Paul Vezina

Sensitization of midbrain dopamine neuron reactivity and the self-administration of psychomotor stimulant drugs

Psychostimulant drugs like amphetamine are readily self-administered by humans and laboratory animals by virtue of their actions on dopamine (DA) neurons in the midbrain. Exposing animals to this drug either systemically or in the cell body region of these neurons in the ventral tegmental area leads to long-lasting alterations in dopaminergic function. These have most often been assessed as increased locomotor activity and enhanced DA overflow in the nucleus accumbens (NAcc) after re-exposure to the drug weeks to months later. Evidence is presented showing that manipulations that produce this sensitization of midbrain DA neuron reactivity enhance the pursuit and self-administration of psychostimulant drugs. Procedures known to prevent the induction of sensitization by amphetamine also prevent the facilitation of drug taking. Enhanced drug self-administration and primed reinstatement of drug seeking are also accompanied by enhanced NAcc DA reactivity. Finally, drugs that increase NAcc DA overflow acutely but fail to produce sensitization of this effect are not associated with the subsequent enhancement of self-administration. These results indicate a direct relationship between the sensitization of midbrain dopamine neuron reactivity and the excessive pursuit and self-administration of psychostimulant drugs. Understanding the neuronal events and adaptations that underlie the induction and expression of sensitization may thus help elucidate how drug abuse develops, how it is reinstated and ultimately how both may be prevented.

Amphetamine administered to the ventral tegmental area but not to the nucleus accumbens sensitizes rats to systemic morphine: lack of conditioned effects.

Different groups of rats received conditioning training with bilateral injections of amphetamine (2.5 micrograms/0.5 microliters/side) either into the ventral tegmental area (VTA) or the nucleus accumbens (NAC) and were tested on separate occasions for conditioned locomotor activity with saline and cross-sensitization to the locomotor activating effects of morphine (1.0 mg/kg, i.p.). Intra-VTA injections of amphetamine had no effect acutely but subsequently produced a sensitized locomotor response to morphine. On the other hand, intra-NAC amphetamine produced increased locomotion but with no evidence of sensitization either during training or on the test with morphine. No evidence for conditioning of the locomotor activating effects of amphetamine or for stimulus control of the expression of the sensitized response to morphine was obtained with either the intra-VTA or the intra-NAC injections. These results confirm earlier findings indicating that the site of action of amphetamine critical for the development of behavioral sensitization is the VTA and not the NAC and extend them to the case of cross-sensitization to morphine. They also demonstrate that behavioral sensitization can be obtained in the absence of conditioned effects and, therefore, that the two phenomena are distinct. Implications of the present findings for an understanding of the mode and site of action of amphetamine in the development of conditioned locomotor activity are discussed.

The effect of dopamine receptor blockade on the development of sensitization to the locomotor activating effects of amphetamine and morphine.

The effect of dopamine (DA) receptor blockade on the development of sensitization to the locomotor activating effects of systemic amphetamine and intra-ventral tegmental area (intra-VTA) morphine was investigated. Rats were pretreated with the D-1 DA receptor antagonist, SCH-23390 (0.04 or 0.2 mg/kg, i.p.) or one of two D-2 DA receptor antagonists, pimozide (0.5 mg/kg, i.p.) and Ro 22-2586 (0.2 mg/kg, i.p.), prior to each of 5 exposures to the sensitizing drug. SCH-23390 blocked the development of sensitization to amphetamine but not to intra-VTA morphine. Pimozide had the opposite effect and Ro 22-2586 had no effect on the development of sensitization to either amphetamine or intra-VTA morphine. All 3 antagonists, at the doses tested, completely blocked the acute locomotor activating effects of these two drugs. Pretreatment in separate animals with low autoreceptor doses of sulpiride (25 mg/kg, i.p. with amphetamine and 10 mg/kg, i.p. with intra-VTA morphine) slightly potentiated the acute locomotor effect and produced a slight enhancement of the sensitized response to amphetamine and intra-VTA morphine. Pretreatment with a higher dose of sulpiride (50 mg/kg, i.p.) blocked the acute locomotor effect of intra-VTA morphine but had no effect on the development of sensitization to this drug. These results suggest that the mechanisms underlying the development of sensitization to the locomotor activating effects of amphetamine and intra-VTA morphine are different even though these may ultimately result in similar changes in the activity of mesencephalic DA neurons. Implications of these findings for the differential involvement of D-1 and D-2 DA receptors and for neural hypotheses of behavioral sensitization are discussed.

