lec 2

Question 1

What did the study conducted by wise (1980) demonstrate?

Answer 1

Used electrochemical detection to demonstrate that increased DA levels were found after amphetamine, cocaine, nicotine and ethanol in comparison to baseline

Question 2

What did the Wiess study (2000) show?

Answer 2

Linked DA concentration to the motivation to take the drug.

Monitored cocaine taking using the self-administration model and noted that after rapidly driving cocaine intake the rats start to regulate their drug intake and this corresponds with the dopamine concentrations measures. Used saline to demonstrate that DA was linked to taking the drug as when drug swapped for saline the rats no longer regulated intake and see a diminishing effect.

Question 3

What is DA involvement in drug abuse?

Answer 3

DA transmission is deeply affected in drug abuse and changes to DA function are involved in various phases of drug addiction and potentially are exploitable therapeutically.

Question 4

What is DA involvement in the addicted brain?

Answer 4

> Rodents- DA release in the nucleus accumbens is decreased in virtually all drug-dependant rodents. This is supported by increases in intracanial self-stimulation thresholds during withdrawal from alcohol, nicotine, opiates and other drugs of abuse, thereby suggesting hypo function of the neural substrate of intracranial self stimulation (ICSS), which is DA.
Humans - imaging studies have shown a reduction in DA receptors accompanied with lesser release of DA in addicted patients supporting the “dopamine impoverished” addicted brain hypothesis.

Question 5

How can be block amphetamine induced euphoria?

Answer 5

D2 receptor antagonist

Question 6

What neurotransmitters are implicated in withdrawal?

Answer 6

> decreased dopamine
> decreased serotonin 
> decreased opioid peptides
> decreased GABA
> increased corticotrophin (releasing hormone due to withdrawal increased stress and anxiety- anxiety commonly associated with withdrawal but can be treated with benzodiazepines that are GABAa agonist - given during drug withdrawal)

Question 7

What is the importance of the nucleus accumbens in drug addiction?

Answer 7

DA release in the nucleus accumbens plays a central tole in reward, pleasure and thus addiction

Often the projection from the ventral tegemental area to the nucleus accumbens is called the pleasure reward pathway.

Question 8

On a molecular level, how does repeated drug use change the brain?

Answer 8

Chronic drug use leads to changes in the nuclear function and to alteration in transcription of certain genes by disturbing intracellular signalling pathways (cAMP-CREB, (triangle) FOSB). However, the biochemical basis of drug dependance is not well understood. Molecular adaptations have been shown to occur at the level of neurotransmitter synthesis, receptor levels/ sensitivity and intracellular signalling pathways.

Question 9

What is the mechanism of action of cocaine?

Answer 9

Cocaine binds at the dopamine transporter (DAT, SERT and NAT) and inhibits the reuptake of DA in the synaptic cleft, prolonging the action of DA in the synaptic cleft. Larger and longer lasting increase of extracellular transmitter activity Hyper activation of D1 and D2 dopamine receptors and depending on concentration can also affect 5-HT and NA too.

Question 10

What is the mechanism of action of amphetamines?

Answer 10

Amphetamies are actively transported into the cell by DAT, SERT or NAT (not selective although most amphetamine is transported by DAT). Amphetamine are very structurally similar to DA and NA. Once inside the presynaptic terminal they trigger cascades that results in the phosphorylation of the DAT transporter. The phosphorylated transporter works in reverse, secreting DA into the synaptic cleft. Ampetamine also enters pre-synaptic vehicles via VMAT (vesicular monoamine transporter) and this results in increased levels of DA in the presynaptic terminal ready for release. Large and longer lasting increase in DA concentrations

Question 11

What is the mechanism of action of opiates?

Answer 11

Bind to the Mu opiate receptor on the GABAergic interneurons in the ventral tegmental area, results in disinhibition of the GABAergic interneuron resulting in increased DA neuron firing and increased levels of DA in the nucleus accumbens

Question 12

What is the mechanism of action of Nicotine?

Answer 12

Binds to the nicotinergic acetylcholine receptors of the ventral tegmental area and increases DA firing resulting in an increase of DA in the nucleus accumbens.

Question 13

What is the mechanism of action of alcohol?

