Rostral Ventral Tegmental Area Research Articles

Effects of the Phenethylamine 2-Cl-4,5-MDMA and the Synthetic Cathinone 3,4-MDPHP in Adolescent Rats: Focus on Sex Differences.

The illicit drug market of novel psychoactive substances (NPSs) is expanding, becoming an alarming threat due to increasing intoxication cases and insufficient (if any) knowledge of their effects. Phenethylamine 2-chloro-4,5-methylenedioxymethamphetamine (2-Cl-4,5-MDMA) and synthetic cathinone 3,4-methylenedioxy-α-pyrrolidinohexanophenone (3,4-MDPHP) are new, emerging NPSs suggested to be particularly dangerous. This study verified whether these two new drugs (i) possess abuse liability, (ii) alter plasma corticosterone levels, and (iii) interfere with dopaminergic transmission; male and female adolescent rats were included to evaluate potential sex differences in the drug-induced effects. Findings show that the two NPSs are not able to sustain reliable self-administration behavior in rats, with cumulatively earned injections of drugs being not significantly different from cumulatively earned injections of saline in control groups. Yet, at the end of the self-administration training, females (but not males) exhibited higher plasma corticosterone levels after chronic exposure to low levels of 3,4-MDPHP (but not of 2-Cl-4,5-MDMA). Finally, electrophysiological patch-clamp recordings in the rostral ventral tegmental area (rVTA) showed that both drugs are able to increase the firing rate of rVTA dopaminergic neurons in males but not in females, confirming the sex dimorphic effects of these two NPSs. Altogether, this study demonstrates that 3,4-MDPHP and 2-Cl-4,5-MDMA are unlikely to induce dependence in occasional users but can induce other effects at both central and peripheral levels that may significantly differ between males and females.

Rostrocaudal subregions of the ventral tegmental area are differentially impacted by chronic stress.

The ventral tegmental area (VTA) is implicated in the pathophysiology of depression and addictive disorders and is subject to the detrimental effects of stress. Chronic stress may differentially alter the activity pattern of its different subregions along the rostrocaudal and dorsoventral axes, which may relate to the variable behavioral sensitivity to stress mediated by these subregions. Here, chronic stress-exposed rats were tested for depressive-like reactivity. In situ hybridization for zif268 as a marker of neuronal activation was combined with in vivo single-unit recording of dopaminergic neurons to assess modifications in the activity of the rostral VTA (rVTA) and caudal VTA (cVTA). Changes in the expression of stress-responsiveglucocorticoid receptors (GR) and brain-derived neurotrophic factor (BDNF) were also assessed. Stress-induced anhedonia-like, hyper-anxious, and passive-like responding were associated with reductions in dopaminergic burst activity in the cVTA and an increase in local GABAergic activity, particularly in GABAA receptor sensitivity. On the other hand, stress increased single-spiking activity, burst activity, and zif268 mRNA levels in the rVTA, which were associated with increased glutamatergic tonus and enhanced GR and AMPA receptor (AMPAR) expression. rVTA and cVTA activity differentially correlated with sucrose preference and passivity measures. These data demonstrate that the rVTA and cVTA respond differently to stress and suggest that while cVTA activity may be related to passivity-like states, the activity of both subregions appears to be related to anhedonia and the processing of incentive value. These region-dependent abnormalities indicate the multi-modular composition of the VTA, which could provide multiple substrates for different symptom features.

Rostral and Caudal Ventral Tegmental Area GABAergic Inputs to Different Dorsal Raphe Neurons Participate in Opioid Dependence

Both the ventral tegmental area (VTA) and dorsal raphe nucleus (DRN) are involved in affective controland reward-related behaviors. Moreover, the neuronal activities of the VTA and DRN are modulated by opioids. However, the precise circuits from the VTA to DRN and how opioids modulate these circuits remain unknown. Here, we found that neurons projecting from the VTA to DRN are primarily GABAergic. Rostral VTA (rVTA) GABAergic neurons preferentially innervate DRN GABAergic neurons, thus disinhibiting DRN serotonergic neurons. Optogenetic activation of this circuit induces aversion. In contrast, caudal VTA (cVTA) GABAergic neurons mainly target DRN serotonergic neurons, and activation of this circuit promotes reward. Importantly, μ-opioid receptors (MOPs) are selectively expressed at rVTA→DRN GABAergic synapses, and morphine depresses the synaptic transmission. Chronically elevating the activity of the rVTA→DRN pathway specifically interrupts morphine-induced conditioned place preference. This opioid-modulated inhibitory circuit may yield insights into morphine reward and dependence pathogenesis.