Predisposition to self-administer amphetamine: the contribution of response to novelty and prior exposure to the drug

The present experiment examined the contribution of locomotor response to novelty and prior exposure to amphetamine to rats’ predisposition to self-administer a low dose of the drug. Rats were screened for their locomotor response to a novel environment and divided into high (HR) or low (LR) responders based on whether their locomotor scores were above or below the median activity level of the subject sample. Animals were then pre-exposed to nine daily injections of either saline (1 ml/kg, IP) or amphetamine (1.5 mg/kg. IP). Starting 1 week after pre-exposure, animals in the four different groups (HR pre-exposed to saline or amphetamine; LR pre-exposed to saline or amphetamine) were given the opportunity, in each of ten daily sessions, to lever press for a low dose of amphetamine (10 µg/kg per infusion) in a two lever (active versus inactive) continuous reinforcement operant task. Initial lever press performance revealed no difference in active versus inactive lever pressing between amphetamine and saline pre-exposed animals. However, in agreement with previous reports, with successive test sessions amphetamine pre-exposed rats maintained higher levels of active versus inactive lever pressing for drug while saline pre-exposed rats showed a progressive decrease in the pressing of either lever. Interestingly, this enhanced active lever pressing was observed in HR but not LR rats pre-exposed to amphetamine. In addition, HR saline pre-exposed animals showed initial active versus inactive lever pressing equivalent to that of HR amphetamine pretreated rats but this enhanced responding for drug diminished over days and by the last day of self-administration was indistinguishable from that of LR animals having been pre-exposed either to amphetamine or saline. These findings confirm that prior exposure to amphetamine promotes the subsequent self-administration of the drug and suggest that response to novelty may be a predictor more closely linked to an animal’s propensity to become sensitized to the facilitatory effects of the drug rather than to an animal’s current sensitization state and predisposition to self-administer the drug.

Microinjections of Sch-23390 into the ventral tegmental area and substantia nigra pars reticulata attenuate the development of sensitization to the locomotor activating effects of systematic amphetamine

Pre-exposure of rats to systemic injections of D-amphetamine sulfate in the presence of bilateral injections of Sch-23390 (0.5 or 1.0 micrograms/side) into the ventral tegmental area (VTA) attenuated the acute locomotor effects of amphetamine and blocked the development of sensitization to amphetamine in a test when only amphetamine was administered, in a dose-dependent manner. Similar, but less potent, effects were observed following injections into substantia nigra pars reticulata. These findings suggest that dopamine released from somatodendritic regions brings about changes in local circuitry in the VTA that underlie the development of sensitization to amphetamine, and that Sch-23390 acts at D1 receptors in these regions to block these changes.

Nicotine-induced upregulation of nicotinic receptors: underlying mechanisms and relevance to nicotine addiction.

A major hurdle in defining the molecular biology of nicotine addiction has been characterizing the different nicotinic acetylcholine receptor (nAChR) subtypes in the brain and how nicotine alters their function. Mounting evidence suggests that the addictive effects of nicotine, like other drugs of abuse, occur through interactions with its receptors in the mesolimbic dopamine system, particularly ventral tegmental area (VTA) neurons, where nicotinic receptors act to modulate the release of dopamine. The molecular identity of the nicotinic receptors responsible for drug seeking behavior, their cellular and subcellular location and the mechanisms by which these receptors initiate and maintain addiction are poorly defined. In this commentary, we review how nicotinic acetylcholine receptors (nAChRs) are upregulated by nicotine exposure, the potential posttranslational events that appear to cause it and how upregulation is linked to nicotine addiction.

