Signal transduction mechanisms and behavioral sensitization to stimulant drugs: an overview of cAMP and PLA2.

Behavioral sensitization refers to the progressive increase of behavioral responses to psychomotor stimulants, which provides a model for the intensification of drug craving and relapse alleged to underlie addiction in humans. Mechanisms related to sensitization may also contribute to schizophrenia and bipolar disorder. While the phenomenon has been observed for years, only recently have molecular or intracellular mechanisms associated with behavioral sensitization been studied. An overview of cAMP and PLA2 (intracellular, signal transduction mechanisms) relevant to behavioral sensitization will be presented.

Enhanced amygdala kindling after electrical stimulation of the ventral tegmental area: implications for fear and anxiety.

Electrical kindling refers to the seizure-generating properties of brain stimulation. In addition to producing epilepsy, the reorganization of forebrain neurocircuitry associated with kindling contributes to psychiatric disturbances involving fear and anxiety. The amygdala is a limbic structure that kindles readily and regulates the complex neurocircuitry underlying emotional responding. Dopamine-containing ventral tegmental area (VTA) neurons, known to be activated by threatening environmental stimuli, are an important component of the amygdala-based fear network. Using amygdala kindling as an indicator of sensitization development, we report here that repeated low-current, high-frequency stimulation of the VTA provoked afterdischarge in the central amygdala and enhanced kindling rate. By establishing a fundamental link between VTA activation and neural excitability in the central amygdala, the present results are consistent with the possibility of a common process underlying epileptogenisis and the fear motivational consequences of amygdala and VTA kindling. Considering the established role of the VTA and the amygdala in emotional responding, such a sensitization mechanism might mediate exaggerated fearfulness.

Neuronal sparing and behavioral effects of the antiapoptotic drug, (-)deprenyl, following kainic acid administration.

(-)Deprenyl is an irreversible inhibitor of monoamine oxidase B (MAO-B) frequently used as an adjunct therapy in the treatment of Parkinson's Disease. Recent evidence, however, has found that deprenyl's metabolites are associated with an antiapoptotic action within certain neuronal populations. Interestingly, deprenyl's antiapoptotic actions appear not to depend upon the inhibition of MAO-B. Due to a paucity of information surrounding (-)deprenyl's ability to spare neurons in vivo, a series of studies was conducted to further investigate this phenomenon within an apoptotic neuronal death model: kainic acid induced excitotoxicity. Results indicated that (-)deprenyl increased hippocampal neuronal survival compared to saline-matched controls following kainic acid insult. Furthermore, it was discovered that (-)deprenyl treatment could be stopped 14 days following CNS insult by kainate, with evidence of neuronal sparing still present by day 28. In open-field locomotor activity testing of kainate-treated animals, those given subsequent (-)deprenyl treatment showed habituation curves similar to control subjects, while saline-treated animals did not. Given deprenyl's antiapoptotic actions, it is proposed that (-)deprenyl may be beneficial in the treatment of a variety of neurodegenerative diseases where evidence of apoptosis exists, such as Parkinson's and Alzheimer's Disease, by slowing the disease process itself.

Gradation of kainic acid-induced rat limbic seizures and expression of hippocampal heat shock protein-70.

Systemic injection of kainic acid (KA) induces limbic seizures in rats, which resemble human temporal lobe epilepsy, the most common form of adult human epilepsy. In this study, we have investigated KA-elicited limbic seizures in the rats by correlating the severity of the seizure attacks with the expression of hippocampal heat shock protein-70 (HSP70) which has been suggested to be a marker for neuronal injury/death in this model of seizures. After a systemic injection of KA, six stages of limbic seizures have been classified, namely, staring (stage 1), wet dog shake (stage 2), hyperactivity (stage 3), rearing (stage 4), rearing and falling (stage 5), and jumping (stage 6). Stages 4, 5 and 6 were further divided into mild and severe sub-stages. HSP70 expression was not detected in animals with stages 1 and 2 seizures. At stage 3 a small amount of HSP70 immunoreactive neurons was detected in the CA3 field and the dentate hilus. From stage 4 to stage 5 the degree of HSP70 immunoreactivity increased in the CA1 field from a few positive cells in stage 4 mild to large numbers of immunoreactive neurons in stage 5 severe. HSP70 became detectable in pyramidal cells in the CA2 field from stage 5 severe and higher. In animals with stage 6 seizures, the majority of HSP70 expression became located in glial cells throughout the whole hippocampus. We concluded that HSP70 expression in the hippocampus positively correlates with the severity of KA-elicited limbic seizures.