Early High-Fat Diet Exposure Causes Dysregulation of the Orexin and Dopamine Neuronal Populations in Nonhuman Primates.

Maternal obesity and consumption of a high-fat diet (HFD) during pregnancy has a negative impact on offspring, including an increased risk for the development of obesity in adolescence. The mechanism for this transferred metabolic risk is unclear, but many studies have focused on the brain due to its important role in appetite and body-weight regulation. Two main pathways regulate appetite in the brain; homeostatic regulation that occurs predominantly in hypothalamic circuits and hedonic regulation of feeding that occurs via dopaminergic pathways. The current proposal examined the impact of early HFD exposure on the dopaminergic control of hedonic feeding pathways in a translational nonhuman primate model. Japanese macaque offspring from mothers consuming a control (CTR) or HFD were weaned onto control or HFD at an average 8 months of age yielding four groups: maternal and post-weaning control diet (mCTRpCTR), maternal control diet and post-weaning HFD (mCTRpHFD), maternal HFD and post-weaning control diet (mHFDpCTR) and maternal and post-weaning HFD (mHFDpHFD). Brains from 13-month-old offspring were evaluated for expression of neuropeptides that regulate dopaminergic pathways including orexin, melanin-concentrating hormone (MCH) in the lateral hypothalamus (LH), and tyrosine hydroxylase expression in the ventral tegmental area (VTA). Orexin cell numbers in the LH were significantly increased in animals exposed to a post-weaning HFD, while no difference was observed for orexin mRNA content or MCH cell numbers. Orexin fiber projections to the rostral VTA were significantly reduced in mCTRpHFD, mHFDpCTR, and mHFDpHFD groups, but these differences were not significant in the caudal VTA. There was no difference in the percentage of dopamine neurons receiving close appositions from orexin fibers in either the rostral or caudal VTA, nor was there any difference between groups in the number of orexin contacts per TH cell. In conclusion, the current study finds that prolonged early exposure to HFD during the in utero and postnatal period causes alterations at several levels in the dopaminergic circuits regulating reward.

Developmental auditory exposure shapes responses of catecholaminergic neurons to socially-modulated song

Developmental sensory experience is critical to the tuning of sensory systems and can shape perceptual abilities and their neural substrates. Neuromodulators, including catecholamines, contribute to sensory plasticity in both older and younger individuals and provide a mechanism for translating sensory experience into changes in brain and behavior. Less well known, however, is whether developmental sensory experience has lasting effects on the neuromodulatory neurons themselves. Here, we used female zebra finches to investigate the degree to which developmental auditory experience can have lasting effects on the density and sensory responsiveness of catecholamine-synthesizing neuron populations. We found that hearing courtship, but not non-courtship, song increased expression of the activity-dependent immediate early gene cFOS in dopamine neurons of the caudal ventral tegmental area (VTA) and this increase was dependent on whether females heard adult song during development. Developmental song exposure also affected the density of dopamine producing neurons in the rostral VTA. In contrast, song-evoked responses in noradrenergic neurons of the Locus Coeruleus were not affected by either developmental song exposure or the social context of the stimulus. These data highlight the lasting effects that developmental auditory experience can have in shaping both the density and sensory responsiveness of dopamine neuron populations.

