Addiction Flashcards
Briefly define addiction
‘Drug addiction is a chronic disease that involves cycles of drug use, abstinence and relapse. It is characterised by compulsive drug seeking and use, despite harmful consequences.’ Wolf, 2016
Explain how drugs increase dopamine release- what structures are involved?
Dopamine (DA) neurons located in the ventral tegmental area (VTA) and projecting to the nucleus accumbens (NAc) play a key role in the processing of reward-related stimuli, including those associated with drugs of abuse (Wise, 2008). Drugs of abuse increase the release of DA in the NAc (Di Chiara, 2002). This leads to the stimulation of D1 receptors (D1R) in the NAc, which activate the direct striatal pathway, and the stimulation of D2 receptors on medium spiny neurons (MSNs) in the NAc, which activate the indirect striatal-cortical pathway.
How does the indirect and direct striatal pathway modulate reward and motivation?
The ventral striatal direct and indirect pathways have distinct roles in modulating reward and motivation. The direct pathway is associated with reward, whereas the indirect one is associated with punishment (Kravitz et al., 2012). Thus, DA receptor stimulation of the direct pathway directly mediates reward, whereas DA-receptor-mediated inhibition of the indirect pathway opposes aversive responses. This could explain why maximal drug reward is obtained when DA binds to both D1R and D2R.
What characteristics does the dopamine release triggered by the drug need to have in order for the drug to have a reinforcing effect?
To be reinforcing, drug-induced DA increases need to be fast and sufficiently large to stimulate low- affinity D1R in addition to D2R, leading to the activation of the direct pathway and the inhibition of the indirect pathway. D1R stimulation in the NAc by itself is sufficient to produce drug reward (Caine et al., 2007), whereas D2R stimulation is not (Caine et al., 2002), and maximal reward occurs when both D1R and D2R are activated (Steinberg et al., 2014).
What is a possible explanation as to why subsquent administrations of cocaine result in a reduced “high” but the motivation to take the drug persists?
The DA increases triggered by cocaine, and presumably other drugs, activate D2R auto-receptors inhibiting DA cell firing and DA release (Bello et al., 2011), which is perhaps why the intensity of the cocaine “high” is reduced with subsequent administrations, whereas the motivation to continue to take the drug continues unabated.
Briefly what is thought to underlie the transition from voluntary drug taking to drug addiction?
The transition from controlled to compulsive drug taking has been associated with a shift in the involvement of ventral striatum (NAc), implicated in the rewarding response to drugs, to the dorsal striatum that is associated with habit formation (Everitt and Robbins, 2013)
Is drug addiction actually just a disease of memory and learning?
Drug-induced neuroplasticity evokes the same types of molecular processes involved in long-term potentiation (LTP) and long-term depression (LTD) that underlie learning and memory. The changes in synaptic strength that occur as a result of LTP are associated with larger synapses and dendritic spines, while those that follow LTD involve smaller synapses and dendritic spines (De Roo et al., 2008). These synaptic modifications generate a long-lasting molecular memory for the drug’s rewarding and conditioning effects that will modify subsequent behaviors (Hyman, 2005).
How does release of dopamine regulate changes in synaptic plasticity which is thought to underlie drug addiction?
Dopamine is thought to increase synaptic strength/ cause LTD as increases in dopamine have been shown to lead to the insertion of high- calcium permeable AMPAR (GluR2 subunit) in MSNs located in the NAc (Boudreau et al., 2007). These AMPAR have higher single-channel conductance than GluA2-containing receptors (Guire et al., 2008), and their upregulation increases the responsiveness of MSNs in the NAc to glutamate which is released by cortical and limbic terminals when exposed to drugs or drug cues (Wolf, 2010).
This responsivness/plasticity of MSNs to glutamate is what is thought to generate that feeling of “craving” .
What has been shown to reverse the effects of increased dopamine on MSNs?
Increased dopamine causes increased glutamate receptor plasitcity in DR1 expressing MSNs in the NAc, which generates feelings of “craving”. Creed et al 2015, showed by low frequency stimulation (10-15Hz) causes LTD, which essentially reverses thethe changes in AMPA receptors in DR1 neurons induced by dopamine. This causes the behavioural aspects of craving to be lost.
