Opioid-induced rewards, locomotion, and dopamine activation: A proposed model for control by mesopontine and rostromedial tegmental neurons.

Opioids, such as morphine or heroin, increase forebrain dopamine (DA) release and locomotion, and support the acquisition of conditioned place preference (CPP) or self-administration. The most sensitive sites for these opioid effects in rodents are in the ventral tegmental area (VTA) and rostromedial tegmental nucleus (RMTg). Opioid inhibition of GABA neurons in these sites is hypothesized to lead to arousing and rewarding effects through disinhibition of VTA DA neurons.

Muscarinic control of rostromedial tegmental nucleus GABA neurons and morphine-induced locomotion.

Opioids induce rewarding and locomotor effects by inhibiting rostromedial tegmental GABA neurons that express μ-opioid and nociceptin receptors. These GABA neurons then strongly inhibit dopamine neurons. Opioid-induced reward, locomotion and dopamine release also depend on pedunculopontine and laterodorsal tegmental cholinergic and glutamate neurons, many of which project to and activate ventral tegmental area dopamine neurons.

Disruption of Src Is Associated with Phenotypes Related to Williams-Beuren Syndrome and Altered Cellular Localization of TFII-I.

Src is a nonreceptor protein tyrosine kinase that is expressed widely throughout the central nervous system and is involved in diverse biological functions. Mice homozygous for a spontaneous mutation in Src (Src (thl/thl) ) exhibited hypersociability and hyperactivity along with impairments in visuospatial, amygdala-dependent, and motor learning as well as an increased startle response to loud tones. The phenotype of Src (thl/thl) mice showed significant overlap with Williams-Beuren syndrome (WBS), a disorder caused by the deletion of several genes, including General Transcription Factor 2-I (GTF2I).

Nicotine receptors mediating sensorimotor gating and its enhancement by systemic nicotine.

Prepulse inhibition (PPI) of startle occurs when intensity stimuli precede stronger startle-inducing stimuli by 10-1000 ms. PPI deficits are found in individuals with schizophrenia and other psychiatric disorders, and they correlate with other cognitive impairments. Animal research and clinical studies have demonstrated that both PPI and cognitive function can be enhanced by nicotine.

Parvalbumin and GAD65 interneuron inhibition in the ventral hippocampus induces distinct behavioral deficits relevant to schizophrenia.

Hyperactivity within the ventral hippocampus (vHPC) has been linked to both psychosis in humans and behavioral deficits in animal models of schizophrenia. A local decrease in GABA-mediated inhibition, particularly involving parvalbumin (PV)-expressing GABA neurons, has been proposed as a key mechanism underlying this hyperactive state. However, direct evidence is lacking for a causal role of vHPC GABA neurons in behaviors associated with schizophrenia.

Cholinergic control of morphine-induced locomotion in rostromedial tegmental nucleus versus ventral tegmental area sites.

M5 muscarinic acetylcholine receptors expressed on ventral tegmental dopamine (DA) neurons are needed for opioid activation of DA outputs. Here, the M5 receptor gene was bilaterally transfected into neurons in the ventral tegmental area (VTA) or the adjacent rostromedial tegmental nucleus (RMTg) in mice by means of a Herpes simplex viral vector (HSV) to increase the effect of endogenous acetylcholine. Three days after HSV-M5 gene infusion in VTA sites, morphine-induced locomotion more than doubled at two doses, while saline-induced locomotion was unaffected.

Acute food deprivation reverses morphine-induced locomotion deficits in M5 muscarinic receptor knockout mice.

Lesions of the pedunculopontine tegmental nucleus (PPT), one of two sources of cholinergic input to the ventral tegmental area (VTA), block conditioned place preference (CPP) for morphine in drug-naïve rats. M5 muscarinic cholinergic receptors, expressed by midbrain dopamine neurons, are critical for the ability of morphine to increase nucleus accumbens dopamine levels and locomotion, and for morphine CPP. This suggests that M5-mediated PPT cholinergic inputs to VTA dopamine neurons critically contribute to morphine-induced dopamine activation, reward and locomotion.

Duplication of GTF2I results in separation anxiety in mice and humans.

Duplication (dup7q11.23) and deletion (Williams syndrome) of chromosomal region 7q11.23 cause neurodevelopmental disorders with contrasting anxiety phenotypes.

