A mechanistic overview of approaches for the treatment of psychostimulant dependence.

Psychostimulant use disorder is a major health issue around the world with enormous individual, family-related and societal consequences, yet there are no effective pharmacological treatments available. In this review, a target-based overview of pharmacological treatments toward psychostimulant addiction will be presented. We will go through therapeutic approaches targeting different aspects of psychostimulant addiction with focus on three major areas; 1) drugs targeting signalling, and metabolism of the dopamine system, 2) drugs targeting either AMPA receptors or metabotropic glutamate receptors of the glutamate system and 3) drugs targeting the severe side-effects of quitting long-term psychostimulant use. For each of these major modes of intervention, findings from pre-clinical studies in rodents to clinical trials in humans will be listed, and future perspectives of the different treatment strategies as well as their potential side-effects will be discussed. Pharmaceuticals modulating the dopamine system, such as antipsychotics, DAT-inhibitors, and disulfiram, have shown some promising results. Cognitive enhancers have been found to increase aspects of behavioural control, and drugs targeting the glutamate system such as modulators of metabotropic glutamate receptors and AMPA receptors have provided interesting changes in relapse behaviour. Furthermore, CRF-antagonists directed toward alleviating the symptoms of the withdrawal stage have been examined with interesting resulting changes in behaviour. There are promising results investigating therapeutics for psychostimulant addiction, but further preclinical work and additional human studies with a more stratified patient selection are needed to prove sufficient evidence of efficacy and tolerability.

A Novel Peripheral Action of PICK1 Inhibition in Inflammatory Pain.

Chronic pain is a major healthcare problem that impacts one in five adults across the globe. Current treatment is compromised by dose-limiting side effects including drowsiness, apathy, fatigue, loss of ability to function socially and professionally as well as a high abuse liability. Most of these side effects result from broad suppression of excitatory neurotransmission. Chronic pain states are associated with specific changes in the efficacy of synaptic transmission in the pain pathways leading to amplification of non-noxious stimuli and spontaneous pain. Consequently, a reversal of these specific changes may pave the way for the development of efficacious pain treatment with fewer side effects. We have recently described a high-affinity, bivalent peptide TAT-P4-(C5)2, enabling efficient targeting of the neuronal scaffold protein, PICK1, a key protein in mediating chronic pain sensitization. In the present study, we demonstrate that in an inflammatory pain model, the peptide does not only relieve mechanical allodynia by targeting PICK1 involved in central sensitization, but also by peripheral actions in the inflamed paw. Further, we assess the effects of the peptide on novelty-induced locomotor activity, abuse liability, and memory performance without identifying significant side effects.

Initial rewarding effects of cocaine and amphetamine assessed in a day using the single-exposure place preference protocol.

In rodents, only a single dose of cocaine or amphetamine is required to cause a marked increase in extracellular dopamine, induce hyperlocomotion and cause persistent plasticity changes within dopaminergic neurons of the ventral tegmental area (VTA). The initial drug experience is suggested to predict vulnerability of developing addiction, but only few studies have assessed the perception of reward accompanying this initial exposure. We recently presented an approach to assess the initial rewarding effects of cocaine in mice with a single-exposure place preference (sePP) protocol, avoiding repeated drug injections. Here, we demonstrate a condensed version of the sePP, allowing assessment of initial subjective reward-perception within a day. By using this protocol, we demonstrate that a single exposure to both cocaine and amphetamine is sufficient to induce place preference. Furthermore, we use chemogenetics ( Designer Receptors Exclusively Activated by Designer Drugs [DREADD]) to show that both inhibitory and stimulatory modulation of VTA DA signalling disrupts cocaine-induced place preference in the condensed sePP. Our findings support the presence of initial reward-perception of both cocaine and amphetamine, and the formation of drug-context association. In addition, our data support that VTA DA signalling prior to drug exposure affects either reward-perception or the time during which associations are formed, thereby preventing induction of cocaine-induced place preference in the sePP. The easy and timesaving sePP protocol should form a critical basis for further deciphering the complex mechanisms underlying the progression from the initial drug experience to escalating drug intake and addiction.

PICK1-Deficient Mice Exhibit Impaired Response to Cocaine and Dysregulated Dopamine Homeostasis.

Protein interacting with C-kinase 1 (PICK1) is a widely expressed scaffold protein known to interact via its PSD-95/discs-large/ZO-1 (PDZ)-domain with several membrane proteins including the dopamine (DA) transporter (DAT), the primary target for cocaine's reinforcing actions. Here, we establish the importance of PICK1 for behavioral effects observed after both acute and repeated administration of cocaine. In PICK1 knock-out (KO) mice, the acute locomotor response to a single injection of cocaine was markedly attenuated. Moreover, in support of a role for PICK1 in neuroadaptive changes induced by cocaine, we observed diminished cocaine intake in a self-administration paradigm. Reduced behavioral effects of cocaine were not associated with decreased striatal DAT distribution and most likely not caused by the ∼30% reduction in synaptosomal DA uptake observed in PICK1 KO mice. The PICK1 KO mice demonstrated preserved behavioral responses to DA receptor agonists supporting intact downstream DA receptor signaling. Unexpectedly, we found a prominent increase in striatal DA content and levels of striatal tyrosine hydroxylase (TH) in PICK1 KO mice. Chronoamperometric recordings showed enhanced DA release in PICK1 KO mice, consistent with increased striatal DA pools. Viral-mediated knock-down (KD) of PICK1 in cultured dopaminergic neurons increased TH expression, supporting a direct cellular effect of PICK1. In summary, in addition to demonstrating a key role of PICK1 in mediating behavioral effects of cocaine, our data reveal a so far unappreciated role of PICK1 in DA homeostasis that possibly involves negative regulation of striatal TH levels.

Subjective perception of cocaine reward in mice assessed by a single exposure place preference (sePP) paradigm.

BACKGROUND: The potential of abused drugs to induce addiction and compulsive drug-related behavior is associated with their ability to alter dopamine signaling. Dopamine plays a key role in reward signaling and it has been of great interest to investigate how various drugs of abuse alter reward-related behavior. COMPARISON WITH EXISTING METHODS: In rodents, the rewarding effects of drugs have often been assessed in self-administration or place preference paradigms; both involving repeated drug exposure and weeks of training and testing. NEW METHOD: Our investigation describes a valid approach to assess the initial rewarding effects of cocaine in mice with a single exposure place preference (sePP) paradigm, avoiding repeated drug injections. RESULTS: We present the sePP paradigm with a 3-day protocol to assess the initial rewarding effects of cocaine. Interestingly, only male mice exhibit sePP to cocaine. To assess subsequent drug-related behavior, the protocol was extended by 3days of extinction followed by reinstatement on day 10. CONCLUSION: The sePP paradigm provides a reliable and convenient approach to assess the initial rewarding effects of cocaine, circumventing the need for repeated drug injections. The sePP protocol allows further dissection of the mechanism and influence of initial cocaine exposure on subsequent drug-related behaviors by including extinction and reinstatement. The lack of sePP in female mice may reflect a biologically relevant sex difference in the initial subjective perception of cocaine-induced reward. This could relate to and explain why males and females have been reported to respond differently to cocaine and cocaine-associated cues.