Search

It is clear that both genetic and environmental factors contribute to drug addiction. Recent evidence indicating trans-generational influences of drug abuse highlight potential epigenetic factors as well. Specifically, mounting evidence suggests that parental ingestion of abused drugs influence the physiology and behavior of future generations even in the absence of prenatal exposure. The goal of this review is to describe the trans-generational consequences of preconception exposure to drugs of abuse for five major classes of drugs: alcohol, nicotine, marijuana, opioids, and cocaine. The potential epigenetic mechanisms underlying the transmission of these phenotypes across generations also are detailed. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

Ample behavioral evidence suggests that ascorbate parallels the action of haloperidol, a widely used neuroleptic. To determine the extent to which this parallel extends to chronic treatment, 21 days of exposure to ascorbate (100 or 500 mg/kg) alone or combined with haloperidol (0.5 mg/kg) were assessed on stereotyped behavior and neostriatal D 2 dopamine receptor binding in rats. Our results indicate that when challenged with the dopamine agonist, apomorphine (0.5 mg/kg), animals chronically treated with haloperidol or high-dose ascorbate alone display a supersensitive sniffing response relative to controls, while animals chronically treated with the combination of haloperidol and high-dose ascorbate display a further potentiation of sniffing relative to the haloperidol groups. In addition, [ 3 H]spiperone saturation studies showed, as expected, an up-regulation of striatal D 2 dopamine receptors in rats treated with haloperidol as reflected by a change in receptor density ( B max but not affinity ( K D ). Ascorbate treatment, however, had no effect on D 2 receptor density or the distribution of [ 3 H]apomorphine in whole brain. Even though chronic treatment with the haloperidol-high-dose-ascorbate combination produced an up-regulation of striatal D 2 dopamine receptors, this treatment did not cause a further up-regulation relative to haloperidol alone nor did it have any effect on [ 3 H]apomorphine distribution. Taken together, these findings indicate that although chronic ascorbate produces behavioral supersensitivity to apomorphine through central mechanisms, they appear to differ from those induced by chronic haloperidol.

The transition from casual drug use to addiction, and the intense drug craving that accompanies it, has been postulated to result from neuroadaptations within the limbic system caused by repeated drug exposure. This review will examine the implications of cocaine-induced alterations in mesolimbic dopamine receptor signaling within the context of several widely used animal models of addiction. Extensive evidence indicates that dopaminergic mechanisms critically mediate behavioral sensitization to cocaine, cocaine-induced conditioned place preference, cocaine self-administration, and the drug prime-induced reinstatement of cocaine-seeking behavior. The propagation of the long-term neuronal changes associated with recurring cocaine use appears to occur at the level of postreceptor signal transduction. Repeated cocaine treatment causes an up-regulation of the 3',5'-cyclic adenosine monophosphate (cAMP)-signaling pathway within the nucleus accumbens, resulting in a dys-regulation of balanced D1/D2 dopamine-like receptor signaling. The intracellular events arising from enhanced D1-like postsynaptic signaling mediate both facilitatory and compensatory responses to the further reinforcing effects of cocaine.

The neostriatum and its major afferent transmitters, dopamine and glutamate, play a critical role in behavior, but relatively little information is available on their postsynaptic effects in behaving animals. As a first step in addressing this shortcoming, single-unit electrophysiology was combined with iontophoresis in the neostriatum of awake, unrestrained rats. Relative to periods of quiet rest, most neurons (58 of 77) changed discharge rate in close temporal association with movement, while the remainder showed no such relationship. When animals resumed a resting posture, iontophoretic current-response curves were established for dopamine and glutamate as well as for ascorbate, a modulator of neostriatal function released from glutamatergic terminals. Application of either glutamate or ascorbate produced current-dependent increases in activity in all neurons, although this effect was somewhat less pronounced for nonmotor cells. In both types of neurons, the excitatory effect of ascorbate either diminished or shifted to an inhibition at high ejection currents. Dopamine, on the other hand, routinely excited motor-related, but inhibited nonmotor-related neurons. Further assessment of motor-related neurons revealed that in most cases the excitatory effects of either glutamate or dopamine alone were supra-additive when these compounds were either administered together or co-administered with ascorbate. Our results suggest that the response of neostriatal neurons to glutamate or dopamine depends, at least in part, on the motor responsiveness of these cells. Motor-related neurons, moreover, respond to the co-administration of glutamate and dopamine with synergistic increases in firing rate. Ascorbate also influences neostriatal activity, but the postsynaptic action of this substance cannot be explained as a simple interaction with either glutamatergic or dopaminergic mechanisms.

It has been suggested that dopamine autoreceptor subsensitivity may play a role in cocaine-induced behavioral sensitization. In order to evaluate this hypothesis, we administered cocaine to rats daily (15 mg/kg ip x 2 days, 30 mg/kg ip x 5 days) and then monitored nucleus accumbens dopamine during the local administration (through the dialysis probe) of the D2/D3 agonist, quinpirole (0, 0.1, 1, and 10 microM). Our results indicate that, relative to saline-pretreated control animals, repeated cocaine administration impaired the ability of quinpirole to decrease extracellular dopamine 1-2 days after the last drug injection. However, quinpirole was equipotent at reducing accumbal dopamine in cocaine- and saline-treated animals following a 21-22 day withdrawal period. These results demonstrate that repeated cocaine produces a short duration functional tolerance in the capacity of autoreceptor stimulation to inhibit accumbal dopamine release.

Unilateral kainate lesions of the neostriatum and 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle were used to assess the role of neostriatal and ascending dopaminergic neurons, respectively, on dopamine-agonist induced release of neostriatal ascorbate as measured voltammetrically in freely moving rats. Electrochemically modified, carbon-fiber electrodes recorded the effects of direct (a combination of 10 mg/kg SKF-38393 and 1.0 mg/kg quinpirole) as well as indirect (2.5 mg/kg D-amphetamine or 20.0 mg/kg GBR-12909) dopamine agonists. Relative to controls, kainate, but not 6-OHDA, lesions abolished the ability of both direct and indirect dopamine agonists to induce neostriatal ascorbate release. These results suggest that unlike dopaminergic afferents, neostriatal output pathways play a critical role in the modulation of neostriatal ascorbate levels.