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In the early stages of substance abuse, subjects receive a drug that is highly reinforcing and are thus likely to repeat the actions that led them to obtain it.  This is termed positive reinforcement. However, in a minority of people who develop an addiction phenotype, negative reinforcement also causes a behavior to be repeated, but in this case, the action causes a bad feeling or situation to go away. The mesolimbic dopamine system, which is thought to generate a teaching signal, is involved in the selection of advantageous behavioral repertoires. This brain pathway is under control of endocannabinoid (eCBs), ubiquitous signaling molecules that bind to the same receptor targeted by marijuana (CB1) known to strengthen responses leading to the procurement of reward. Here, we investigate how eCBs modulate dopaminergic encoding of cues predicting either, appetitive stimuli, the avoidance of punishment or aversive outcomes. We find that disrupting eCB signaling by treating animals with a CB1 receptor antagonist dose-dependently decreased concentrations of dopamine release in the nucleus accumbens that were time-locked to a warning signal that predicts avoidance of punishment while simultaneously weakening shock avoidance behavior, effectively shifting the behavioral outcome from avoidance to escape. We further demonstrate, using directed mutagenesis approaches, that 2AG release from dopamine neurons in the midbrain is a canonical mechanism responsible for the pursuit of rewards.

It has been posited that compromised motivation in HD or “apathy” arises from a deficit in preparing for and initiating goal-directed behavior. Apathy is always the primary deficit in motivation associated with frontal-subcortical diseases such as HD. Indeed, apathy may be a core feature of HD disease pathology itself. In many cases apathy follows a similar trajectory as motor symptom progression in PD, although it can become prevalent before phenoconversion. It can be the result of several neurobiologically maladaptive systems, including affective (flattening of emotional responsiveness), behavioral (reduced initiation of spontaneous behavior), and executive dysfunction (difficulty planning/executing). Thus, motivational dysfunction in HD is a deficit primarily in preparation for motivated behavior that can have debilitating co-morbid consequences.

Gaps in knowledge

  • Loss of striatal cannabinoid type 1 (CB1) receptors is a key pathogenic of several neurodegenerative diseases, including HD.
  • Treatment for metabolic syndrome with the CB1 receptor antagonist Rimonabant was halted by the FDA because of loss of motivation and depressive ideation.
  • HD patients tend to smoke marijuana as a way to self-medicate and to prevent feelings of loneliness and helplessness.
  • Loss of goal-directed behavior in HD is specific to the incentive value of the reinforcer.
  • Treatment with indirect cannabinoid agonists profoundly increases operationally defined indices of motivation in normal animals and reverses apathy via dopaminergic mechanisms in mouse models of HD.

Together these data suggest that eCBs might modify distinct behavioral responses related to exteroceptive stimuli by modulating conditioned mesolimbic dopamine release events.  These findings suggest that therapies aimed at modifying tissue levels of eCBs may be used to prevent drug seeking driven by negative affective states or improve motivational indices in animal models of HD.



March 31, 2023
11:00 am - 12:00 pm


Rudy North Lecture Theatre, Djavad Mowafaghian Centre for Brain Health
2215 Wesbrook Mall
Vancouver, British Columbia V6T 1Z3 Canada

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