Neuroanatomical circuitry mediating the sensory impact of nicotine in the central nervous system

Direct actions of nicotine in the CNS appear to be essential for its reinforcing properties. However, activation of nicotinic acetylcholine receptors (nAChRs) on afferent sensory nerve fibers is an important component of addiction to, and withdrawal from, cigarette smoking. The aim of the present study was to identify the neuroanatomical substrates activated by the peripheral actions of nicotine and to determine whether these sites overlap brain structures stimulated by direct actions of nicotine. Mouse brains were examined by immunohistochemistry for c-Fos protein after intraperitoneal injection of either nicotine hydrogen tartrate salt (NIC; 30 and 40 μg/kg) or nicotine pyrrolidine methiodide (NIC-PM; 20 and 30 μg/kg). NIC-PM induced c-Fos immunoreactivity (IR) at multiple brain sites. In the brainstem, c-Fos IR was detected in the locus coeruleus, laterodorsal tegmental nucleus, and pedunculotegmental nucleus. In the midbrain, c-Fos IR was observed in areas overlapping the ventral tegmental area (VTA), which includes the paranigral nucleus, parainterfascicular nucleus, parabrachial pigmental area, and rostral VTA. Other structures of the nicotine brain-reward circuitry activated by NIC-PM included the hypothalamus, paraventricular thalamic nucleus, lateral habenular nucleus, hippocampus, amygdala, accumbens nucleus, piriform cortex, angular insular cortex, anterior olfactory nucleus, lateral septal nucleus, bed nucleus of stria terminalis, cingulate and medial prefrontal cortex, olfactory tubercle, and medial and lateral orbital cortex. NIC, acting through central and peripheral nAChRs, produced c-Fos IR in areas that overlapped NIC-PM-induced c-Fos-expressing sites. These neuroanatomical data are the first to demonstrate that the CNS structures that are the direct targets of nicotine are also anatomical substrates for the peripheral sensory impact of nicotine.

Interaction between cholecystokinin and the fibroblast growth factor system in the ventral tegmental area of selectively bred high- and low-responder rats

Individual differences in the locomotor response to novelty have been linked to basal differences in dopaminergic neurotransmission. Mesolimbic dopaminergic outputs are regulated by cholecystokinin (CCK), a neuropeptide implicated in anxiety. In turn, CCK expression is regulated by fibroblast growth factor-2 (FGF2), which has recently been identified as an endogenous regulator of anxiety. FGF2 binds to the high-affinity fibroblast growth factor receptor-1 (FGF-R1) to regulate the development and maintenance of dopamine neurons in the ventral tegmental area (VTA). However, the relationship between the FGF and CCK systems in the VTA is not well understood. Therefore, we utilized the selectively-bred low-responder (bLR; high-anxiety) and high-responder (bHR; low-anxiety) rats to examine the effects of repeated (21-day) FGF2 treatment on CCK and FGF-R1 mRNA in the rostral VTA (VTAr). In vehicle-treated controls, both CCK and FGF-R1 mRNA levels were increased in the VTAr of bLR rats relative to bHR rats. Following FGF2 treatment, however, bHR–bLR differences in CCK and FGF-R1 mRNA expression were eliminated, due to decreased CCK mRNA levels in the VTAr of bLR rats and increased FGF-R1 expression in bHR rats. Differences after FGF2 treatment may denote distinct interactions between the CCK and FGF systems in the VTAr of bHR vs. bLR rats. Indeed, significant correlations between CCK and FGF-R1 mRNA expression were found in bHR, but not bLR rats. Colocalization studies suggest that CCK and FGF-R1 are coexpressed in some VTAr neurons. Taken together, our findings suggest that the FGF system is poised to modulate both CCK and FGF-R1 expression in the VTAr, which may be associated with individual differences in mesolimbic pathways associated with anxiety-like behavior.

