ABSTRACT
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 â¼30% 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.
Subject(s)
Carrier Proteins/metabolism , Cocaine/administration & dosage , Dopamine/metabolism , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/metabolism , Homeostasis/drug effects , Nuclear Proteins/metabolism , Animals , Carrier Proteins/genetics , Cell Cycle Proteins , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Dopamine Plasma Membrane Transport Proteins/metabolism , Locomotion/drug effects , Male , Mice, Inbred C57BL , Mice, Knockout , Nuclear Proteins/genetics , Reinforcement, Psychology , Signal Transduction/drug effects , Tyrosine 3-Monooxygenase/metabolismABSTRACT
The high co-morbidity of eating disorders and substance abuse suggests that nutritional status can impact vulnerability to drug abuse. These studies used rats to examine the effects of food restriction on dopamine clearance in striatum and on the behavioral effects of amphetamine (locomotion, conditioned place preference), the dopamine receptor agonist quinpirole (yawning), and the dopamine receptor antagonist raclopride (catalepsy). Amphetamine increased locomotion and produced conditioned place preference. Food restriction reduced dopamine clearance, which was restored by repeated treatment with amphetamine or by free feeding. Food restriction also decreased sensitivity to quinpirole-induced yawning and raclopride-induced catalepsy; normal sensitivity to both drugs was restored by free feeding. The same amphetamine treatment that normalized dopamine clearance, failed to restore normal sensitivity to quinpirole or raclopride, suggesting that in food-restricted rats the activity of dopamine transporters and dopamine receptors is differentially affected by pathways that are stimulated by amphetamine. These studies show that modest changes in nutritional status markedly alter dopamine neurotransmission and the behavioral effects of direct-acting dopamine receptor drugs (agonist and antagonist). These results underscore the potential importance of nutritional status (e.g., glucose and insulin) in modulating dopamine neurotransmission and in so doing they begin to establish a neurochemical link between the high co-morbidity of eating disorders and drug abuse.
Subject(s)
Behavior, Animal/drug effects , Brain Chemistry/drug effects , Caloric Restriction/psychology , Dopamine Agents/pharmacology , Amphetamine/pharmacology , Animals , Blood Glucose/metabolism , Body Weight/drug effects , Catalepsy/chemically induced , Catalepsy/psychology , Conditioning, Operant/drug effects , Diabetes Mellitus, Experimental/metabolism , Dopamine/metabolism , Dopamine Agonists/pharmacology , Dopamine Antagonists/pharmacology , Dopamine Plasma Membrane Transport Proteins/metabolism , Male , Motor Activity/drug effects , Nutritional Status , Quinpirole/pharmacology , Raclopride/pharmacology , Rats , Rats, Sprague-Dawley , Yawning/drug effectsABSTRACT
Experimentally-induced diabetes can modify the behavioral and neurochemical effects of drugs acting on dopamine systems, possibly through insulin-related regulation of dopamine transporter activity. In this study, several behavioral procedures were used to examine possible changes in sensitivity to amphetamine and other drugs in rats rendered diabetic by a single injection of streptozotocin. Conditioned place preference developed to food (Froot Loops) in both control and diabetic rats, demonstrating that conditioned place preference with tactile stimuli can occur in streptozotocin-treated rats. Baseline locomotion was lower in streptozotocin-treated as compared to control rats, although amphetamine significantly increased locomotion in all rats. Conditioned place preference developed to amphetamine regardless of whether rats had received streptozotocin or saline. A second study compared the potency of drugs to decrease lever pressing maintained by food, before and after streptozotocin treatment. Gamma-hydroxybutyrate and amphetamine were less potent after streptozotocin while the potency of raclopride, quinpirole, ketamine, haloperidol and cocaine was not significantly changed by streptozotocin. While markedly affecting locomotion, body weight and blood glucose, streptozotocin only modestly affected sensitivity to the behavioral effects of amphetamine and other drugs; these results fail to confirm previous reports of decreased behavioral actions of stimulants in diabetic rats.
