Becoña (2015)
conducted a literature review of the Vietnam Veteran Study in relation to drug consumption ○ Found that soldiers greatly increased their consumption of heroin in Vietnam ■ Had easy access to heroin (in the golden heroin triange of countries surrounding Vietnam), was very pure heroin, cheap ■ The consumed it to bear army rules and reduce homesickness ○ Showed that heroin consumption and dependence upon returning home was similar to that reported before going to Vietnam, where consumption increased temporarily ○ This reduction did not reflect treatment results ○ They call this spontaneous remission ○ If addiction was only biological – would this trend still be true? No, this is a criticism of the brain disease model Demonstrated that opiate use does not necessarily lead to addiction
James Olds and Peter Milner 1954
○ Electrodes were implanted into various points in the brain of rats, and the animals were placed in a Skinner box, arranged so that they could stimulate themselves by pressing a lever. ○ Especially when this brain stimulation was targeted at certain areas of the brain in the region of the septum and nucleus accumbens, the rats would repeatedly press the lever – even up to 2000 times per hour ○ This lead to the postulation by Olds (1956) of “pleasure centers” in the lateral hypothalamus and related brain regions ● Criticism: there would have to be multiple levers in the box for the rat to investigate, one of which resulted in delivery of a hedonic reward; rats are naturally curious and explore their environment – so if there was only one lever, they may have pressed it not because of the hedonic reward, but because it was something to play with ○ Also trauma of have the electrode put into the rat’s brain ● However, this is the work that ultimately lead to the notion that an identifiable brain mechanism subserves the fact that animal behaviour is driven by reward and punishment
Robert Heath 1960s
○ In one case, he even implanted electrodes to try and cure homosexuality (1972), with this line of research ultimately stopped and rightfully deemed unethical ○ Although the researchers also found compulsive lever pressing in some patients, it was never clear from these patient’s subjective reports that the electrodes did indeed cause real pleasure – this is criticism of this study ○ Some researchers today suggest that the electrodes never caused intense pleasure or ‘liking’ after all, but only a form of ‘wanting’ or motivation to obtain the stimulation ○ This does not support the animal studies above – suggests a more complex process in humans
Yokel and Wise 1975 and 1976
“● Rats were trained to lever-press for IV injections of amphetamine, a drug that causes release of each of the four monoamine neurotransmitters – noradrenaline, adrenaline, dopamine and serotonin. They trained animals to self-administer IV amphetamine and challenged with selective antagonists for adrenergic or dopaminergic receptors ● With dopamine antagonists, low and moderate doses – animals increased their responding (as do animals tested with lower than normal amphetamine doses) ● Rats treated with higher doses of dopamine antagonists increased responding in the first hour or how but responded intermittantly thereafter (as do animals tested with saline substitued for amphetamine. ● Wise observed similar effects in rats lever-pressing for cocaine in 1977, a year after ● These findings were interpreted as reflecting a reduction of the rewarding efficacy of amphetamine and cocaine, such that the duration of reward from a given injection was reduced by dopaminergic, but not noradrenergic, antagonists “
Wise 1978
○ Took 4 groups of rats and 2m long runways, where 3 of 4 groups had food rewards at the end. Used a dopamine antagonist in selected groups as well (pimozide) they were leaver-pressing for food ■ One was no antagonist given ■ One was give 0.5mg/kg of DA receptor antagonist ■ One was give 1 mg/kg of DA receptor antagonists ■ One control with no food ○ When initially tested, the animals responded normally to food reward – the pimozide-treated animals responded just as well as the animals that were given food in the absence of pimozide ○ Conducted repeats days later where food was again presented ■ In group with no antagonist → down walkway with normal speed ■ Control group with no food → no running = slower ■ The two groups that had the DA system blocked, on the first day they responded normally, but on following tries they began behaving more and more like the control with no food – ‘when retrained and tested a third and fourth time under pimozide, the animals still initiated responding normally but ceased responding progressively earlier’
Di Chiara and Imperato 1988
Microdialysis of DA (dialysis tubing inseretd into Nac and VTA) following administration of opiates, ethanol, nicotine, amphetamine, cocaine. Showed all drugs increase Nac DA.