Differential patterns of neuronal activation in rostral versus caudal ventral tegmental area involved in behavioral sensitization induced by an escalating-dose morphine administration paradigm

The transition to addiction often involves a gradual process of escalated drug intake. The purpose of the present study was to characterize neuronal activation in the ventral tegmental area (VTA) and substantia nigra (SN) following chronic escalating-dose morphine exposure (days 1–7, 2mg/kg/d; days 8–21, beginning at 10mg/kg/d, increasing by 2mg/kg/d), with steady-dose morphine (2mg/kg/d, i.p., for 21 days) as the comparison. Using immunohistochemical double-staining for tyrosine hydroxylase (TH) and Fos, we found that the number of Fos+TH+ neurons in the rostral VTA and number of Fos+TH− neurons in the lateral SNr were significantly increased in escalating-dose morphine-treated rats compared with steady-dose morphine-treated rats and acute morphine-treated rats. Meanwhile, this increase was associated with robust expression of behavioral sensitization after a challenge with 10mg/kg morphine. The number of Fos+TH+ neurons was significantly increased by acute morphine in the caudal VTA and SNc, but this number did not increase further with morphine pretreatment. These results demonstrate that behavioral sensitization was associated with elevated activation of dopaminergic neurons in the rostral VTA and nondopaminergic neurons in the lateral SNr, which could only be induced by chronic escalating-dose morphine rather than chronic steady-dose morphine pretreatment.

The Glutamatergic Component of the Mesocortical Pathway Emanating from Different Subregions of the Ventral Midbrain

The mesocortical pathway projecting from the ventral tegmental area (VTA) to the prefrontal cortex (PFC) plays a critical role in a number of cognitive and emotional processes. While this pathway has been traditionally viewed as dopaminergic, recent data indicate that a considerable proportion of rostromedial VTA neurons possess markers for glutamate transmission. However, the relative density of the glutamatergic projection to the PFC from these rostromedial regions is unknown. In the present study, anterograde tracer injections into 4 ventral midbrain subregions were coupled with immunohistochemical analysis of labeled axons in PFC for markers of dopamine (DA; tyrosine hydroxylase [TH]) and glutamate (vesicular glutamate transporter 2; VGLUT2). We found that while tracer injections into the interfascicular nucleus produced labeled fibers in the PFC that were mainly TH positive, tracer injections into the rostral linear nucleus, rostral VTA, and parabrachial pigmented nucleus produced labeled fibers in PFC that contained mainly VGLUT2-positive rather than TH-positive varicosities. When viewed in the light of the previously documented strong γ-aminobutyric acidergic component, it would seem that the rostromedial mesocortical projection is actually an amino acid pathway that in addition has a DA component.

Social affiliation relates to tyrosine hydroxylase immunolabeling in male and female zebra finches (Taeniopygia guttata)

The catecholamines dopamine and norepinephrine are implicated in affiliative behaviors, yet few studies have addressed the extent to which affiliative behaviors within distinct social settings rely upon similar or distinct catecholaminergic mechanisms. To explore the role of catecholamines in affiliative behavior within distinct long-term social contexts, we examined the density of the catecholamine synthetic enzyme tyrosine hydroxylase (TH) in brain regions within both the mesolimbic dopaminergic system and “social behavior network” in male and female zebra finches (Taeniopygia guttata) paired for 21 days with either a same- or opposite-sex conspecific. On days 16–21 after pairing, members of both same- and mixed-sex pairs produced similar rates of affiliative behaviors. Measures of affiliation related to TH labeling in the ventral tegmental area (VTA), nucleus accumbens (Ac), medial preoptic nucleus (POM), and ventromedial nucleus of the hypothalamus (VMH). Relationships between TH labeling density and specific measures of affiliative behavior differed in rostral compared to caudal subregions of Ac and VTA, suggesting distinct roles for these subregions in the regulation of affiliative behavior. Finally, TH labeling density in the VMH and rostral VTA were positively related to the amount of courtship received from the partner and TH labeling in Ac was denser in opposite-sex pairs compared to same-sex pairs, indicative of socially induced brain plasticity. Overall, results highlight a complex region- and behavior-specific role for catecholamines in vertebrate affiliation.

