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PY365 Substance Misuse > Physiology of reward circuit > Flashcards

Physiology of reward circuit Flashcards

1
Q

give examples of illicit substances

A

alcohol, amphetamine, cocaine, benzodiazepines, heroin and other opioids

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2
Q

define substance misuse

A

the recurrent use of illegal drugs and substances for the purposes not indicated within the legal and medical guidelines

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3
Q

what was found when the brains reward circuitry was discovered

A
  1. found that animals would repeatedly return to an area of the lab in which they received mild electrical stimulation of subcortical structures, anatomically associated with the medial forebrain bundle
  2. animals would perform hard and painful tasks ro receive such brain stimulation
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4
Q

what were mapping studies used for

A

conducted to identify the brain reward pathways

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5
Q

what are translational studies

A

transform animal findings to human body

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6
Q

why do our brains develop a reward circuit

A

to motivate performing behaviours and tasks including eating and drinking, or taking psychoactive drugs
- such activities induce a behavioural reward feedback (positive reinforcement)

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7
Q

what 2 pathways are included in the reward circuit

A
  1. mesocortical pathway
  2. mesolimbic pathway
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8
Q

what is the function of the ventral tegmental area

A
  1. receives information from several brain regions responsible for processing information on fundamental needs, such as the hypothalamus and how human needs are being satisfied
  2. the vTA functional diversity is partly reflected by its cellular and circuit heterogeneities
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9
Q

what is the VTA composed of

A

60% dopaminergic neurons, 35% GABAergic neurons and 5% glutamate neurons

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10
Q

what does the mesolimbic pathway consist of

A

VTA and nucleus accumbens

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11
Q

where does the dopaminergic pathway run from

A

from VTA of the midbrain through medial forebrain bundle to reach nucleus accumbens and the limbic regions

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12
Q

describe the role of dopaminergic neurons in the mesolimbic pathway

A
  1. the dopaminergic neurons connecting VTA to Nac receive information from other parts of the brain, such as the cortex, hippocampus, thalamus, amygdala and raphe nuclei, to modify the reward feeling and therefore contribute to reward associated learning
  2. dopaminergic neurons activate GABAergic neurons in the Nac that project to multiple regions, including the vTA
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13
Q

What is the mesolimbic pathway responsible for

A

responsible for regulating emotional expression, learning reinforcement and hedonic capacity

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14
Q

where does the dopaminergic pathway run from in the mesocortical pathway

A

dopaminergic pathway runs from VTA of the midbrain through medial forebrain bundle to reach the prefrontal cortex

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15
Q

describe the role of dopaminergic neurons in the mesocortical pathway

A
  1. dopaminergic neurons activate glutaminergic neurons in the PFC that project to multiple regions, including the Nac
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16
Q

what is the mesocortical pathway responsible for

A

involved in regulating motivation, concentration and executive cognitive functions

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17
Q

what other neurotransmitters are involved in the mesocortical and mesolimbic pathways

A

GABA and glutamate

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18
Q

describe what occurs in the mesocorticolimbic pathways in terms of GABA

A
  1. y-amino butyric acid (GABA) binds to its post synaptic GABA receptor to exert inhibitory effects in the mature mammalian CNS and decrease neuronal excitability of many neural circuits
  2. GABA neurons of the VTA receive inhibitory, excitatory and neuromodulatory inputs from throughout the brain
  3. VTA GABA neurons synapse onto VTA DA neurons
    - inhibiting the dopamine firing from dopaminergic neurons
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19
Q

what is the role of GABA autoreceptors

A
  1. found on GABA neurons
  2. inhibit the release of GABA through negative feedback and therefore inhibit the inhibitory effect of GABA
    - disinhibition
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20
Q

which brain areas is GABA released from

A
  1. VTA interneurons
  2. Nac shell
  3. ventral pallidum
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21
Q

name the types of GABA receptors

A
  1. fast acting ionotropic GABA-A receptor
  2. slow acting metabotropic GABA-B receptor
  3. fast acting ionotropic GABA-C receptor
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22
Q

describe the properties of fast acting ionotropic GABA-A receptors

A
  1. consist of 5 receptor subunits
  2. each of the subunits is 1 of 3 predominant subtypes (a,b,y)
  3. receptor activation requires the simultaneous binding of 2 GABA molecules to the receptor, 1 to each of the 2 binding sites at the interface of the a and b subunits
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23
Q

describe the properties of slow acting metabotropic GABA-B receptors

A
  1. G protein coupled receptors that activate K+ channels to mediate the efflux of K+
    - therefore, inhibiting cell excitation
    - autoreceptors
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24
Q

describe the properties of fast acting ionotropic GABA-C receptors

A
  1. the GABA-A and GABA-C receptors are Cl- channels that mediate fast synaptic inhibition
  2. both GABA-A and GABA-C receptors are members of a superfamily of transmitter gated ion channels that includes the nicotinic Ach and 5HT3 receptors
25
Q

what is dopamine firing stimulated by

A

glutamate

26
Q

where in the brain is glutamate released from

A
  1. pre frontal cortex has been shown to send glutaminergic afferents to the VTA to control burst firing
  2. VTA receives a number of excitatory inputs including glutamate from subcortical brain structures, that may be relevant to the integration of environmental stimuli
  3. orbitofrontal cortex
  4. VTA glutamate neurons can drive positive reinforcement by releasing glutamate in the Nac, even in the absence of dopamine release
27
Q

what is the role of the orbitofrontal cortex

A

a key region for the encoding of reward value and prediction error

28
Q

explain how glutamate is synthesised

A

glutamate is synthesised through a-ketoglutarate from the Krebs cycle and transaminated to glutamate in CNS nerve terminals