Conditioning and place-specific sensitization of increases in activity induced by morphine in the VTA

The conditionability of increases in locomotor activity induced by morphine administration into the ventral tegmental area was studied in rats. Morphine produced a clear increase in locomotor activity that was reversed by the opiate receptor blocker, naloxone, and blocked by the neuroleptic, pimozide, suggesting the mediation of this effect by the ascending mesolimbic dopamine system. The increase in locomotor activity showed sensitization with repeated morphine administrations and this sensitization was found to be specific to the environment in which morphine was administered. Conditioning tests also revealed that, in the absence of morphine, increased locomotor activity was elicited by the administration environment. Pimozide blocked the development of the conditioned sensitization. These data demonstrate that a learned association developed between this excitatory action of morphine and the administration environment. These results have important implications for the role of conditioning factors in relapse to drug use and may provide an explanation for conditioning data obtained when morphine is administered systemically.

Amphetamine injected into the ventral tegmental area sensitizes the nucleus accumbens dopaminergic response to systemic amphetamine: an in vivo microdialysis study in the rat.

Different groups of rats received three injections of either D-amphetamine (2.5 micrograms/0.5 microliters/side) or saline into the ventral tegmental area (VTA), one injection every third day. Two weeks following the last injection, dopamine (DA) neurotransmission in the nucleus accumbens (N. Acc.) was assessed with in vivo microdialysis before and after a challenge with systemic D-amphetamine (1.0 mg/kg, i.p.). Prior to challenge, basal extracellular concentrations of DA in the N.Acc. did not differ in VTA amphetamine- and saline-preexposed animals. Following challenge, however, both groups showed an increase in N.Acc. DA but this was significantly greater (2-fold) in VTA amphetamine-preexposed animals. These latter animals also showed significantly higher DA metabolite levels in comparison to saline-preexposed animals prior to (DOPAC) as well as after challenge (HVA). These findings extend those of behavioral experiments showing that intra-VTA amphetamine produces sensitized locomotor responding to drug challenge (J. Pharmacol. Exp. Ther., 245 (1988) 1095-1102; Brain Res., 516 (1990) 99-106; Ann. NY Acad. Sci., 654 (1992) 444-447) and demonstrate that amphetamine applied to the somatodendritic region of mesolimbic DA neurons sensitizes these neurons as evidenced by their enhanced N.Acc. DA response to a systemic amphetamine challenge.

Sensitization occurs to the locomotor effects of morphine and the specific μ opioid receptor agonist, DAGO, administered repeatedly to the ventral tegmental area but not to the nucleus accumbens

Several recent reports have demonstrated that opiate action in both the ventral tegmental area (VTA) and the nucleus accumbens (N.Acc.) produces an increase in locomotor activity. In the present experiments, the effect of repeated bilateral injections into these sites of either morphine or the mu opioid receptor agonist Tyr-D-Ala-Gly-NMe-Phe-Gly-ol (DAGO) was investigated. As previously reported with morphine and other opioids, repeated injections of either morphine or DAGO into the VTA produced a progressive enhancement or sensitization of their locomotor activating effects. On the other hand, although both substances injected into the N.Acc. elicited increased locomotion, repeated injections did not lead to sensitization. It has been suggested that the increased locomotor activity produced by opiate injection into the VTA is dopamine-dependent while that produced by intra-N.Acc. injections is not. The present findings provide neuroanatomical support for the view that sensitization to the locomotor activating effects of opiates and opioids brought about by repeated drug exposure involves the mesolimbic dopamine system.

Opposed behavioural outputs of increased dopamine transmission in prefrontocortical and subcortical areas : a role for the cortical D-1 dopamine receptor

The possibility that the dopaminergic neurons innervating the medial prefrontal cortex (mPFC) can inhibit locomotor behaviour has been suggested in several studies. The evidence remains indirect, however, because the manipulations tested aimed exclusively at permanently depleting mPFC dopamine. Here we demonstrate in rats that acute increases in dopamine transmission in this site by local injections of amphetamine inhibit the known locomotor‐activating effects of amphetamine in the nucleus accumbens (N.Acc). Further, intra‐mPFC injections of the D‐1 dopamine receptor antagonist SCH‐23390, but not other dopamine antagonists with greater affinities for noradrenergic, serotonergic and D‐2 dopamine receptors, enhanced the locomotion induced by intra‐N.Acc. amphetamine. These findings provide direct evidence for the inhibition of locomotor activity by mPFC dopamine and suggest that it is acting at D‐1 dopamine receptors in this site.