Cocaine reward and hyperactivity in the rat: Sites of mu opioid receptor modulation

Opioid receptor agonists and antagonists have profound effects on cocaine-induced hyperactivity and conditioned reward. Recently, the role specifically of the mu opioid receptor has been demonstrated based on the finding that i.c.v. administration of the selective mu opioid receptor antagonist, d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), can attenuate cocaine-induced behaviors. The purpose of the present study was to determine the location of mu opioid receptors that are critical for cocaine-induced reward and hyperactivity. Adult male Sprague–Dawley rats received injections of CTAP into the caudate putamen, the rostral or caudal ventral tegmental area (VTA) or the medial shell or core of the nucleus accumbens prior to cocaine to determine the role of mu opioid receptors in cocaine-induced reward and hyperactivity. Cocaine-induced reward was assessed using an unbiased conditioned place preference procedure. Results demonstrate that animals pre-treated with CTAP into the nucleus accumbens core or rostral VTA, but not the caudal VTA, caudate putamen or medial nucleus accumbens shell, during conditioning with cocaine showed an attenuation of the development of cocaine-induced place preference. In contrast, CTAP injected into the nucleus accumbens shell but not the core attenuated the expression of cocaine place preference. Intra-nucleus accumbens core, caudate putamen or caudal VTA CTAP significantly attenuated cocaine-induced hyperactivity. In addition, the number of cFos positive cells was increased in the motor cortex, medial and ventromedial aspects of the nucleus accumbens shell, basolateral amygdala and caudal VTA during the expression of cocaine place preference, and this increase was attenuated in the animals that received intra-accumbens core CTAP during daily cocaine conditioning. These results demonstrate the importance of mu opioid receptors in the nucleus accumbens and VTA in cocaine-induced reward and hyperactivity and suggest that some aspects of the behavioral effects of cocaine are mediated by endogenous activation of mu opioid receptors in these brain regions.

Rostral–caudal differences in the effects of intra-VTA muscimol on cocaine self-administration

We have found that dopamine (DA) in the ventral tegmental area (VTA) plays an important role in cocaine self-administration. DA in the VTA acts at D1-type receptors on the terminals of GABA afferents causing release of this neurotransmitter. Thus, the neurochemical pathways whereby VTA DA might be involved in cocaine self-administration may include GABA neurotransmission. In the present study, we investigated this possibility. Rats were prepared with intravenous catheters and bilateral guide cannulae positioned to allow microinjections directly into the VTA or a site 1 mm dorsal to it. The rats were then trained to self-administer cocaine (1.0 mg/kg/injection) under a fixed-ratio 1 schedule of reinforcement and tested with microinjections of muscimol (0, 0.05 and 0.1 μg/0.25 μl) or picrotoxin (0, 0.025 and 0.05 μg/0.25 μl) or trained under a progressive ratio (PR) schedule and tested with vehicle and 0.05 μg/0.25 μl muscimol. Muscimol in the VTA, but not immediately dorsal to it, significantly reduced cocaine intake under the FR1 schedule. Furthermore, when analyzed by rostral/caudal site of injection, it was found that rostral injections of muscimol significantly reduced cocaine self-administration whereas caudal injections produced non-significant decreases in self-administration. Inspection of individual records revealed no signs of non-specific behavioral effects of the muscimol treatments. Muscimol in the rostral VTA also significantly increased break points in responding under the PR schedule. Intra-VTA picrotoxin did not significantly affect cocaine self-administration. These data suggest that stimulation of GABA-A receptors in the VTA is involved in cocaine self-administration and reward and that this involvement is more pronounced in the rostral than in the caudal VTA.

Localization of 5-HT 2A receptors on dopamine cells in subnuclei of the midbrain A10 cell group

