA of mice -This change may be the result of the insertion of additional AMPA receptors in the post-synaptic membrane of dopamine neurons in the nucleus accumbens.
What are the different ways that aberrant gene expression may lead to unipolar depression?
-one hypothesis is that due to abnormal gene expression, the target gene for BDNF is repressed. This leads to atrophy and apoptosis of hippocampal neurons. BDNF binds to the tyrosine kinase receptor. -Recent evidence (2005) showed that serum brain-derived neurotrophic factor (sBDNF) of drug-free depressed patients are lower than those of healthy controls and proposed that low sBDNF levels might reflect failure of neuronal plasticity in depression.
How can we explain the delayed response of antidepressant drugs?
1) Antidepressants will eventually result in down regulation of the receptors that key neurotransmitters bind to. The time course of this down-regulation corresponds to the delayed on-set of the action of the antidepressant.- correlational not causal 2) Depression results from abnormal functioning of gene expression ( A target gene for the expression of brain-derived neurotrophic factor) that is induced as a consequence monoamine neurotransmitters binding to receptors. The action of antidepressants is to eventually cause key genes to prevent the repression of BDNF. - Antidepressants up-regulate BDNF- increase concentrations of BDNF- more released.
What is the conditioned place preference procedure?
A box in which the middle is gray and one side is black and one white and the rat can move freely between the spaces. Obtain a baseline (measure the amount of time spent in each side). Rats are nocturnal and prefer the black side. 24 hours later, inject rats with cocaine, place the rat in least preferred side (white) for 15 minutes. Next day rat is injected with saline and placed in the black side. Alternate injections for three days. TEST: put rat in gray center and allow exploration. How much time do they spend in the black and white. -If cocaine is rewarding, the rat will spend significantly more time in the white side than at base line.
What is the differences between an FR and a progressive ratio schedule of reinforcement?
A fixed ratio schedule means that for every so many presses (a fixed value) the rat is rewarded. A progressive ration schedule means that the number is not fixed.
What are the findings reported by DiChiara (1995)?
Addictive drugs including cocaine, opiates, nicotine, alcohol, PCP and cannabis all have been shown to increase the release of dopamine at the n accumbens as assessed using microdyalysis.
What receptors or pathways are effected by tricyclics ? if given
As explained above tricyclics impact the muscarinic cholinergic receptors, H1 histamine receptors, alpha 1 adrenergic receptors, they also impact reuptake of serotonin, norepinephrine and dopamine.
What are the mechanisms of action of typical antipsychotic drugs at the mesolimbic pathway?
Blockade of the D2 receptor (competitive antagonist at D2 receptors) in the mesolimbic pathway is the major therapeutic mechanism in the treatment of schizophrenia using the conventional antipsychotic compounds
What are the mechanisms of action of typical antipsychotic drugs at the nigrostriatal pathway?
Blockade of the D2 receptors along this pathway can result in extrapyramidal symptoms, called drug induced Parkinson's (shaking)If the D2 receptors are blocked for extended periods of time then you can see Tardive dyskinesia. This is a movement disorder that causes facial and tongue movements including constant chewing, tongue protrusions and facial grimacing. Limb movements can be quick and jerky. Up-regulation of D2 receptors may lead to tardive dyskenesia.
What is the evidence for the mesolimbic dopamine hypothesis of the positive symptoms schizophrenia?
Dopamine binds at D2 receptors. Diseases or drugs that increase dopamine in this area will increase or produce the positive symptoms of schizophrenia. Drugs that decrease dopamine in this area will reduce or eliminate the positive symptoms- antipsychotic medications serve as competitive antagonists at the D2 receptors. -these empirical findings have lead to the mesolimbic dopamine hypothesis of positive psychotic symptoms of schizophrenia: Hyperactivity of the DA system in this area accounts for the positive symptoms as observed in either schizophrenia or drug induced psychoses. It may also play a role in aggressive and hostile symptoms that are seen in schizophrenia.
Why are drugs negatively reinforcing?
Drug dependence leads to drug withdrawal - drug withdrawal is aversive- Explain. Drug removes the aversive consequences of withdrawal, serving as a negative reinforcer.