Answer 13

3 mechanism of action - 1. potentiates GABA mediated effects of GABAa receptor (inhibitory so reduction of firing) on GABA interneurons in ventral tegmental area 2. inhibits glutamate effects via NMDA receptors on GABA interneurons in ventral segmental area. 3. Enhances excitatory effects of DA neuron via the 5-HT3 neuron. Results in increased levels of DA in the nucleus accumbens.

Question 14

3 different ways of analysing a drug reward system using rodents?

Answer 14

1. Pharmacological blockage
2. Microinjection of drugs into the proposed brain loci - should induce systemic effects of drug. Can contrast positive and negative loci to essentially map the brain regions involved.
3. Attenuation of the drug response by brain lesioning

Question 15

What is intra-cranial stimulation and what does it tell us about drugs?

Answer 15

The reinforcing properties of a drug - useful to understand how neurotransmitters mediate behaviour.

Animals learn to work for an electrical stimulation, indicating a reward threshold - the current required to maintain working/ lever press. The lower the threshold the more important the brain areas is for reward/ reinforcement.

Doesn’t tell us anything about which brain regions are involved in reward as rats are not selective with the brain regions they stimulate.

Question 16

What is the mesolimbic reward pathways and what is it’s relevance to drug addiction?

Answer 16

The mesolimbic reward pathway is identified as being a key component in the reward system- mediates reward. Pathway originates from ventral tegmental area and projects to nucleus accumbens in the ventral striatum.

Drugs of abuse increase concentrations of DA in the mesolimbic pathway. There is a wealth of studies investigating whether increase or decrease DA in the nucleus accumbens has effect on self-administration. Using micro dialysis, minute changes can be assessed in real time and DA release has been correlated with cocaine self-administration.

Question 17

How does blocking D1 and D2 receptors affect intracranial self-stimulation behaviour?

Answer 17

Attentuates it but only when applied to the nucleus accumbens and not to the stratium - demonstrating that DA critical in the mesolimbic dopamine pathways and not in the straital negra.

Question 18

What happens to intracranial self stimulation threshold if you introduce a rewarding drug?

Answer 18

Wise 1996-

Reduction in intracranial self-stimulation thresholds when introduce a drug of abuse. If give cocaine then the curve shifts to the left. This lowering of threshold is found with various drugs of abuse! Also can use this model to pick up withdrawal as see an increase in threshold following chronic use of drug.

Question 19

Outline the role for CREB is opioid addiction?

Answer 19

CREB is a transcription factor and presumably causes behavioural alterations associated with drug addiction through the alteration of expression of other genes.

1. TOLERANCE - With chronic opioid use, CREB (cyclic-AMP response element binding protein) levels have been shown to be increase. A study that over expressed CREB in the nucleus accumbens showed that the rewarding effects of cocaine and opiates were decreased. Additionally transgenic mice over expressing CREB showed a decreased preference for cocaine in the conditioned-place-preference paradigm, suggesting that increased CREB expression is somehow involved with drug tolerance
2. WITHDRAWAL - target gene of CREB (Dynorphin) is associated with dysphoria during withdrawal. Dynorphin is induced by CREB in the NAC and acts as negative feedback in the VTA. Dynorphin binds to the K opiod receptor on cell body of VTA dopamine neurones and inhibits dopamine release in the NAC.

Question 20

Outline the role for FosB in chronic cocaine/ opioid use?

Answer 20

FosB is a transcription factor and presumably causes behavioural alterations associated with drug addiction through the alteration of expression of other genes. Increasing amount of evidence suggest fosB is a mechanism that drug of abuse form stable changes int he brain - e.g changes that mean an addict is at risk of relapse many years after abstinence. FosB itself is extraordinarily stable and persists in neurones for long periods of time. Postulated that changes gene expression - something that persists long after withdrawal.

> Mice that over express FosB show increased drug seeking behaviour and will self-administer lower dose of cocaine than little mates that do not over express fosB

> Chronic cocaine and morphine use cause lasting increases in FosB. FosB is a transcription factor so an increase in fosB can alter gene expression and may underlie to the neuronal changes seen with tolerance/dependance and sensitisation.

> FosB has been shown to accumulate in the nucleus accumbens in drug addiction and this accumulation has been shown with many other types of compulsive behaviour.

Question 21

Why are transcription factors implicated in drug addiction?

Answer 21

The longevity of behavioural abnormalities that characterise drug addiction have suggested regulation of neuronal gene expression are involved in the process by which neuronal changes contribute to drug addiction.