Considerable evidence suggests that a dysfunction of the dopamine and serotonin (5-hydroxytryptamine or 5-HT) neurotransmitter systems contributes to a diverse range of pathological conditions including schizophrenia, depression and drug abuse. Recent electrophysiological and behavioral studies suggest that 5-HT modulates dopaminergic neurons in the ventral tegmental area via activation of 5-HT 2A receptors. It is currently unknown if 5-HT 2A receptors mediate their actions on dopaminergic neurons in the ventral tegmental area via direct or indirect mechanisms. This study investigated whether 5-HT 2A receptors were localized on dopamine cells within the A10 dopamine subnuclei of the rat, including the ventral tegmental area. We discovered that 5-HT 2A receptor-like immunoreactivity colocalized with tyrosine hydroxylase, a marker for dopamine neurons, throughout the A10 dopamine cell population. Colocalization was most prominent in rostral and mid A10 regions, including the paranigral, parabrachial, and interfascicular subnuclei. Though more rare, non-dopaminergic neurons also expressed 5-HT 2A receptor immunoreactivity in the ventral tegmental area. Additionally, although a dense population of 5-HT 2A immunoreactive cells was observed in the rostral dorsal raphe nucleus, rarely were these cells immunoreactive for tyrosine hydroxylase. The linear raphe A10 dopamine subdivisions also displayed a low degree of 5-HT 2A receptor and tyrosine hydroxylase colocalization. These findings provide an anatomical basis for the physiological modulation of dopamine neurons in the rostral ventral tegmental area either directly, by 5-HT 2A receptors localized on dopamine cells, or indirectly, through a non-dopaminergic mechanism. Interestingly, 5-HT 2A receptors were expressed on dopamine neurons in several A10 subnuclei that project to mesolimbic forebrain regions implicated in drug addiction, and recent evidence indicates that ventral tegmental area 5-HT 2A receptor activation may modulate reward-related behavior in rodents. 5-HT 2A receptors were also expressed on dopamine cells in A10 subnuclei that project to forebrain areas that have been implicated in schizophrenia, and atypical antipsychotic drugs have high affinities for 5-HT 2A receptors. Thus, findings in this study could have important implications for understanding 5-HT and dopamine circuitry dysfunction in schizophrenia.

Distinct Sites of Opiate Reward and Aversion within the Midbrain Identified Using a Herpes Simplex Virus Vector Expressing GluR1

Repeated administration of morphine increases expression of GluR1 (an AMPA glutamate receptor subunit) in the ventral tegmental area (VTA) of the midbrain, an important neural substrate for the rewarding actions of morphine. Microinjections of a herpes simplex virus (HSV) vector that causes local overexpression of GluR1 (HSV-GluR1) into the VTA can enhance the ability of morphine to establish conditioned place preferences, suggesting that altered GluR1 expression in this region is directly associated with changes in the rewarding efficacy of morphine. We now report that in rats given HSV-GluR1 directly into the VTA, morphine is most rewarding when maximal transgene expression is in the rostral VTA, whereas morphine is aversive when maximal transgene expression is in the caudal VTA. Dual-labeling immunohistochemistry shows that this difference cannot be explained by a different fraction of dopaminergic neurons infected in the rostral versus caudal VTA. No such anatomical specificity is seen in rats given VTA microinjections of HSV-LacZ, a vector expressing a control protein (-galactosidase). These results suggest that distinct substrates within the VTA itself differentially contribute to the rewarding and aversive properties of opiates.

Delayed plasticity of the mesolimbic dopamine system following neonatal 6-OHDA lesions.

In this study, we determined the ontogenetic profile (at postnatal days 7, 14, 35, and 90) of tyrodine hydroxylase (TH) mRNA in the ventral mesencephalon, and the levels of TH immunoreactivity (TH-IR) and dopamine (DA) transporter (DAT) sites in the striatum of rats that had received intrastriatal 6-hydroxy dopamine (6-OHDA) or vehicle lesions on day of birth (DO) or postnatal day 1 (P1). TH-IR was significantly decreased in all quadrants of the caudate-putamen at all time points, while TH-IR in the nucleus accumbens was unchanged, as compared to controls. Relative to the earliest time point (P7 lesion group), TH-IR recovered significantly in the medial caudate-putamen (CPu) of the P14, P35 and P90 6-OHDA-lesioned groups. Quantitative autoradiography of [3H]-mazindol binding to DAT sites showed significant, lesion-induced losses throughout the caudate-putamen of the 6-OHDA-lesioned groups at all time points and did not show appreciable recovery. Using in situ hybridization, significant (P < .05) decreases in TH mRNA levels were found at all time points in the lateral and medial substantia nigra pars compacta of 6-OHDA-lesioned animals. TH mRNA levels in the rostral ventral tegmental area (VTA), which were significantly decreased at P7, P14 and P35, returned to control levels at P90. TH mRNA levels in the caudal VTA were unchanged through P35 and became significantly elevated as compared to controls (+22%, P < .05) by P90. Thus, recovery of TH-IR in the medial caudate-putamen occurred prior to the elevation in levels of TH mRNA of the VTA. Our findings suggest that compensation exists in early development in certain subpopulations of mesostriatal DA neurons that differs from that in the adult.