How do researcher study if a drug is reinforcing?
Drug self-administration procedures- lever press activates liquid pump, drug infused into vein of rat o If you use an FR (fixed ratio) schedule of reinforcement and measure a dose response curve, it is not linear but rather an inverted U shaped function. The dose response curve measures the number of infusions as a function of the dose. -Use a progressive ratio schedule of reinforcement to determine a breaking point (Continue to increase the FR value over time. The FR value in which the organism stops pressing is called the breaking point.)
What are the receptors that are involved in the side-effects of typical antipsychotic medication?
H1 histamine receptor, alpha 1 adrenergic receptors and muscarinic cholinergic receptors.
How is the mechanism of action of haloperidol different from other typical antipsychotic medications?
Haloperidol is different from many other conventional antipsychotic compounds. First, it has greater potency and it also does not show potent antimuscarinic and antihistamine effects. Side effects produced at the alpha 1 adrenergic receptor but not at the H1 or M1 receptor. Less likely to see shaking because not blocking the M1 receptor- low likelihood of EPs- won't see Parkinson like adverse events
What is the anatomy and symptoms that are related to the tuberoinfundibular pathway?
Has axons from hypothalamus (arcuate nucleus) to anterior pituitary. Mediates a medication induced side effect. Normally these neurons are active and inhibit prolactin release. After a baby is born the activity of dopamine neurons is reduced and prolactin levels rise during breast feeding so lactation will occur. Antipsychotic meds can affect this pathway and lead to breast secretions and possibly sexual dysfunction.
What is the anatomy and symptoms that are related to the mesolimbic pathway?
Has axons from the VTA to nucleus accumbens. There is evidence of the importance of this area in the biological basis of schizophrenia. Excessive amounts of dopamine mediate the positive symptoms of schizophrenia.
What is the anatomy and symptoms that are related to the nigrostriatal pathway?
Has axons from the substantia nigra to basal ganglia (caudate n. and putamen). Involved in medication induced side effects (mediates side effect of antipsychotic drugs). When there is a deficiency of dopamine here it can lead to movement disorders like Parkinson's. Antipsychotic meds can produce tremors and difficulty with movement as a consequence of reducing the available dopamine along this pathway. Hyperactivity along this pathway may result in tics.
What is the anatomy and symptoms that are related to the mesocortical pathway?
Has axons that project from the VTA to limbic cortex in the frontal lobe. Role of this pathway is unresolved; however, evidence suggests it may play a role in negative symptoms of schizophrenia. -Some researchers argue that negative symptoms of schizophrenia are due to a deficit of dopamine in this pathway. -Another possibility is that there is too much glutamate that is killing neurons in that area, exocitotoxic overactivity of the glutamate systems
What research examines the effect of the injection of a dopamine antagonist into the dorsal striatum?
If a dopamine antagonist was injected directly into the dorsal striatum (motor), lever pressing was suppressed. Lever pressing was reinforced by a conditioned stimulus, a light that was paired with the IV injection of cocaine.
How does it allow you to study if a drug is reinforcing or rewarding?
If a drug is reinforcing or rewarding, the rat will go to the side on which they got the drug, it is form of Pavlovian conditioning.
What are the mechanisms by which cholinergic pathways interact with dopamine neurons along the nigrostriatal pathway to either produce or reduce EPS?
If an antipsychotic has high affinity for the M1 receptor are less likely to have Parkinsonian symptoms. If it has low affinity for M1 receptors more likely to see shaking -The NTs acetylcholine and dopamine have reciprocal actions in the nigrostriatal pathway. When dopamine is released and binds to the postsynaptic receptors on the Ach neuron it will inhibit the release of Ach. -If a conventional antipsychotic compound is given it will block the D2 receptors along the nigrostriatal pathway causing an increase in the activity of Ach. This consequence is associated with EPS. Thus, the EPS is due to both, underactivity of dopamine and overactivity of Ach -When a conventional antipsychotic compound has anticholinergic activity, it will block the M1 receptor site, so that even though the D2 receptors are blocked and there is an excess of Ach released, it has more difficulty getting to the M1 receptor and the EPS are reduced.