Muscarinic receptors in brain stem and mesopontine cholinergic arousal functions.

All five muscarinic receptor subtypes and mRNAs are found widely in the brain stem, with M₂ muscarinic receptors most concentrated in the hindbrain. Three cholinergic cell groups, Ch5: pedunculopontine (PPT); Ch6: laterodorsal tegmental (LDT); Ch8: parabigeminal (PBG), are found in the tegmentum. Ch5,6 neurons are activated by arousing and reward-activating stimuli, and inhibited via M₂-like autoreceptors.

M₅ muscarinic receptors mediate striatal dopamine activation by ventral tegmental morphine and pedunculopontine stimulation in mice.

Opiates, like other addictive drugs, elevate forebrain dopamine levels and are thought to do so mainly by inhibiting GABA neurons near the ventral tegmental area (VTA), in turn leading to a disinhibition of dopamine neurons. However, cholinergic inputs from the laterodorsal (LDT) and pedunculopontine (PPT) tegmental nucleus to the VTA and substantia nigra (SN) importantly contribute, as either LDT or PPT lesions strongly attenuate morphine-induced forebrain dopamine elevations. Pharmacological blockade of muscarinic acetylcholine receptors in the VTA or SN has similar effects.

GABA receptors and prepulse inhibition of acoustic startle in mice and rats.

The acoustic startle reflex is strongly inhibited by a moderate-intensity acoustic stimulus that precedes the startling stimulus by roughly 10-1000 ms (prepulse inhibition, PPI). At long interstimulus intervals (ISIs) of 100-1000 ms, PPI in rats is reduced by the muscarinic receptor antagonist scopolamine. Here, we studied the role of GABA receptors in PPI at full ISI ranges in both mice and rats.

CBP histone acetyltransferase activity regulates embryonic neural differentiation in the normal and Rubinstein-Taybi syndrome brain.

Increasing evidence indicates that epigenetic changes regulate cell genesis. Here, we ask about neural precursors, focusing on CREB binding protein (CBP), a histone acetyltransferase that, when haploinsufficient, causes Rubinstein-Taybi syndrome (RTS), a genetic disorder with cognitive dysfunction. We show that neonatal cbp(+/-) mice are behaviorally impaired, displaying perturbed vocalization behavior.

M5 muscarinic receptor knockout mice show reduced morphine-induced locomotion but increased locomotion after cholinergic antagonism in the ventral tegmental area.

M(5) muscarinic receptors are the only muscarinic receptor subtype expressed by mesencephalic dopamine neurons and provide an important excitatory input to mesolimbic and nigrostriatal dopamine systems. Here, we studied locomotion induced by systemic morphine (3, 10, and 30 mg/kg i.p.

Ultrasonic vocalizations induced by sex and amphetamine in M2, M4, M5 muscarinic and D2 dopamine receptor knockout mice.

Adult mice communicate by emitting ultrasonic vocalizations (USVs) during the appetitive phases of sexual behavior. However, little is known about the genes important in controlling call production. Here, we study the induction and regulation of USVs in muscarinic and dopaminergic receptor knockout (KO) mice as well as wild-type controls during sexual behavior.

Carbachol injections into the intergeniculate leaflet induce nonphotic phase shifts.

Nonphotic phase shifts of the circadian clock in mammals are mediated by the intergeniculate leaflet (IGL) of the thalamus via a geniculohypothalamic projection to the suprachiasmatic nucleus. These shifts can be induced by arousing stimuli, such as wheel running, brain stimulation reward and foot shock. Because mesopontine cholinergic neurons are also activated by arousing stimuli, we tested the hypothesis that cholinergic input to the IGL mediates nonphotic phase shifts.

Casein kinase I epsilon gene transfer into the suprachiasmatic nucleus via electroporation lengthens circadian periods of tau mutant hamsters.

Circadian activity rhythms in mammals are controlled by the expression and transcriptional regulation of clock genes in the suprachiasmatic nucleus (SCN). The circadian cycle length in hamsters is regulated in part by casein kinase I epsilon (CKIepsilon). A semidominant mutation (C-->T, R178C, CKIepsilon(tau)) appears to act as a dominant-negative allele to shorten the period of circadian rhythms.