Microdialysis has poor temporal resolution - they looked at DA release over 5 hours, need something more acute (need to see subsecond dyamics)
Daberkow 2013
Amphetamine increased phasic DA. Very dynamic dopamine changes in response to amphetamine. ‘Not like turning up volume’
Did not relate this phasic signalling to development of addiction, and only looked at amphetamine
Correlational, next studies show causation
Tsai et al 2009
● Focussed on DA neurones selectively ● Used optogenetics to stimulate VTA neuron action potentials ● Used a Cre-inducible adeno-associated virus (AAV) ● Used the conditioned place preference paradigm ● There were two chambers → one light and one dark ● Mice recieved phasic optical stimulation in one chamber ● Displayed a conditioned place prefernce for the environment where the VTA neurones were stimulated, in absence of other role ● Demonstrates role of VTA in reward
Pascoli et al 2015
- Used DAT-Cre mice and injected them with an Cre-inducible AAV expressing channelrhodopsn-2 and yellow fluorescent protein
- This produces specific expression of ChR2 in dopaminergic mesolimbic neurons
- Placed mice in a Skinner box where they could lever press, which elicited a burst of laser stimulation in the VTA
- This induced phasic firing in dopaminergic neurones, and led to a strong reinforcement of lever pressing
- After a few weeks of withdrawal, the first example of addictive behaviour was seen, where the mice pressed the lever although there was no stimulation present → this was only seen in mice that self-stimulated to begin with
- As well as this, they conducted a second series of experiments
- Self-stimulation was associated with foot shock
- Mice fell into two classes → those that self-stimulated (70%) and those that did not (30%)
- This is about 3x more than mice given cocaine (where 25% resisted punishment)
- Furthermore, cocaine infusion limited this self-stimulaiton
- Self-stimulation and action of cocaine therefore share underlying circuits, involving the VTA
- They only investigated cocaine - do drugs w different mechanisms have the same effect?
Mansvelder et al 2002
They studied the effects of nicotine application to horizontal sections of rat brains containing the VTA. Whole cell patch clamp recordings were made from VTA dopaminergic neurons. After application of 250nM nicotine, which is a nicotine concentration experienced by smokers, GABAergic IPSC frequency increased briefly and then rapidly returned to normal or below normal levels. After this, sensitivity to 1microM nicotine application was completely abolished, indicating effective desensitisation of nAChRs on GABAergic inputs to VTA neurons. However, after application of 250nM nicotine, 1microM nicotine application further increased EPSC frequency. Therefore, nicotine desensitises nAChRs on GABAergic inputs more than receptors on glutamatergic inputs, and therefore enhances excitation of postsynaptic dopaminergic neurons.
Corre et al 2018
- Put a channel rhodopsin known as Chrimson into DA neurons (by injecting a Cre-dependent virus into DAT-Cre mice) which allowed them to shine light on Chrimson to activate DA neurons. They used a new flourescent reporter technology to detect DA directly - this is called DLight - when DA is detected this sensor increases its flourescence. They showed that optogenetic activation in vivo of DA neurons led to increase in the DLight reporting where it was injected (in the medial part of the NAc). They found that after heroin injection there was an increase in flourescence (also saw this when administering cocaine). In a similar way, they used a genetically-encoded Ca2+ reporter - when they injected heroin into mice they report increase in Ca2+ fluorescence in DA cell body regions - greater DA neuron activity
- Chemogenetic inhibition of DA neurons suppresses heroin self-administration - Trained animals to DA via lever pressing - expression of DREADD in DA neurons, injected animals with CNO (leads to inhibiotry Gi casacde - this silencing of VTA DA neurons decreasedthe number of lever presses and heroin infusions - suggest that VTA DA activity is required for initial reinforcing properties of opioids from the v early stages of drug exposure
- Heroin occludes the reinforcing effects of self-inhibition of VTA GABA neurons - very clever twist Expressed light-gated inhibtory proton pump - Arch - in the VTA of GAD-Cre mice (GAD present preferentially in presynaptic terminlas for synthesis of GABA). Gave mice control over laser switch - quickly learned which was active and which wa sinactive laser. Injection of heroin lead to decrease of this behaviour. Indicates that heroin and VTA GABA self-inhibition share underlying circuits. Criticism - CNO may be metabolism to clozapine which which antagonises DRD2 and may have widespread effects - authors controlled for this using DAT-Cre- mice to demonstrate if CNO has non-specific effect in absence of the DREADD
Assumption - That direct light activation of presynaptic axon terminal recaoutulates the normal release process compared to APs generated at the soma
Rice and Cragg 2004
FSCV to look at effects of nicotine in guinea pig brain. Looked at dynamic release probability of dopamine during phasic burst (1-7 pulses of phasic bursts). Control - increasing burst number results in the same amount of DA release. Nicotine - increased DA release with increased bursts. Mimicked by beta 2 antagonist of nAChR. Concluded that nicotine acts of B2 subunit containing receptors to densensitise them
Nicotine given to whole cell so we don’t know know where in the neuron nicotine is acting and if it is physiologically releavnt (physiological release will be more local from INs for example)
Berridge et al 1989
injected 6-hydroxydopamine into rat midbrain VTAs to destroy dopaminergic neurons. Taste tests were then conducted on this rat group and a control rat group. Many different solutions were used- at the two ends of the spectrum, sweet sucrose and bitter quinine were used. Ingestive rat responses include paw licking and lateral tongue protrusions, while aversive responses include gaping and forelimb flailing. There was no significant difference in taste responses between dopamine-deficient and control rats, which indicates that hedonic reward experience is intact.