Delayed plasticity of the mesolimbic dopamine system following neonatal 6‐OHDA lesions

In this study, we determined the ontogenetic profile (at postnatal days 7, 14, 35, and 90) of tyrodine hydroxylase (TH) mRNA in the ventral mesencephalon, and the levels of TH immunoreactivity (TH-IR) and dopamine (DA) transporter (DAT) sites in the striatum of rats that had received intrastriatal 6-hydroxy dopamine (6-OHDA) or vehicle lesions on day of birth (DO) or postnatal day 1 (P1). TH-IR was significantly decreased in all quadrants of the caudate-putamen at all time points, while TH-IR in the nucleus accumbens was unchanged, as compared to controls. Relative to the earliest time point (P7 lesion group), TH-IR recovered significantly in the medial caudate-putamen (CPu) of the P14, P35 and P90 6-OHDA-lesioned groups. Quantitative autoradiography of [3H]-mazindol binding to DAT sites showed significant, lesion-induced losses throughout the caudate-putamen of the 6-OHDA-lesioned groups at all time points and did not show appreciable recovery. Using in situ hybridization, significant (P < .05) decreases in TH mRNA levels were found at all time points in the lateral and medial substantia nigra pars compacta of 6-OHDA-lesioned animals. TH mRNA levels in the rostral ventral tegmental area (VTA), which were significantly decreased at P7, P14 and P35, returned to control levels at P90. TH mRNA levels in the caudal VTA were unchanged through P35 and became significantly elevated as compared to controls (+22%, P < .05) by P90. Thus, recovery of TH-IR in the medial caudate-putamen occurred prior to the elevation in levels of TH mRNA of the VTA. Our findings suggest that compensation exists in early development in certain subpopulations of mesostriatal DA neurons that differs from that in the adult. Synapse 25:293–305, 1997. © 1997 Wiley-Liss, Inc.

GABA in the ventral tegmental area: Differential regional effects on locomotion, aggression and food intake after microinjection of GABA agonists and antagonists

The potent and specific GABA agonists muscimol and THIP have been injected into the caudal and rostral parts of the ventral tegmental area (VTA) containing the A 10 dopaminergic cell bodies. Muscimol (10 and 25 ng), THIP (100–500 ng) and GABA (100 μg) all induced a compulsive hypermotility with low exploratory activity following bilateral injection into the caudal VTA. In addition, the rats showed fighting, attack behavior and increased food intake. The hypermotility was attenuated by picrotoxin (3 mg/kg), haloperidol (0.1–0.5 mg/kg) and completely prevented by reserpine (7.5 mg/kg) plus α-methyltyrosine (200 mg/kg). Picrotoxin (100 ng) injected into the caudal VTA induced mild sedation whereas bicuculline methiodide (BMI) (120 ng) induced convulsions. Morphine (5 μg) injected bilaterally into the caudal VTA induced a different behavioral stimulation shown as rearing, motility, sniffing and licking. Bilateral apomorphine (5 μg) and carbachol (2.5 μg) injections into caudal VTA produced sedation and catalepsy. In the rostral VTA muscimol and THIP decreased spontaneous activity, whereas BMI and picrotoxin induced strong hypermotility. The results indicate that different kinds of hyperactivity can be elicited from the VTA and it is suggested that this reflects the regional and topographical organization of the VTA dopamine projections to cortical and limbic areas. The effects of GABA agonists injected into caudal VTA seem to mimic the effects described after electrolytic or 6-hydroxydopamine lesions of VTA, whereas the morphine response resembles the behavioral stimulation produced by systemic administration of dopaminergic stimulants such as amphetamine or cocaine.