University of Arizona



ABNORMAL BEHAVIOR

- successful completion of goal leads to rewarding stimulus that further reinforces behavior, making it more likely to be repeated

1. Regions of brain supporting intracranial self-administration

- intracranial self-stimulation (ICSS); placing electrodes in limbic system supports ICSS; rats would press lever when electrode implanted in certain brain regions many times while they ignored natural rewards such as food or a mate

- brain regions supported included septal area, nucleus accumbens, amygdala, lateral hypothalamus and the cingulate cortex; placing electrodes along white matter tract called medial forebrain bundle, MFB (axons that ascend from dopaminergic, noradrenergic, and serotonergic brainstem nuclei to project diffusely to limbic and cortical structures) brainstem supports ICSS

- MFB widespread innervation suggests that this system is involved in regulating behaviors associated with drives or emotions, and in signaling cortex and limbic system to engage in behaviors to fulfill these drives

2. Dopaminergic pathways

- MFB contains axons of dopamine, NE, and serotonin containing neurons; dopamine is NT involved in supporting ICSS; neurons in substantia nigra (compact part ( basal ganglia) and ventral tegmental area, VTA (( limbic structures and cortex); destruction of dopaminergic neurons in VTA ( reduced ICSS

- key structures that support ICSS, such as nucleus accumbens, cingulate cortex and amygdala are structures that receive dopaminergic innervation through mesolimbic and mesocortical dopaminergic pathways

- normal pleasurable stimuli (eating, sex) induce release of dopamine; dopamine is key in regulating the ability to experience certain types of activities as pleasurable

3. Lines of evidence supporting the hypothesis that the reinforcing actions of cocaine are mediated through its actions on dopaminergic systems

1. Analogues of cocaine can be synthesized that vary in affinity for dopamine transporter and vary in ability to block dopamine reuptake into dopaminergic terminals. There is a close correlation between potency of these drugs in blocking dopamine reuptake and their potency in supporting self-administration.

2. Selective antagonists of dopamine receptors block cocaine self-administration, while selective antagonists of NE or serotonin receptors are without effect.

3. Selective destruction of the dopaminergic input from ventral tegmental area into nucleus accumbens by neurotoxin 6-hydroxydopamine disrupts cocaine self-administration.

4. Rats can be trained to press lever for injections of cocaine directly into nucleus accumbens or prefrontal cortex

4. The structure in the human brain in which increased dopamine release has been demonstrated following engagement in pleasurable activities is the ventral striatum (including nucleus accumbens)

5. The three brain structures whose increase in activity correlates with the high of cocaine intoxication included the ventral tegmentum, the basal forebrain, cingulate cortex and lateral prefrontal cortex; basal forebrain receives afferents from nucleus accumbens and dopaminergic input; these areas receive direct dopaminergic projections from mesolimbic and mesocortical pathways

6. The brain structures whose increase in activity correlates with craving following cocaine administration include nucleus accumbens, right parahippocampal gyrus, and some regions of the lateral prefrontal cortex

- Cocaine induces a sustained decrease in activity in the amygdala which correlates with subjective ratings of cravings

7, 8. OCD – Obsessive-compulsive disorder

- involves serotonin and dopamine pathways involved in reward

- changes in activity of caudate nucleus, right orbitofrontal cortex in patients with OCD

- OCD may be related to disturbance in basal ganglia

Possible mechanisms:

- head of caudate and pathway that connects caudate with prefrontal (orbitofrontal) cortex and cingulate gyrus is hyperactive in OCD patients

- Caudate nucleus ( sends GABAergic inhibitory projections to globus pallidus ( sends inhibitory projections to thalamus ( sends excitatory projections to orbitofrontal cortex

- disease state ( disinhibition ( continuous active state

- mutation in serotonin, 5-HT transporter ( increased expression and function of 5-HT transporter ( decrease amount of serotonin in synapse

- striatum innervated by serotonergic fibers; innervation localized to medial-ventral aspects of the head of the caudate nucleus and to the nucleus accumbens, regions that receive input from orbitofrontal and cingulated cortex regions through to be involved in emotional behavior

- serotonin pathways arise in raphe nuclei

- Correlation between Sydenham chorea and abnormal behavior patterns?

- Sydenham chorea patients had a number of reoccurring abnormal behaviors including OCD

- correlation between hyperintensity between head of the caudate nucleus and abnormal behavior

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