How does cocaine lead to changes in the dorsal striatum?
Though not as extensively investigated as the NAc, the dorsal striatum also undergoes neuroplastic changes with repeated cocaine exposure; these are implicated in habit learning and in the automatic cocaine consumption triggered by repeated cocaine exposures (Everitt et al., 2008, Parikh et al., 2014)
How does repeated drug exposure affect DR2 receptors?How does this effect other brain regions?
Repeated exposure to different types of drugs has been associated with downregulation of D2R in striatum (Volkow et al., 2001). This down regulation of D2R in the striatum (including the NAc) has also been shown in rodents with a propensity to self-administer drugs (Everitt et al., 2008). This study showed that in rodents, the low levels of D2R in striatum correlate with increased impulsivity and predict escalating and compulsive administration of cocaine (Everitt et al., 2008).
Low levels of D2R in the striatum will result in reduced DA inhibition of the indirect pathway. Reduced D2R-mediated DA inhibition of the indirect pathway will lead to reduced thalamo-cortical stimulation and consequently reduced activity in PFC brain regions (Black et al., 2010). This includes the anterior cingulate (ACC) and orbitofrontal (OFC) cortical regions. Volkow and Fowler, 2000 have shown that the ACC and OFC are necessary for self-control and for processing salience attribution, and that their disruption is associated with a propensity for impulsive and compulsive behaviors. Thus it is likely that low levels of D2R in striatum may mediate the risk for compulsive drug taking in part by impairing PFC regions that inhibit prepotent responses and enable flexibility of behavioral choices as a function of changing environments (Volkow et al., 2006a). This is supported by the study by Chen et al 2013, who showed that in rodents, optogenetic stimulation of the PFC prevented cocaine relapse.
What else is different about dopamine in addicted individuals?
It has been reported that without the drug, they are in a hypodopaminergic due to reduced dopamine release - this would explain an addicted individual’s decreased sensitivity to natural rewards (e.g. food, sex, etc) and the perpetuation of drug use as a means to temporarily compensate for this deficit
What changes in DA signalling occur when transitioning from a normal individual to a drug intoxicated one?
DA signaling though D1R versus D2R was biased in favor of DA-mediated D1R signaling during the state of intoxication (Park et al., 2013). Since DA stimulation of D1R is associated with enhanced sensitivity to drug reward, a higher D1R-to-D2R signaling ratio during drug intoxication could contribute to compulsive drug taking.
What are some of the differences in brain areas between controls and drug addicts?
The regional brain activation responses to a stimulant drug also differ between controls and cocaine abusers in ventral prefrontal regions. In control subjects, intravenous stimulant administration decreased the activity of ventral medial frontal regions (OFC and ventral ACC), whereas in cocaine abusers, it activated these regions, which are involved in salience attribution and conditioning (Dosenbach et al., 2006, O’Doherty et al., 2001, Shackman et al., 2011). Activation of the OFC in cocaine abusers was associated with craving (Volkow et al., 2005). In contrast, activity in the right inferior frontal region Ba 44, a key brain region involved in inhibitory control (Aron et al., 2004), was associated with the deactivation of the NAc and ventral PFC upon successful control of cocaine craving (Volkow et al., 2010). This pattern of responses uncovers distinct contributions of PFC regions to addiction on the basis of their striatal projections: dorsalateral-dlPFC and inferior frontal regions that project to the dorsal caudate facilitate self-control, whereas ventral PFC regions projecting to NAc facilitate drug taking (Goldstein and Volkow, 2011).
The ventromedial PFC (including OFC and ventral ACC) in drug-addicted individuals, which in the absence of drug or drug cues is hypofunctional, becomes hyperactive when exposed to drugs or cues, enhancing reward salience calculation through its involvement in the processing of the outcome value of that reward (Volkow et al., 1996).
What is reward prediction error? Define briefly
Reward prediction errors consist of the differences between received and predicted rewards. They are crucial for basic forms of learning about rewards and make us strive for more rewards—an evolutionary beneficial trait.