Hnsako et al 2005
- Administered morphine to tyrosine hydroxylase KO mice
- Tested conditioned place preference
- Mice repeatedly exposed to morphine in distinct chambers if a conditioning box and tested for preference to occupy that chamber
- Found that dopamine-deficient mice developed a CPP comparable to control mice that where administered morphine
- Dopamine deficient mice can develop a preference for the place where they recieved the morphine
- This suggests that dopamine may not be essential for the hedonic experience of reward
- Limitation - These animals suffered from severely reduced locomotion and other developmental adaptations, which precluded the testing for later-stage drug-adaptive behaviour
Kringelbach et al. (2003)
used BOLD fMRI to demonstrate that activation of the mid-anterior orbitofrontal cortex correlated with subjective rating of food pleasantness in healthy volunteers - 10 men given tomato juice, flavourless solution or chocolate milk - shows that dopamine neurons do not necessarily encode the pleasure of reward - pleasurable aspects of reward are encoded by other brain nuclei - such as the OFC.
Limitations - Does not exclude the nigostriatal pathway, only male subjects, only food reward (not necessarily drug addiction - could only be linked to taste)
Hollerman and Schultz 1998
“experiments on monkeys ○ Monkeys were simultaneously presented with two pictures ○They performed a discrimination learning task - when they pulled a lever associated with one of the pictures, they obtained a reward while the other picture was unrewarded ○ Response measured using an electrode implanted in the VTA - initially the monkeys did not know which picture was associated with reward ○ It was found that, on first exposure to the pictures, Neuron activity increases briefly after rewarded stimulus, Neuron activity is briefly inhibited after unrewarded stimulus (unexpected reward) ■ As the monkey learned which the rewarded stimulus was (the pictures were varying in left to right position), both excitatory and inhibitory responses disappeared (a low level of tonic firing occurs) They further found that after learning, dopamine neurons are activated by unexpected rewards (primary or novel enforcers) but not expected rewards AND and that dopamine neurons become activated by reward predicting cues (CS)”
Day et al 2007
used FCV to measure NAc dopamine levels in mice given sucrose (reward). As expected, dopamine initially increased upon sucrose delivery (unexpected reward), but after Pavlovian conditioning it increased upon cue presentation with no rise upon expected reward administration
Volkow et al 2005
administered 11[C]-raclopride to cocaine addicts, which is a D2 antagonist, and visualised the dorsal striatum with PET. One group was shown nature scenes, while the other group was shown scenes of cocaine purchase and preparation. A significantly smaller signal was observed in the second group due to greater displacement of the radioligand by dopamine release.
Chen et al 2013
- Investigated PFC hypoactivity in rats with compulsive cocaine-seeking behaviour.
- Rats underwent extended cocaine self-administration training (lever pressing).
- After greater than 8 weeks of SA, rats received foot shocks paired with lever pressing (as well as cocaine administration).
- They separated shock sensitive from shock resistant rats.
- Shock-resistant rats are a better model of addiction, since srug-seeking behaviour persists in the face of negative consequences.
- They performed whole-cell recording in deep layer pyramidal neurons of the prelimbic cortex, since these neurons project to subcortical structures implicated in drug-seeking behaviour.
- The amount of current needed to induce an AP was sig greater in neurons from shock-resistant rats compared to neurons from shock-sensitive and naive rats
- This indicated reduced excitability of these neurons.
- To test whether increasing PFC activity could reduce compulsive cocaine-seeking behvaiour, they injected AAV expressing ChR2-eYFP into the prelimbic cortex.
