Targeted pharmacological treatments to normalise reward processing? In terms of improving quality of life, pondering longer-term, low abuse potential, viable options to restore some 'normality' to a highly dysregulated dopamine system, and the concept of normalising reward processing interests me. My latest experiment, under the guidance of my psychiatrist, has been, after a very long time, to recover some 'D2 receptor freedom', from about 80% occupancy with a partial agonist, which was not at all working, to more selective antagonism of the presynaptic D2 receptors with low dose amisulpride At one end of the scale, high levels of occupancy of D2 receptors via antagonism or partial agonism is considered important for attenuating positive symptoms but at the other end of the scale, reduced D2 receptor availability is an important pathophysiological mechanism for addiction that is both consequential and causal for other molecular, cellular, and neuronal network differences seen in SUDs. Some have explored targeting this 'Reward Deficiency' state as a therapeutic option While clinically in psychotic disorders, the emphasis is often on reducing positive symptoms, reducing the burdens of cognitive and negative symptoms seem to be better determinants of improved quality of life. If the positive symptoms are otherwise manageable, shifting the focus to things that better determine improved quality of life seems worthwhile. In dual diagnosis, I've pondered if too high a D2 occupancy might precipitate, or worsen addictive behaviours as a compensatory strategy for a reward-deficient state of hypodopaminergic signalling. Also, "striatal dopaminergic activity is not uniformly elevated in all ... patients, and the sub-group of individuals with lower baseline dopamine function are at an increased risk for dysphoric responses during antipsychotic therapy with dopaminergic blocking drugs". It makes rational sense that one would self medicate extreme negative affect or other unpleasant experiences induced by antipsychotics. We see a notable induction of anhedonia through small, clinically relevant doses of D2 antagonists in healthy patients, making it likely "antipsychotic medication contributes to clinical anhedonia, probably via antagonistic effects at the dopamine D2 receptor" along with reactions such as dysphoria and unpleasant states such as akathisia etc. Presynaptic D2 receptor antagonism with low-dose amisulpride Blunted activation in frontostriatal brain regions and poor behavioural responses during reward- and motivation-related decision-making were observed in depression etc. Chronic stress induced deficits in reward learning were reversed by low dose amisulpride Pharmacological reduction of DA levels in rodents reduces the willingness to choose behavioral options with high costs and high rewards (Salamone et al., 2016; Yohn et al., 2015), while increasing DA levels has opposite effects (Salamone et al., 2016; Sommer et al., 2014). Moreover, rodents with impaired DA functioning show deficits in their goal-directed behavior 1 "at low doses amisulpride preferentially blocks presynaptic D2/D3 dopamine autoreceptors controlling the release and synthesis of dopamine in the rat brain leading to an enhanced dopaminergic transmission, while postsynaptic dopamine receptor antagonism is apparent only at higher doses." In humans, a 50-mg dose of amisulpride has been associated with reduced blockade of postsynaptic D2/D3 receptor in comparison to higher doses, allowing more significant presynaptic effects, where blockade of these presynaptic autoreceptors acts to increase dopamine signalling. On the contrary, at 200mg, human SPECT binding suggest a predominant antagonistic effect via a D2 receptor occupancy between 60 and 80%. It seems to have limbic selectivity for specific brain areas involved in the control of cognitive functions, motivational and emotional behavior - animal work showing that low doses of amisulpride potentiate striatal dopamine release, have strong hedonic effects, and increase the incentive value of environmental cues - acts to enhance striatal response to reward, most likely via increased phasic dopamine signaling -In humans, low doses increased the ability to select the best of two high rewards - participants receiving low-dose amisulpride exhibited increased striatal activity in response to cues, and increased striatal activity and corticostriatal functional connectivity in response to reward outcomes. - Low-dose amisulpride has been shown to have antidepressant and antianhedonic effects in depressive disorders Berg M, Riehle M, Rief W, Lincoln T. Does partial blockade of dopamine D2 receptors with Amisulpride cause anhedonia? An experimental study in healthy volunteers. 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