Opposite effects of tetanic stimulation of the auditory thalamus or auditory cortex on the acoustic startle reflex in awake rats.

The amygdala mediates both emotional learning and fear potentiation of startle. The lateral amygdala nucleus (LA) receives auditory inputs from both the auditory thalamus (medial geniculate nucleus; MGN) and auditory association cortex (AAC), and is critical for auditory fear conditioning. The central amygdala nucleus, which has intra-amygdaloid connections with LA, enhances startle magnitude via midbrain connections to the startle circuits.

M3-like muscarinic receptors mediate Ca2+ influx in rat mesencephalic GABAergic neurones through a protein kinase C-dependent mechanism.

GABAergic neurones in the mesencephalon are important regulators of dopamine neurones. Cholinergic projections from mesopontine nuclei preferentially synapse onto these GABAergic neurones, thus suggesting that ACh can regulate dopamine neurones indirectly by modulating GABAergic interneurones. Muscarinic receptors mediate excitation of these interneurones through a Ca(2+)-dependent mechanism.

Linkage of M5 muscarinic and alpha7-nicotinic receptor genes on 15q13 to schizophrenia.

Most antipsychotic drugs act on the forebrain by blocking dopamine receptors. In rodents, the M5 muscarinic receptor (CHRM5) is important for prolonged dopamine release. We typed polymorphisms in CHRM5 and alpha7-nicotinic receptor (CHRNA7) genes on 15q13 in 82 Canadian families having at least 1 schizophrenic patient.

Decreased amphetamine-induced locomotion and improved latent inhibition in mice mutant for the M5 muscarinic receptor gene found in the human 15q schizophrenia region.

M5 muscarinic receptors are coexpressed with D2 dopamine receptors in the ventral tegmentum and striatum, and are important for reward in rodents. Previously, we reported that disruption of the M5 receptor gene in mice reduced dopamine release in the nucleus accumbens. In this study, we established a polymerase chain reaction (PCR) genotyping method for M5 mutant mice, and, using RT-PCR, found that M5 mRNA expression was highest in the ventral tegmentum, striatum, and thalamus in wild-type mice.

Reward and aversive stimuli produce similar nonphotic phase shifts.

Circadian rhythms in rodents respond to arousing, nonphotic stimuli that contribute to daily patterns of entrainment. To examine whether the motivational significance of a stimulus is important for eliciting nonphotic circadian phase shirts in Syrian hamsters (Mesocricetus auratus), the authors compared responses to a highly rewarding stimulus (lateral hypothalamic brain stimulation reward [BSR]) and a highly aversive stimulus (footshock). Animals were housed on a 14:10-hr light-dark cycle until test day, when they were given a 1-hr BSR session (trained animals) or a 1-mA electric footshock at 1 of 8 circadian times, and were maintained in constant dark thereafter.

Role of cholinergic receptors in locomotion induced by scopolamine and oxotremorine-M.

Mesopontine cholinergic neurons activate dopamine neurons important for reward-seeking and locomotor activity. The present studies tested whether cholinergic receptor blockade in the ventral tegmental area (VTA) altered locomotion induced by scopolamine (3 mg/kg i.p.

Enhancement of electrically evoked startle-like responses by tetanic stimulation of the superior colliculus.

Single-pulse unilateral electrical stimulation of either the amygdala or the inferior colliculus elicited startle-like responses in chloral hydrate anesthetized rats. EMG responses to intracranial stimulation were recorded from the anterior biceps femoris muscles. The EMG responses were generally enhanced following unilateral tetanic stimulation of the deep layers of the superior colliculus, but the enhancement was stronger for amygdala sites than inferior colliculus sites.

Increased drinking in mutant mice with truncated M5 muscarinic receptor genes.

The rarest and least understood of the muscarinic receptors is the M5 subtype. Recombinant methods were used to create mutant mice with a deletion in the third intracellular loop of the M5 receptor gene. Salivation induced by the nonselective muscarinic agonist pilocarpine (1 mg/kg s.

Tactile, acoustic and vestibular systems sum to elicit the startle reflex.

The startle reflex is elicited by intense tactile, acoustic or vestibular stimuli. Fast mechanoreceptors in each modality can respond to skin or head displacement. In each modality, stimulation of cranial nerves or primary sensory nuclei evokes startle-like responses.