- Photoactivation of ChR2 in the prelimbic cortex sig attenuated foot shock-resistant cocaine seeking.
- In a contrasting experiment, AAV expressing eNpHR3.0 (halorhodopsin)-eYFP was injected into the prelimbic cortex (optogenetic inhibition)
- Photoactivation of halorhodopsin led to increased cocaine-seeking behaviour during foot shock-sessions in rats that were previously shock-sensitive.
- Therefore, the degree of prefrontal cortex activity seems to have an important impact on cocaine-seeking behaviour in rats
- Limitation - For their optogenetics - the ChR2-eYFP was injected into thr prelimbic cortex - this is p general - could be activating many different neurons and different circuits. Also acute foot shock does not represent chronic aversive stimuli in real life
Ungless et al 2001
- Reported that a single dose of cocaine was sufficient to induce a trace at excitatory synapses onto VTA DA neurons that lasted for about a week - compared the relative contributopn of AMPARs and NMDARs to excitatory posy-synaptic currents (EPSCs) recorded in DA in midbrain slices of cocaine-injected or saline-injected mice. Held neurons in voltage clamp at +40mV in the absence and presence of NMDAR antagonist APV and AMPAR/NMDAR ratio computed. Cocaine injection = sig higher AMPAR/NMDAR ratio - indicated LTP since a key feature of this is upregulation of AMPARs - cocaine exposue also increased AMPAR association mEPSC frequency and amplitude - upregulation
- Did not study behavioural effects
Yuan et al 2013
Recently before this paper, it was also shown that after a single cocaine exposure, NMDA-EPSC amplitude is also reduced. This indicated that the increased AMPA/NMDA ratio also has an NMDA-mediated component. GluN3A has reduced Mg2+ sensitivity and lower conductance. Used GluN3A KO mice and heterozygous littermates as controls. IN these KOs, cocaine evoked plasticity of NMDARs was absent, as demonstrated by the normal I/V curve of the NMDAR-EPSCs
Hearing et al 2016
They found that morphine enhanced synaptic strength and transmission at D1 MSN synapses and reduced signalling in D2 MSN synapses - morphine and saline injected into mice, 14 post-injection, did electrophyioloigcal resocrding in NAc shell, morphine increased A/N ratios in NAc shell D1R-MSNs but not D2R-MSNs, AMPAR-mEPSCs amplitude and frequency was elevated in D1R-MSNs w morphine compared to saline whereas frequency but not amplitude was reduced in D2R-MSNs
They knew opioid SA downregulates NAc GLT-1 expression (transporter responsible for 90% glutamate uptake). Antibiotic ceftriaxone increases GLT-1 expression. Treated mice with saline or ceftriaxone for 7-10 days following saline or morphine exposure. Ceftriaxone restored morphine-induced increases in D1R-MSN A/N ratios as well as mEPSC amplitude and frequency to control levels. Ceftriaxone also normalised morphine-induced reductions D2R-MSN mEPSC frequency compared with vehicle-treated morphine mice and saline controls. Cef normalises morphine-induced alterations in glutamate release at both cell types. Cef also blocked morphine induced reinstatement of CPP compared to vehicle treated animals
Investigated if projections from infralimbic cortex to NAc shell were important. Optogenetics - they evoked LTD of ILC inputs to D1 MSNs which blocked morphine induced reinstatment of CPP
Don’t know ceftriaxone MoA - shouldve done GLT1 KD and seen if it still worked then. Also Cef is acting globally (cannot extrapolate effects to only NAc changes). Morpine was experimenter-administered - differs from self-stimulation
Robinson et al 1997
Layer III pyramidal cells in the prefrontal cortex and medium spiny neurons in the core and shell of the nucleus accumbens were identified. Sholl analysis of ring intersections was used to estimate dendritic length. In the core and shell of the nucleus accumbens, dendritic length was significantly increased in amphetamine-treated rats compared to controls. Spine density was also significantly increased, as was the number of branched spines. The apical dendritic length of layer III prefrontal cortical neurons was also significantly increased in amphetamine-treated rats compared to controls.
Grimm et al 2003
used ELISAs to examine BDNF expression in the VTA and nucleus accumbens of mice who had undergone chronic cocaine self-administration several months after drug withdrawal. They found persistent elevation of BDNF in both brain areas, and BDNF levels correlated with cue-induced reinstatement tests of cocaine craving
