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Researchers begin to map brain regions and circuits changed by cocaine-use.

Cocaine is a strong central nervous system stimulant that increases levels of the neurotransmitter dopamine in brain circuits regulating pleasure and movement.  Normally, dopamine is released by neurons in these circuits in response to potential rewards and then recycled back into the cell that released it, thus shutting off the signal between neurons. Cocaine prevents the dopamine from being recycled, causing excessive amounts to build up in the synapse, or junction between neurons. This amplifies the dopamine signal and ultimately disrupts normal brain communication. It is this flood of dopamine that causes cocaine’s characteristic high.

With repeated use, cocaine can cause long-term changes in the brain’s reward system as well as other brain systems, which may lead to addiction. With repeated use, tolerance to cocaine also often develops; many cocaine abusers report failing to achieve as much pleasure as they did from their first exposure.  It is this ‘dope fiend’ or newly developed reward and seek circuitry, the slow build-up to addiction, that researchers are interesting in mapping to uncover more targets.  Now, a study from researchers at Bordeaux University has mapped out the network of circuits in a murine cocaine model that cause wild firing of neurons that produce dopamine, a neurotransmitter that regulates movement and emotion. The team state that their findings also help explain how cocaine use eventually leads to desensitization.  The opensource study is published in the journal Cell Reports.

Previous studies show that the circuit-based plastic adaptation of ventral tegmental area (VTA) dopamine neurons is an indispensable initial step in reward-related circuitry, leading to the behavioural effects of cocaine. Recently, it has been shown that interactions between the hippocampus and the VTA are important for context-reward associations. The ventral subiculum (vSUB), which is the output region of the ventral hippocampus, plays a critical role in several fundamental cognitive functions, including the integration of information to modulate goal-directed behaviours as well as behaviors associated with cocaine seeking and the release of dopamine in the nucleus accumbens, which is associated with an increase in locomotor activity. Two mechanisms have been proposed to account for the activation of dopamine neurons in response to vSUB stimulation. The first assumes that vSUB inputs to the Nac lead to the disinhibition of dopamine neuron activity and control the proportion of spontaneously active dopamine neurons. The second proposed mechanism involves a glutamatergic structure that would receive vSUB inputs and project to the VTA, thereby controlling the activation of the dopamine neurons in response to vSUB stimulation, triggering cocaine-seeking behaviour.  However, the glutamatergic circuit by which vSUB and VTA interact remains to be elucidated.  The current study shows that synaptic plasticity in the anteromedial area of the bed nucleus of the stria terminalis, driven by a single episode of electrical stimulation of the vSUB could trigger hyperactivity of dopamine neurons that would in turn influence the locomotor effect of cocaine.

The current study used tracer molecules to follow electrical activity in the brain in rats exposed to cocaine. Results show that a network of neurons in the extended amygdala, the brain’s motivation/learning center, acts as a relay between activation of the brain’s addiction center, known as the the ventral subiculum, and the hyperactive release of dopamine.  The lab observed that over time, increasing activation of a key part of the extended amygdala, the bed nucleus of the stria terminalis produces a long-lasting increase in signal transmission onto neurons that produce dopamine so that the rats became desensitized to the cocaine. The group state that since this change happens within the amygdala, it may explain some of the long-term effects on behaviour and motivation that occur after prolonged cocaine use.

Results show that a single stimulation of the vSUB had the same impact on the brain and dopamine neurons as a massive injection of cocaine. Data findings show that these effects lasted up to five days and raise the possibility that dopamine-producing neurons can be changed so that they respond differently to stimuli.  Findings also show that the vSUB recruits the bed nucleus of the stria terminalis to drive a persistent hyperactivity of dopamine neurons and control cocaine-induced activity.

The team surmise that unraveling the neuronal circuit and characterizing the synaptic mechanisms by which the vSUB alters the excitability of dopamine neurons is a necessary first step in understanding the resulting behavioural changes induced by cocaine.   For the future, the researchers state that in addition to providing insights on the circuits involved in drug addiction, the findings might be helpful for understanding and even changing the perception of natural rewards; for example, those related to food or exercise, which they plan to pursue next.

Source: Bordeaux University



Graphical abstract depicts discovery that the ventral subiculum alters the excitability of dopamine neurons in vivo via a relay within the bed nucleus of the stria terminalis, revealing a neuronal circuit controlling behavioral effects of cocaine. Credit: Glangetas and Fois et al./Cell Reports 2015.
Graphical abstract depicts discovery that the ventral subiculum alters the excitability of dopamine neurons in vivo via a relay within the bed nucleus of the stria terminalis, revealing a neuronal circuit controlling behavioral effects of cocaine. Credit: Glangetas and Fois et al./Cell Reports 2015.

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