Isradipine Suppresses Amphetamine-Induced Conditioned Place Preference and Locomotor Stimulation in the Rat

Abstract

The locomotor activating and the reinforcing effects of psychomotor stimulants are considered to be correlated with and responsible for the development and maintenance of stimulant addiction. Experiments were conducted to examine the effects of isradipine, the L-type calcium channel inhibitor, on the d-amphetamine-inducedinduced conditioned place preference in rats (Pani et al. 1991;Pucilowski et al. 1993) and to suppress intravenous cocaine self-administration in rats (Martellotta et al. 1994) and mice (Kuzmin et al. 1992). The positive reinforcing properties of psychomotor stimulants are thought to be directly correlated with their ability to induce locomotor stimulation (Wise 1990). It is hypothesized that effective pharmacological treatment for drug abuse should suppress conditioned responses, that is, reinforcing and locomotor stimulant effects, to a greater extent than the acute effects of addictive drugs. This is because potent acute antireinforcing or aversive effects of a therapeutic drug would likely compromise the necessary patient compliance with the therapy (Hursh 1993).The ability of dihydropyridine CCis (e.g., isradi-0893-133X/95/$9 .50 SSDI 0893-133X(94)00080-J

L-type Ca2+ channel blockade with antihypertensive medication disrupts VTA synaptic plasticity and drug-associated contextual memory

“…Systemic injection (i.p.) of isradipine has been shown to suppress the acquisition of psychostimulant (cocaine and amphetamine) CPP 23 , 24 . Blockade of NMDAR LTP induction in the VTA might contribute to CPP suppression.…”

CACNA1C (Cav1.2) in the pathophysiology of psychiatric disease

“…This pathway traditionally defines the ventral tegmental area (VTA) to nucleus accumbens (NAc) circuit, modulated by interactions with the hippocampus, medial prefrontal cortex, and amygdala (Pierce and Kumaresan, 2006), and is thought to be critical for reward and motivation that can be altered in mood disorders and schizophrenia (Juckel et al, 2003; Nestler and Carlezon, 2006). In rats, administration of the hydrophobic dihydropyridine LTCC antagonist isradipine dose-dependently attenuates intake of sweetened drinking water, a rewarding liquid (Calcagnetti and Schechter, 1992), as well as the reinforcing effects of amphetamine (Pucilowski et al, 1995), while nimodipine suppresses the effect of nicotine (Biala, 2003) in conditioned place preference. Additionally, there is evidence that the LTCC antagonist D-cis-diltiazem enhances the rewarding effects of cocaine in the conditioned place preference test when injected in the ventral NAc shell (Chartoff et al, 2006).…”

Practical Radiosynthesis and Preclinical Neuroimaging of [11C]isradipine, a Calcium Channel Antagonist

“…This pretreatment dose represents the upper level of previously reported i.p. dosing of isradipine [ 8 , 9 ], as well as the solubility threshold in vehicle (5% DMSO, 5% Tween 80, 90% saline). Whole brain uptake peaked at 0.19 ± 0.05% ID/cc (1.1 ± 0.1 SUV) 15–60 s after TOI and cleared much more slowly over the course of the imaging session.…”

“…A subunit of the LTCC was among the first to be associated with neuropsychiatric diseases, including schizophrenia and bipolar disorder [ 3 , 4 ]. While Ca 2+ -channel antagonists have a long history in the treatment of hypertension and cardiac disease [ 5 ], the promise these pharmaceuticals hold for treatment of neurological and psychiatric disorders has yet to come to fruition [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. For example, it is believed that LTCC antagonists protect dopamine neurons in the substantia nigra from degeneration associated with Parkinson’s disease by dopamine D 2 receptor desensitization [ 15 ].…”