29
Q

describe how glutamate is released

A
  1. released in the synaptic cleft via calcium dependent exocytosis to bind:
    - excitatory post synaptic ionotropic receptors
    - modulatory metabotropic receptors
30
Q

give an example of a excitatory post synaptic ionotropic receptor

A

NMDA, AMPA

31
Q

give an example of a modulatory metabotropic receptors

A

mGluRs

32
Q

what is the effect of modulatory metabotropic receptors

A

change the excitation rate of postsynaptic ion channels, leading to either inhibition or excitation

33
Q

what is the glutamate signal terminated by

A
  1. reuptake into the presynaptic nerve by Na+ dependent transporters
  2. diffusion away from the cleft
  3. receptor desensitisation- loss of sensitivity to neurotransmitter
34
Q

what does increased glutamate in the synaptic cleft lead to

A

leads to a positive feedback cycle that increases intracellular Ca2+ levels
- leading to further glutamate release and excessive excitation, causing hyperalgesia, seizures, neurodegenerative diseases and stroke

35
Q

describe how dopamine is synthesised

A

synthesised from amino acids
1. tyrosine- mainly obtained from diet
2. phenylaline- from liver
- dopamine is synthesised from L-tyrosine in the cytoplasm of the neurons
- dopamine is then transported into secretory vesicles for storage and release

36
Q

what is the role of tyrosine

A

the precursor amino acid in catecholamines synthesis

37
Q

how is the insertion of dopamine into vesicles achieved

A

achieved through pumps:
1. proton ATPase pumps that facilitate H+ influx into the vesicle
2. proton antiporter- vesicular monoamine transporter (VMAT) that works as a dopamine/H+ exchanger

38
Q

describe the process of dopamine synaptic transmission

A
  1. after synthesis, dopamine is stored in vesicle
  2. as action potential arrives, voltage gated Ca channels open leading to influx of calcium ions that bind to loaded synaptic vesicles
  3. vesicles translocated and docked with the membrane of the nerve, leading to the release of dopamine in the synaptic cleft
  4. dopamine binds to dopamine receptors in the postsynaptic affected organ/tissue leading to excitatory or inhibitory postsynaptic action
  5. Dopamine binds to dopamine autoreceptors in the presynaptic affected organ/tissue leading to inhibitory effect
39
Q

what occurs once dopamine is transported to the cleft in dopamine synaptic transmission

A
  1. dopamine is transported from the cleft back into the presynaptic cell by a 12 transmembrane domain protein, dopamine sodium co-transporter to be either recycled in the vesicle, or metabolised by MAOA
  2. Dopamine is metabolised by COMT
40
Q

what is Homovanillic acid (HVA)

A

a major metabolite of dopamine, which is excreted in urine

41
Q

what type of receptors are dopamine receptors

A

G protein coupled receptors

42
Q

what do dopamine projection pathways act on

A

act on D1-like (excitatory) or D2 like (inhibitory) receptors

43
Q

what are the D1 like receptors

A

D1 and D5

44
Q

describe the effect the D1 receptor has

A
  1. on postsynaptic neurons has a moderate stimulatory effect on locomotor activities
  2. critical roles in learning and memory mechanisms, such as working memory
45
Q

what are the functions of the D5 receptor

A

minimal learning and cognitive roles

46
Q

how do D1 like receptors have an excitatory effect

A

increase cAMP and PKA

47
Q

what are the D2 like receptors

A

D2, D3 and D4

48
Q

how do D2 like receptors have an inhibitory effect

A

decrease cAMP and PKA

49
Q

what are the functions of D2

A
  1. On the postsynaptic neurons has a moderate stimulatory effect on locomotor activities
  2. critical roles in learning and memory mechanisms
  3. may contribute to negative feedback as autoreceptors
50
Q

what are the functions of D3 receptors

A

may contribute to negative feedback as autoreceptors

51
Q

what are the functions of D4 receptors

A

minimal learning and cognitive roles

52
Q

what may happen if the presynaptic neuron is stimulated twice

A
  1. may lead to paired pulse depression- when longer inter stimulus intervals are applied, it leads to a transient depletion of the release ready pool of vesicles docked at the presynaptic terminal
53
Q

why do many synapses exhibit paired pulse depression at shorter inter stimulus intervals (20ms)

A

mainly because of the residual ca2+ left from the invasion of the first action potential
- contributes to additional release during the second stimulation

54
Q

when are longer lasting forms of plasticity observed

A

following repetitive or tetanic stimulation of synapses when prolonged trains of stimulation applied

55
Q

what does repeated pairing of postsynaptic spiking within 20ms after presynaptic activation lead to

A

leads to long term potentiation

56
Q

what is an example of short term synaptic plasticity

A

paired pulse depression

57
Q

give examples of long term synaptic plasticity

A
  1. long term potentiation
  2. long term depression
58
Q

what is long term potentiation

A
  1. mainly involves up regulation of either presynaptic or postsynaptic receptors
  2. when glutamate is released and binds to AMPA, it enhances Ca2+ influx that leads to more AMPA calcium membrane docking and hence amplifying glutamate induced excitation
59
Q

what is long term depression

A
  1. mainly involves downregulation of either presynaptic or postsynaptic receptors or cascade components
  2. when glutamate is released and binds to NMDA, a lower threshold Ca2+ current is generated that leads to AMPS dephosphorylation and internalisation
    - therefore depressing glutamate induced excitation

PY365 Substance Misuse (10 decks)

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