(-)Deprenyl reduces delayed neuronal death of hippocampal pyramidal cells.

Ischemia-induced delayed neuronal death can be mediated by apoptosis, and (-)deprenyl has been shown to block apoptosis in dopaminergic and cholinergic neurons. This study has investigated whether (-)deprenyl can prevent delayed neuronal death of hippocampal pyramidal cells. Rats were subjected to unilateral hypoxia-ischemia and treated with (-)deprenyl (0.25 mg/kg, s.c.) or saline daily. After sacrifice the left and right hippocampi were examined histologically. Unilateral delayed neuronal death was seen in the CA1, CA3 and CA4 fields up to 14 days after the ischemia. After 14 days' treatment with (-)deprenyl there was 66%, 91% and 96% reduction in delayed neuronal death in the CA1, CA3 and CA4 fields, respectively. (-)Deprenyl was effective when given at the onset or after ischemia, but not when given 2 h before ischemia. The reduction in ischemia-induced delayed neuronal death is consistent with an anti-apoptotic mechanism of (-)deprenyl.

Chronic L-deprenyl or L-amphetamine: equal cognitive enhancement, unequal MAO inhibition.

The effect of chronic (4 month), subcutaneous injections of saline, L-deprenyl (0.25 mg/kg), or L-amphetamine (0.25 mg/kg) on the acquisition of a learned spatial habit in a modified Morris Water Maze was investigated in middle aged rats. Injections, given three times weekly starting at 6 months of age, were continued during behavioral testing, which occurred at 10 months of age. The cognitive performance of the middle aged rats was compared to that of 2-month-old control rats. Twenty-four hours after the last behavioral test, the rats were sacrificed and their brains were removed, dissected, and frozen in liquid nitrogen. The activities of MAO-A and MAO-B in the lateral cortex were determined. Results indicate that rats in the L-deprenyl group, the L-amphetamine group, and the young control group all learned the water maze task equally rapidly and significantly faster than rats in the saline group. MAO-A did not differ among the saline, amphetamine, and young control rats, but MAO-B was significantly higher in the middle aged saline and L-amphetamine rats than in the young controls. Both MAO-A and MAO-B activities were significantly lower in the L-deprenyl group than in the other three groups. This indicates that low-dose L-deprenyl can also inhibit MAO-A following chronic SC administration. Moreover, the improved cognitive performance produced by L-deprenyl may not be due to its ability to inhibit MAO-B, but rather to some other effect such as the activation of growth factors.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of amygdaloid stimulation on amphetamine-elicited locomotor sensitization.

Systemic injection of d-amphetamine (1.0 mg/kg) resulted in a progressive increase in locomotor activity as a function of repeated daily drug administration. The magnitude of the stimulant-induced sensitization effect was enhanced by low-current electrical stimulation of the central nucleus of the amygdala during open-field testing. Amygdaloid stimulation in the absence of amphetamine treatment did not influence spontaneous locomotor activity, and there was no behavioral evidence of epileptogenesis following amygdaloid stimulation over the course of the experiment. However, with continued stimulation of the amygdala, early-stage convulsive activity was apparent in animals after approximately 40 days of testing, signifying the advancement of kindling evolution. These results suggest that the processes responsible for kindling acquisition, prior to the behavioral expression of epileptiform events, interact with the underlying substrates of amphetamine sensitization.

The effects of amphetamine preexposure on electrical kindling of the hippocampus and related transfer phenomena.

Earlier research has established that repeated amphetamine administration can interact synergistically with the processes responsible for the genesis of kindled seizures after intermittent electrical stimulation of the amygdala. In this study, the effects of amphetamine preexposure on primary hippocampal kindling, secondary kindling of the contralateral amygdala, and rekindling of the original hippocampal focus were evaluated. It was shown that amphetamine treatment did not modify kindling rates when electrodes were situated in the dorsal hippocampus. However, transfer kindling of the contralateral amygdala evolved after fewer afterdischarges, and rekindling of the dorsal hippocampus progressed significantly faster in amphetamine-pretreated animals. The effects of amphetamine on ventral hippocampal kindling were also determined, and it was found that although epileptogenesis developed more rapidly relative to the dorsal region of this structure, kindling rates were not affected by amphetamine preexposure. These results were related to the possibility that the amygdala might have a unique function in the relationship between kindling- and stimulant-induced sensitization effects.